Quick viewing(Text Mode)

The Matrix Revolution: Matricellular Proteins and Restructuring of The

The Matrix Revolution: Matricellular Proteins and Restructuring of The

Published OnlineFirst March 19, 2020; DOI: 10.1158/0008-5472.CAN-18-2098

CANCER RESEARCH | REVIEW

The Revolution: Matricellular and Restructuring of the Microenvironment A C Casimiro Gerarduzzi1,2, Ursula Hartmann3, Andrew Leask4, and Elliot Drobetsky1,2

ABSTRACT ◥ The (ECM) surrounding cells is indis- aberrantly expressed MCPs can support multiple hallmarks of pensable for regulating their behavior. The dynamics of ECM carcinogenesis by interacting with various cellular components signaling are tightly controlled throughout growth and develop- that are coupled to an array of downstream signals. Moreover, ment. During remodeling, matricellular proteins (MCP) MCPs also reorganize the biomechanical properties of the ECM are secreted into the ECM. These factors do not serve classical to accommodate and tumor colonization. This real- structural roles, but rather regulate matrix proteins and – ization is stimulating new research on MCPs as reliable and matrix interactions to influence normal cellular functions. In the accessible biomarkers in cancer, as well as effective and selective , it is becoming increasingly clear that therapeutic targets.

Introduction pathways essential for cancer progression. This may underlie the correlation between the upregulation of many MCPs and poor The behavior of individual cells is influenced by a plethora of signals prognosis in cancer patients (9) and, moreover, provide rationale originating from the surrounding microenvironment, which includes for exploring the utility of MCPs as cancer biomarkers and ther- the extracellular matrix (ECM). Previously regarded as merely a static apeutic targets. scaffold for cell/tissue organization, the ECM is now viewed as a critical This review will focus on the burgeoning roles of the MCP families niche contributing to the regulation of cellular survival, proliferation, SPARC, CCN, SIBLING, , and Gla-containing proteins in and migration. This realization has positioned the ECM at the center both cancer development, and detection and treatment. Certainly, stage of normal physiologic processes such as development, tissue members of these particular families are aberrantly expressed in homeostasis, and . various tumor types, and moreover exhibit biochemical, biomechan- The dynamic of ECM signaling is determined by a secreted ical, and metastatic properties influencing cancer progression. subset of nonstructural matricellular proteins (MCP; ref. 1), in contrast to the structural roles of “classical” ECM proteins such as and fibronectin (2). MCP functional versatility is achieved by its multiple Normal Physiologic Roles of MCPs domains that either (i) bind ECM proteins and/or cell surface recep- The ever-growing number of newly discovered MCPs has neces- tors, (ii) bind and regulate the activity or accessibility of extracellular sitated their classification into families. Members are grouped on the signaling molecules such as growth factors, , chemokines, and basis of shared domains, which in turn reflect the functional diversity cytokines, or (iii) mediate intrinsic enzymatic activities to precisely between families. orchestrate the assembly, degradation, and organization of the ECM. The SPARC (secreted protein acidic and rich in ; MCPs are tightly controlled, with expression promptly occurring in hereafter alternative protein names are included in parentheses; BM40, context-specific scenarios. Typically, they are highly expressed during ), one of the original MCPs to be characterized, is consid- early development, ultimately subsiding in adult tissues under phys- ered prototypical due to its simple and rich functionality. The iologic conditions. However, transient reexpression is observed during subsequent discovery of other MCPs with structural similarity revealed injury repair, and can also be sustained in chronic pathologies such as a broader family of SPARC-related proteins (10). Such SPARC family cancer (2–7). Indeed, chronic unscheduled expression of various members share follistatin-like and extracellular -binding (EC) MCPs, either by tumor cells or the surrounding stromal cells (8), domains, and are classified into five distinct groups based on sequence leads to abnormal ECM remodeling and stimulation of mitogenic homology of their EC domains (10): SPARCs, SPARCL1, SMOCs, SPOCKs, and follistatin-like protein-1 (FSTL1). SPARC family mem- bers were shown to regulate ECM assembly and deposition, influence 1 ^ Centre de Recherche de l'Hopital Maisonneuve-Rosemont, Montreal, Quebec, cytokine activity, inhibit and cell-cycle progression, Canada. 2Departement de Medecine, Universite de Montreal, Montreal, Quebec, regulate cell differentiation, and activate matrix metalloproteinases Canada. 3Center for , Medical Faculty, University of Cologne, Cologne, Germany. 4College of Dentistry, University of Saskatchewan, Saska- (MMP; ref. 10). While most SPARC members exhibit ubiquitous toon, Saskatchewan, Canada. expression throughout early development, in adults, expression is C. Gerarduzzi is senior author of this article. largely limited to tissues that are diseased or undergoing repair/remodeling. ^ Corresponding Author: Casimiro Gerarduzzi, Centre de Recherche de l'Hopital The CCN (centralized coordination network) family is Maisonneuve-Rosemont, Universite de Montreal, 5415, boul. de l'Assomption, Montreal, Quebec H1T 2M4, Canada. Phone: 514-252-3400, ext. 2813; Fax: 514- composed of six homologous cysteine-rich members (11): CCN1 252-3430; E-mail: [email protected] (CYR61), CCN2 (CTGF), CCN3 (NOV), CCN4 (WISP-1), CCN5 (WISP-2), and CCN6 (WISP-3). Each is comprised of an N-terminal Cancer Res 2020;80:2705–17 secretory and four functional domains: -like growth doi: 10.1158/0008-5472.CAN-18-2098 factor-binding (IGFBP), 2020 American Association for Cancer Research. type C domain (VWC), type-1 repeat module (TSR),

AACRJournals.org | 2705

Downloaded from cancerres.aacrjournals.org on October 3, 2021. © 2020 American Association for Cancer Research. Published OnlineFirst March 19, 2020; DOI: 10.1158/0008-5472.CAN-18-2098

Gerarduzzi et al.

and carboxy-terminal cysteine-knot (CT) motif (11). In response to MCPs into the tumor microenvironment, in turn promoting tissue remodeling, CCN proteins are expressed principally in mesen- cancer development (5, 51). Nonetheless, we note there are certain chymal cells during development and in patholo- cases where MCP expression has been shown to oppose cancer gies (12). The postnatal role of CCN proteins is known for promoting development (51, 52). collagen stability or organization (13). SPARC protein is highly expressed in cancer cells and the (TN) comprise a family of four large ECM glyco- of certain , including glioma, , and cervical proteins, that is, TNC, -R, -W, and -X, which exist as either trimers melanoma (53–56), where it exhibits oncogenic roles in cell growth, or hexamers (14). Tenascins share a characteristic modular structure , and . Interestingly, SPARC has also been associated composed of tandem EGF-like domains, fibronectin-type III domains, with tumor suppression by influencing these same processes (57). This and a C-terminal fibrinogen-related domain (FReD). Consequently, discrepancy might be explained by cancer type and stage, and/or the tenascins share functions in modulating cellular responses to the concentration of SPARC in the tumor microenvironment (57). Like ECM and growth factors, specifically regulating growth, differentia- SPARC, the role of FSTL1 in carcinogenesis has generated significant tion, adhesion, and migration during tissue remodeling events (15). controversy. Endometrial and ovarian cancers exhibit low FSTL1 However, each member has distinct spatial and temporal expression. levels; moreover, ectopic FSTL1 expression exerts antineoplastic activ- TNC expression is typically present in all organs during fetal devel- ity by inducing apoptosis (58). Among SPOCK isoforms (SPOCK1–3), opment and mechanical stress, whereas TN-W expression is restricted SPOCK1 is upregulated in different tumor types, and its expression to developing/remodeling and certain niches (14). positively correlates with invasive/metastatic potential and hence poor TN-R is expressed exclusively in the developing and adult nervous prognosis (59–61). However, in brain tumors, expression of all SPOCK system, while TN-X represents a constitutive ECM component of most family members decreases with increasing tumor grade (62). SMOC2 connective tissues, being hardly influenced by external factors (14). was shown to be upregulated in hepatocellular, endometrial, and The SIBLING (small -binding ligand N-linked glycopro- colorectal cancers where it modulated proliferation, chemoresistance, tein) family includes (BSP), (SPP1, also and metastasis, respectively (63–65). Very little is known regarding any known as OPN), dentin sialophosphoprotein (DSPP), matrix extra- role for SMOC1 in carcinogenesis, although its expression is increased cellular phosphoglycoprotein (MEPE), and dentin matrix protein-1 in brain tumors, where it interacts with TNC to counteract the chemo- (DMP1). These proteins are primarily implicated in bone morpho- attractive effect of the latter on glioma cells in vitro (66). genesis and , and were thus thought to be exclusively Among the CCN family, CCN1 and CCN2 are the most studied in localized to mineralized tissue such as bone and teeth (16). However, cancer (11). Specifically, CCN1 expression is elevated in many tumor apart from these traditional functions, SIBLING members were also types including brain, breast, prostate, and pancreas (67–70); similarly, shown to influence cellular proliferation/survival pathways, collagen CCN2 upregulation is implicated in proliferation, apoptosis, and fibrillogenesis, MMPs activities, and response to injury (17–20). migration for numerous cancers (71), including gastric (72), pancre- The Gla-protein family members contain K–dependent atic (73), melanoma (74, 75), and breast (76). In addition to cancer g-carboxyglutamic acid residues (21), which have high affinity for cells, a potential origin of these MCPs may be cancer-associated calcium ions, thus conferring important roles in and bone fibroblasts (CAF; ref. 77), and indeed this cell type was shown to be homeostasis (22). Among the 17 Gla-protein members, the source of CCN1/CCN2 expression in murine models of (POSTN) and matrix Gla-protein (MGP) are known to affect ECM cancer (78, 79). Although unscheduled expression of CCN1 and CCN2 cross-linking and various cellular behaviors, such as migration, adhe- are generally associated with tumor promotion, in some cases these sion, and proliferation in epithelial, endothelial, fibroblast, , proteins were reported to inhibit cancer development (80, 81). Like and myocyte cells (23–27). POSTN is expressed in osteoblast, mesan- CCN1/2, CCN3, and CCN4 exhibit a mixture of pro- versus anti- gial, fibroblast, mesenchymal, and vascular cells (22), tumorigenic effects, whereas CCN5 and CCN6 are predominantly while MGP is typically secreted and localized in the surrounding ECM regarded as tumor suppressors (11, 82). of or endothelial cells (28). Each tenascin family member differs substantially in spatial (tissue Considering that MCP expression is context dependent, MCP- specificity) and temporal expression patterns (14). In the case of TNC knockout mouse models generally lack any postnatal phenotype and TN-W, de novo expression is prominent in tumors versus healthy unless challenged by injury or disease, in which case they exhibit an tissue, where they promote tumor progression on multiple levels, that impaired yet subtle response [see references for further details: SPARC is, proliferation, invasion, metastasis, and . TNC is recov- family (29–34); CCN family (11, 35); tenascin family (36–38); ered in the stroma of most cancers, while TN-W is primarily SIBLING family (39–42); and POSTN (43–45)]. However, some MCP restricted to brain, colon, , and cancers (14). In contrast, mouse knockouts are characterized by severe complications. For TN-R and TN-X are constitutively expressed and largely unaffected by example, FSTL1- and CCN2-null mice die shortly after birth, while tumorigenic signals, that is, to date have not been reported to play a CCN1 and CCN5 whole-body knockouts are embryonic lethal, show- substantial role in carcinogenesis (14). ing that these proteins are essential for development (11, 46, 47). As Among SIBLING proteins, SPP1 and BSP have been the most for MGP-knockout mice, they show severe vascular calcification, extensively studied in the context of cancer (16). Consistent with arteriovenous malformation, and craniofacial anomalies, and die their roles in osteogenesis, SPP1 and BSP have been implicated within 8 weeks after birth (48–50). in bone malignancy (16). However, while these proteins were initially thought to be expressed only during bone , both were subsequently shown to be broadly expressed in human Expression of MCPs in Cancer epithelial carcinomas, including but not limited to breast (83, 84), MCP overexpression is characteristic of tissue remodeling process- lung (85, 86), prostate (87), liver (88), pancreas (89), and colon (87, 90), es, including those occurring during carcinogenesis, as opposed to low/ where their pathophysiologic roles have recently been thoroughly undetectable levels in normal tissue. Tumor cells and the surrounding reviewed (16, 91). Furthermore, CAFs have been shown to produce activated stromal cells are the major cell types that aberrantly secrete and secrete SPP1, which contributes to melanoma tumor growth (92).

2706 Cancer Res; 80(13) July 1, 2020 CANCER RESEARCH

Downloaded from cancerres.aacrjournals.org on October 3, 2021. © 2020 American Association for Cancer Research. Published OnlineFirst March 19, 2020; DOI: 10.1158/0008-5472.CAN-18-2098

The Role of Matricellular Proteins in Cancer

A) BIOCHEMICAL B) BIOMECHANICAL SMOC2 ECM CCN1 SPARC BSP BSP MGP CCN2 CCN6 MGP INCREASE IN ECM ECM SPARC TN-X SPARC POSTN Increased matrix organization CCN4 TNC Collagen cross-linking SPP1 Deregulation of (i.e. LOX)

TNC POSTN TGFβ1 BMPs CCN3 TNC SPP1 β CCN TGF Receptor ECM -4 Integrin Family β α CD44 Matrix β α Assembly β α & Signaling ILK FAK P Focal FAK Src ILK ILK FAK P FAK ILK ILK Adhesion FAK FAK Force Maturation Filamentous Recruited RhoA Crk Ras Crk ILK RhoA Proteins

ROCK Rac1 ERK Jnk Akt ROCK P Contraction

NFκB HIF-2α P P Force Myosin P MMP2 AP1 MIGRATION INVASION SURVIVAL and PROLIFERATION STEMNESS P Formation MMP9 Myosin Actin of Stress bundling Fibers

SPARC Migration tracks MGP C) METASTATIC NICHE Collagen POSTN cross-linking POSTN TNC MGP TNC POSTN MGP SPARC TNC Colonization

MMP MMP POSTN MGP TNC

SPARC POSTN SPARC TNC MGP Epithelial-to- POSTN Enzymatic MMP MMP Invasion BSP activity MMP Mesenchymal TNC SPP1 MMP TNC Transition CCN1

SMOC2 SPOCK1

Figure 1. Activation of the biochemical, biomechanical, and metastatic effects by MCPs. Tumor cells and the surrounding activated stromal cells are the major cell types that abnormally secrete MCPs into the microenvironment to affect cellular behavior and ECM remodeling. A, Biochemical pathways. MCPs can activate an array of cell surface receptors. Most MCPs can bind and signal through , with a specific heterodimer signature accounting for signaling diversity (see text for details). In addition, it has been shown that CCN and TNC can bind and signal through , while osteopontin (SPP1) mediates its effects through CD44. B, Biomechanical pathways. MCPs are able to increase the stiffness of the normal ECM tension by influencing matrix organization and collagen cross-linking, as well as deregulating enzymatic activity. Stiffness is converted by integrins into biochemical signals that can influence pathways in A. In addition, matrix stiffness can lead to the maturation of integrin and the actin into focal adhesions and stress fibers, respectively. This occurs by activating the integrin–RhoA–ROCK–myosin axis, which is reviewed in detail elsewhere (158, 159). C, Metastatic niche. Various MCPs prepare cancer cells and the local and secondary tumor sites for metastasis through numerous steps. MCPs stimulate cancer cells into a motile phenotype through the EMT but also to promote formation at the invasion site. For metastatic cells to exit the embedded state for intravasation, MCPs can break down the ECM through MMPs and guide cells out of their embedded state by cross-linking into migration tracks. At the secondary site, MCPs once again activate MMPs to remodel the ECM for colonization after invasion. At the distant site, MCPs also prime the ECM for colonization to accommodate disseminated tumor cells in the new environment. Figure was produced using Servier Medical Art (http://smart.servier.com/).

POSTN, the most well-characterized Gla-protein family member, and metastatic microenvironment. These versatile functions depend was shown to be a major determinant in proliferation for a number of on the diverse biochemical, biomechanical, and metastatic niche aggressive, advanced solid tumors with poor prognosis (22). MGP is effects induced by MCPs (Fig. 1), as discussed in more detail much less understood than POSTN, but is gradually emerging as a immediately below. determinant in cancer progression, exhibiting increased expression in colorectal, glioblastoma, breast, cervical, osteosarcoma, and skin can- cers with unfavorable prognosis (93–97). MCP Biochemical Effects In general, MCPs are capable of regulating a variety of mechan- Much evidence has shown that MCPs possess biochemical isms necessary for tumorigenesis, such as survival, proliferation, properties essential for regulating various cellular behaviors, including migration, matrix stiffness, and development of a signal reservoir ones implicated in tumor development. These properties mainly

AACRJournals.org Cancer Res; 80(13) July 1, 2020 2707

Downloaded from cancerres.aacrjournals.org on October 3, 2021. © 2020 American Association for Cancer Research. Published OnlineFirst March 19, 2020; DOI: 10.1158/0008-5472.CAN-18-2098

Gerarduzzi et al.

pertain to the ability of MCPs to activate a number of cell surface through the FAK/Akt/p38/NF-kB pathway (128). CCN4 also pro- receptors and elicit their downstream signaling (Fig. 1A). Most MCPs motes FAK and p38 signaling through avb1 integrin in prostate cancer are well-known to directly bind integrins, which are ab heterodimers cells; however, this pathway specifically induces migration and vas- composed of 18 a subunits and 8 b subunits (98). Integrins are cular -1 (VCAM-1) expression by downregu- commonly bound by members of the SPARC, CCN, SIBLING, tenas- lating miR-126 (129). Furthermore, osteoblast-derived CCN4 plays a cin, and Gla-protein families (99–101), each bound to varying hetero- key role in prostate cancer cell adhesion to bone through VCAM-1/ dimer combinations. Other than integrins, members of CCN and integrin a4b1 (130). CCN4 also promotes lymphangiogenesis in oral tenascin families can also bind syndecans, while SPP1 is reported to squamous cell carcinoma (SCC) via integrin avb3/Akt signaling and also bind CD44 receptors (99, 100). In addition, MCPs can act upregulation of VEGFC expression, as well as promotes integrin avb3/ indirectly by binding a variety of ligands (i.e., growth factors and cyto- FAK/JNK signaling to induce VEGFA activation of angiogenesis in kines), thereby affecting ligand distribution and accessibility, and/or osteosarcoma cells (131, 132). Conversely, CCN4 inhibits migration in coactivating or inhibiting their function (101). melanoma and lung cancer cells by inactivating the family of Rho-like SPARC has been reported to mediate a variety of signaling path- (133, 134). ways. For example, SPARC can bind directly to integrin receptors TNC has been shown to stimulate proliferation and survival in a (avb1, avb3, and avb5), resulting in the activation of the proximal variety of cancers by activating several pathways downstream of intracellular kinases Akt, kinase (FAK), and integrin- integrins and syndecans (135), including integrin a9b1 activation of linked kinase (ILK; refs. 102–105). These kinases were associated with Akt and MAPK (136) and avb3 activation of FAK and paxillin (137). SPARC-mediated invasion and survival of glioma cells (105). SPARC However, a recent study showed that TNC signaling through integrin may also directly interact with the TGFb1 receptor to mediate Smad a2b1, but not a9b1oravb3, induced autocrine growth in brain tumor signaling, as shown in lung cancer cells (106). Recently, SPARC was cells (138). Through an indirect mechanism of tumorigenesis, TNC is reported to bind TGFb1 to regulate its deposition in the ECM (107). In able to compete with syndecan-4 binding to fibronectin, thereby addition, SPARC may bind other growth factors but with unknown interfere with fibronectin inhibition of proliferation (139). Instead, effects (108, 109). Interestingly, SPOCK1 was identified as a down- the FReD domain of TN-X was reported to convert latent TGFb1 into stream target of TGFb1 and a key player in lung cancer metastasis and its biologically active form to indirectly control mesenchymal proliferation (110), as well as in antiapoptosis via activation of the differentiation (140). PI3K/Akt pathway (111, 112). SMOC2 acts to maintain ILK activity POSTN is primarily known for binding integrins avb3 and avb5 fl during G1-phase, which in turn in uences cell-cycle progression by to elicit activation of FAK/JNK and PI3-K/Akt signaling pathways modulating cyclin D1 expression and DNA synthesis (113). This controlling , survival, or migration in various cancers possibly involves ILK interaction with integrin b1 and b3 cytoplasmic (141–143). POSTN may also signal through EGFR to influence domains, which also leads to inhibition of anoikis and apoptosis migration in esophageal SCC (144), potentially through cross-talk through activation of PI3K/Akt signaling (114). Studies by Maier and with integrin avb5. Unlike POSTN, little is known regarding the colleagues suggested that SMOC2 can bind directly to integrins aVb1 mechanism of MGP in cancer development, although the latter can and aVb6 (115), consistent with recent data showing that SMOC2 influence the TGFb superfamily, including activation of TGFb1 binds integrin b1 to activate FAK in kidney fibroblasts (29). receptor and inhibition of the bone morphogenetic proteins BMP-2 CCNs act through multiple mechanisms to regulate a plethora of and BMP-4 (27, 145). dynamic cellular processes (11, 101, 116). In particular, these proteins The SIBLING family members BSP and SPP1 exhibit similar activate ILK/Akt, MAPK, and associated growth-promoting pathways activities in cancer development. BSP supports adhesion, proliferation, in cancer, with each CCN member exerting distinct effects and and migration through avb3 and avb5, and the prometastatic activity temporal expression profiles. For example, CCN1 signals through of TGFb1 in breast cancer cells (146, 147). SPP1 can interact with integrin aVb3/Sonic hedgehog to promote motility in vitro and several integrin receptors (avb1, 3, and 5, a8b1, a9b1 and 4, and tumorigenic growth in vivo (117), as well as integrin a6b1-mediated a4b1) to regulate cell proliferation, angiogenesis, adhesion, and invasion (118), in pancreatic cancer. In glioma, CCN1 overexpression migration (116, 148). SPP1 can also signal through CD44 (149) to enhances tumorigenicity through integrin aVb3- and aVb1-linked activate HIF2a-induced stemness in hepatocellular carcinoma and ILK-mediated activation of Akt, b-catenin-TCF/Lef, and associated glioblastoma cells (150, 151), and Akt-mediated cell survival in survival and proliferation pathways (119). In breast cancer cells, CCN1 mesothelioma and colorectal cancer cells (152, 153). can promote (i) resistance to anoikis, partly via integrin b1 (120), as well as (ii) proliferation, survival, and apoptosis resistance through the avb3-activated ERK1/2 pathway (121). Similar to CCN1, ectopic MCP Biomechanical Effects expression of CCN2 (i) promotes migration and angiogenesis (122), Remodeling of the ECM is an integral process in cancer develop- and (ii) confers apoptosis resistance through integrin avb3/ERK1/2 ment that accommodates the structural architecture of the tumor and upregulation of antiapoptotic Bcl-xL and cIAP (76) in breast cancer provides necessary physical changes such as increased matrix and cells. Although most CCNs act primarily through binding various tissue stiffness to promote and sustain neoplastic transformation (154). integrin heterodimer combinations, they also bind several other is a process in which perturbations in ECM receptors (11, 101, 123, 124), for example syndecan-4 and Notch in mechanical stiffness are transduced into biochemical signals. ECM the case of CCN1/2 and CCN3, respectively. Interestingly, CCN stiffness can communicate with cells through mechano-responsive proteins may be activated by proteolytic (125, 126). integrins (98). In a normal setting, the ECM forms a structural The opposing effects of CCN3 and CCN4 in different cancers raise microenvironment of relaxed nonoriented fibrils that exerts the question of which biochemical pathways are responsible for their homeostatic stiffness on embedded cells. In cancer, disruption signaling diversity. In colorectal cancer cells, CCN3 inhibits survival by of this local ECM structure can occur through MCP-mediated regulating -3/-8 while inhibiting JNK-mediated migra- remodeling (5, 8, 155–157), which results in that are often tion (127). On the contrary, CCN3 promotes osteoclastogenesis stiffer, more highly linearized, and have a different orientation relative

2708 Cancer Res; 80(13) July 1, 2020 CANCER RESEARCH

Downloaded from cancerres.aacrjournals.org on October 3, 2021. © 2020 American Association for Cancer Research. Published OnlineFirst March 19, 2020; DOI: 10.1158/0008-5472.CAN-18-2098

The Role of Matricellular Proteins in Cancer

to normal stroma (7). In response to this, matrix bound integrin ture and integrity to promote cancer cell accessibility into intact structures convert these physical mechanical signals into conventional structures, that is, basement membrane (178). MCPs can also affect integrin biochemical signals to influence survival, proliferation, and physical properties of the ECM, including spatial arrangement, ori- growth (158). Moreover, integrin and their associated intracellular entation, rigidity, permeability, and , in such a way as to alter cytoskeleton mature into reinforced focal adhesions and stress fibers, anchorage sites and create motility tracks suitable for metastasis (178). respectively, to compensate for changes in ECM stiffness (Fig. 1B). Normally, epithelial cells maintain their polarity, intercellular Stress fibers are formed from the bundling of actin, and generate a tight junctions, and adherence to the basement membrane neces- counter-force, both of which are regulated by phosphoactivating sary for proper tissue architecture and function (179). During myosin through the stiffness-induced integrin–RhoA–ROCK EMT, epithelial cells undergo reorganization of adhesion and axis (159). Some of the biomechanical processes regulated by MCPs cytoskeletal structures to acquire a mesenchymal morphology. This that affect ECM stiffness include increased matrix organization, allows cells to detach, which, in conjunction with enhanced migra- collagen cross-linking, and deregulation of enzymatic activity. tory capacity associated with the mesenchymal phenotype, stimu- SPARC is well-known to be implicated in rearranging the matrix lates metastasis (179). through collagen cross-linking. SPARC binds to several fibrillar SPARC family members promote EMT in a variety of cancers collagens (I, II, III, and V) as well as to collagen IV, a prominent (Fig. 1C). Recently, SMOC2 was shown to participate in a prometa- constituent of basement membranes (160, 161), and is critical for static secretome mediated by the ARNTL2 in lung organization of collagenous ECMs. SPARC-knockout mice manifest adenocarcinoma (180), and SMOC2 induction is required for colon significant changes in collagen fibril morphology, as well as a sub- cancer invasion by stimulating EMT (65). Several studies also show stantial decrease in adult tissue concentrations of collagen (32). that SPOCK1 promotes EMT (110, 181). Among SPARC family SPARC also influences the response of host tissue to implanted tumor members, SPARC is the most characterized for influencing cells and a lack of endogenous SPARC engenders decreased capacity to EMT (106, 182, 183): (i) in lung cancer cell lines, TGFb1 activation encapsulate the tumor, as well as a reduction in the deposition of of migration and EMT is in part through SPARC (106), (ii) in head and collagen (162). SPARC exerts at least two roles in collagen fibril neck cancer cells, SPARC enhances EMT signaling via activation of assembly, that is, by modulating interactions of collagen with cell Akt (182), and (iii) overexpression of SPARC in melanoma cells surface receptors and directly regulating collagen incorporation into increases invasiveness mediated by phosphorylation of FAK and Snail fibrils (163). Loss of SPARC also disrupts the homeostasis of basement repression of E-cadherin promoter activity (184). membranes and alters tissue biomechanics and physiologic func- The CCN family exerts varying effects on EMT. An early study tion (164). Finally, SPARC can act as an extracellular for using pancreatic cancer cells reported that CCN1 promotes EMT collagens that enhance the tumorigenic environment (164–166). and stemness, and that silencing this MCP forestalled aggressive In a recent study, TNC significantly colocalized with aligned tumor cell behavior by reversing the EMT phenotype (67). Recent collagen fibers in patients with breast cancer, compared with the wavy studies have continued to dissect CCN1 signaling leading to EMT. In and randomly organized layout of collagen (167) typically observed in osteosarcoma, pharmacologic or knockdown of integrin avb5/ normal tissue (168). TNC contains multiple ECM-binding partners, Raf-1/MEK/ERK signaling components inhibited CCN1-induced including collagen; however, its involvement in collagen alignment EMT (185), as well as CCN1-mediated expression of EMT markers may be mediated through binding to fibronectin, which serves to direct and cell spreading through an IGF1Rb-JNK–dependent path- collagen organization (169–171). Similarly, POSTN plays a mecha- way (186). In contrast, CCN5 and CCN6 exert opposing effects on nistic role in intermatrix interactions through formation of a POSTN– EMT. In triple-negative breast cancer cells, CCN5 activates the Bcl-2/ BMP-1–LOX complex, where BMP-1 promotes LOX activity for Bax apoptotic pathway and inhibits both EMT and migration (187), collagen cross-linking (172, 173). In fact, POSTN-knockout while activation of the JAK/Akt/STAT pathway reverses such CCN5- models exhibit aberrant collagen fibrillogenesis (174). Furthermore, mediated events (188). Similarly, CCN6 reversed the EMT features and the mechanotransduction pathways of both ROCK in SCC and the inhibited metastasis of breast cancer cells in vivo, but through a Slug transcription factor TWIST from various mechanical stress models are signaling axis that regulates Notch1 activation (189). Another mech- known to increase POSTN deposition (24, 175). The POSTN family anism involves CCN6-BMP-4 binding in breast cancer cells, which member MGP was recently shown to be incorporated into cross-linked reduces BMP-4 signaling through p38/TAK1 and subsequent down- multimers of fibronectin, which enhanced cancer cell attachment to stream activation of invasion and migration (190). fibronectin (23). As for the CCN family, recent studies have shown TNC and POSTN have also been associated with CCN1, CCN2, and CCN4 to promote alignment and stability of metastasis (191–195). While the influence of TNC (196, 197) and collagen fibers (13, 157, 176). POSTN (198, 199) can be exerted through the EMT process, inter- estingly, these MCPs are also capable of remodeling the ECM to form fl migratory tracks that support rapid dissemination of cancer cells MCP In uence on the Metastatic Niche (Fig. 1C). TNC is frequently observed to be expressed along the The matrix environment needs to achieve a level of plasticity for border of matrix tracks in skin (200), pulmonary (201), colorec- cellular displacement during metastasis. To disseminate, cancer cells tal (202), and breast (203) cancers. In fact, TNC assembles into matrix require a local ECM niche to support and tracks with ECM molecules such as fibronectin, , and several intravasation, and an ECM at the secondary metastatic site to permit collagens (200, 204), which are also linked to metastatic poten- invasion and colonization (Fig. 1C). There are various ways in which tial (200, 205, 206). Evidence reveals that these TNC matrix tracks MCPs are able to establish a metastatic niche by influencing the ECM have a functional purpose in metastasis. In coculture experiments, and its embedded cells. First, MCPs induce cancer cells to undergo an leading fibroblasts were able to create matrix tracks composed of TNC epithelial-to-mesenchymal transition (EMT), a genetic program that and fibronectin, which were left behind for the movement of SCC promotes metastatic dissemination of cancer cells from primary cells (207). For fibronectin and TNC to coassemble into such tracks, epithelial tumors (177). Second, MCPs reorganize the ECM architec- POSTN is responsible for incorporating TNC into the meshwork

AACRJournals.org Cancer Res; 80(13) July 1, 2020 2709

Downloaded from cancerres.aacrjournals.org on October 3, 2021. © 2020 American Association for Cancer Research. Published OnlineFirst March 19, 2020; DOI: 10.1158/0008-5472.CAN-18-2098

Gerarduzzi et al.

architecture (208). While integrating TNC, it is possible that POSTN significance for breast cancer cell dissemination to the , it remains could also serve as a scaffold for BMP-1, LOX-1, and collagen to possible that both POSTN and TNC are interdependent in promoting accelerate collagen cross-linking into migratory tracks during metas- colonization of the metastatic niche, because POSTN anchors TNC to tasis (172). Mechanistically, track mobility involves TNC competing the ECM (208). MGP was also recently shown to influence the for syndecan-4 binding to fibronectin, which blocks integrin a5b1– metastatic niche by promoting osteosarcoma adhesion, extravasation, mediated cell adhesion for detachment (139), followed by TNC and MMP activities in murine lung in vitro (94). promotion of migration through integrin a9b1 following YAP inac- tivation (209). As previously discussed, TNC and POSTN can bind multiple ECM proteins (i.e., fibronectin and various collagens) and Future Clinical Applications enzymes (i.e., LOX) to serve as scaffolds of collagen cross-linking MCPs are generally expressed at low levels in adult tissues but highly needed for cancer cell proliferation and survival. This is a similar upregulated in various pathologies or injuries (4–6). This has process that comes into play when TNC and POSTN interact to build prompted researchers to elucidate the potential functions of different ECM scaffolds for migration tracks (24, 167, 204, 208, 210). MCPs in diseases such as cancer. As discussed throughout this review, Finally, for metastatic cells to exit the embedded state for intra- numerous studies have shown that MCPs play critical roles in cancer vasation, and then return into the ECM for colonization after invasion development. In addition, the presence of certain MCPs in circulation at a distant site, a degree of matrix plasticity is required. Such ECM as well as diseased tissue indicates their utility as noninvasive diag- remodeling is achieved by the degradative activity of extracellular nostic and prognostic cancer biomarkers. Furthermore, their extra- proteases (Fig. 1C), in particular MMPs. Like several other MCPs, cellular location and involvement in cancer pathology indicate that SIBLINGs bind and activate MMPs to promote metastasis. SPP1 MCPs represent accessible and potentially effective therapeutic targets. binds CD44 to activate MMP-3 while BSP binds to integrin avb3to In the following sections, we discuss various preclinical studies and activate MMP-2 to increase invasiveness in various cancer cell clinical trials exploring the above possibilities. types (20, 211). Furthermore, SPP1 and BSP bind and activate MMP-3 and MMP-2, respectively (20). Early studies reported that SPARC upregulates the expression and activity of MMP-2 and MMP- MCPs as Cancer Biomarkers 14 in glioma cells and MMP-2 in breast cancer cells (212, 213). On SPARC has been suggested as a prognostic biomarker for certain the other hand, the SPARC family member SPOCK2 was recently cancers such as sarcoma, esophageal SCC, and glioblastoma shown to inhibit the expression of MMP-2 and MMP14, and activa- because its expression correlates with poor survival (232–234). In tion of MMP-2 in endometrial cancer cells (214, 215). TNC may also addition, SPP1 may be prognostic for breast, lung, gastric, liver, and influence the invasion of chondrosarcoma, colon cancer, and glioma colon cancers because it is associated with tumor progression and cells by interacting with and upregulating MMP-1, -2/9, and -12, decreased patient survival (235–238). Subsequently, a number of respectively (216, 217). ongoing clinical trials have been established to validate their applica- MCPs can also serve as a substrate for MMPs (218), that is, SPARC tion. Recently, SPARC has been the subject of a clinical study probing and SPP1 in the case of MMP-2, -3, -7, -9, -12, and -14, and MMP-3, -7, its utility as a diagnostic marker for brain cancer [registered number -9, and -12, respectively. From the SPARC family, SPARCL1 and clinical trial (NCT) 01012609], given prior investigations correlating SPARC are cleaved by MMP-3 in gliomas (219) and K in increased tumor vascular SPARC expression with decreased brain bone cancer (220), respectively, whose fragments could affect SPARC cancer patient survival (239). Several groups have also reported that activity. Recently, MMP-9 cleavage of SPARC was reported to enhance high plasma SPP1 concentrations might be predictive of poor outcome SPARC-collagen binding, preventing collagen degradation by MMPs for several cancers, including breast cancer (240). Consequently, one in lung cancer (166). As for SPP1, and plasmin can cleave its clinical study is currently probing the relevance of SPP1 serum levels C-terminal, which increases adhesion of melanoma cells (221) and for diagnosis of breast cancer (NCT 02895178). Other MCP families migration of breast cancer cells (222), while cleavage of SPP1 by MMP- await successful clinical trials since the expression of several CCN 9 is essential for hepatocellular carcinoma invasion, which correlates family members in pancreatic, breast, oral, esophageal, and brain with metastatic potential (223). cancers (241–245), TNC in colorectal, glioma, pancreatic, and bladder Apart from targeting MMPs, the role of TNC in influencing the cancers (196, 246–248), and POSTN in various solid cancers (249) ECM to promote invasion is multifaceted. In Ewing sarcoma, TNC have all been touted as potential diagnostic and prognostic biomarkers. expression and Src activation cooperate to promote invadopodia formation, an actin-rich protrusion of the plasma membrane involved in degradation of the ECM during cancer cell extravasation (224). In MCPs as Therapeutic Targets order for distant sites to accommodate disseminated tumor cells, Targeting MCPs for therapeutic purposes has received relatively MCPs are also required at the secondary target tissue to prime the little attention, primarily because of limited data concerning mechan- metastatic niche for colonization. TNC has been shown to be involved isms of action. The fact that MCPs are located in the in metastatic colonization because loss of this MCP in breast cancer, during cancer development renders them attractive as accessible melanoma, or metastatic niche stromal cells inhibited colonization in targets for drug delivery; moreover, their context-specific expression the lungs (225–227). Gla-containing proteins have also been impli- implies that targeting these proteins would result in minimum pleio- cated in establishing a metastatic niche. Tumor-derived POSTN was tropic side-effects. Neutralizing antibodies against MCPs have shown reported to form a microenvironmental niche supportive of breast success in various preclinical settings; however, to the clinic cancer stem cells via the integrin avb3/ERK pathway (228). In various has been difficult. One group showed that an SPP1 mAb (AOM1) mouse models, POSTN was responsible for metastatic colonization of significantly inhibited tumor growth and metastasis in a mouse model the lung by breast and melanoma cells as evidenced by POSTN- of non–small lung cancer (250). In addition, a commonly used mAb neutralizing antibodies, antisense oligonucleotides, and knockout for antagonizing CCN2 (FG-3019) has reportedly been used in pre- mice, all independently inhibiting metastasis (229–231). Given their clinical models with success in both monotherapy and combination

2710 Cancer Res; 80(13) July 1, 2020 CANCER RESEARCH

Downloaded from cancerres.aacrjournals.org on October 3, 2021. © 2020 American Association for Cancer Research. Published OnlineFirst March 19, 2020; DOI: 10.1158/0008-5472.CAN-18-2098

The Role of Matricellular Proteins in Cancer

therapy for different tumor types, including pancreatic and new approaches are clearly needed to dissect the daunting complexity melanoma (251–256). With such progress, neutralizing antibodies of the ECM environment and its role in carcinogenesis. targeting MCPs have advanced to registered clinical trials. For exam- While confronting the above challenges it remains important to ple, FG-3019 is currently in phase III for CCN2-targeted treatment of concomitantly work toward characterizing particular MCPs, alone pancreatic cancer (LAPIS, NCT03941093). or in combination, as impactful diagnostic/prognostic cancer bio- Alternatively, MCPs could be targeted by inhibiting gene expres- markers and therapeutic targets. In fact, given their burgeoning sion in patients. In fact, one of the first studies using RNAi to treat roles in cancer development and extracellular accessibility, MCPs cancer with promising results involved targeting TNC in 11 have long been regarded as potentially useful for diagnosing and patients with glioma (257). This was followed up with an inves- treating various pathologies such as fibrosis and cancer; nonetheless tigation of a larger cohort of 46 patients, which reported significant clinical data supporting this notion have been relatively scant. improvement in overall survival (258). Other promising MCP Toward addressing this knowledge gap, over the past decade, targets for posttranscriptional gene silencing include SPP1, progress has been made in defining better the fundamental mechan- POSTN, CCN1, and CCN2, where inhibition of RNA expression isms of MCPs, opening new questions that entice the generation of was shown to reduce cancer progression in various animal mod- the next needed tools to understand sufficient detail for optimal els (68, 73, 229, 235). Another therapeutic approach involves therapeutic design. exploiting the high expression of MCP within the tumor environ- Herein we have summarized some important ways in which mis- ment as a strategy to deliver therapeutic molecules. Using a high regulation of MCP expression promotes cancer development, includ- affinity antibody to deliver radiotherapy (mAb 81C6), TNC was ing perturbation of intracellular signaling and aberrant coordination of targeted for treatment of glioma and lymphoma (259, 260), show- ECM remodeling. Although we focused on MCP families with the ing safe and promising antitumor benefit. most well-characterized roles, others are emerging as potentially important players, such as the EMILIN and R-Spondin families. Recently, R-Spondin-1 and 2 were shown to promote liver, glioblas- Conclusion and Future Perspective toma, and ovarian cancer through their well-defined influence on Upon perturbation of tissue homeostasis during multistage carci- Wnt/b-catenin signaling (265–267). In addition, EMILIN2 promotes nogenesis, MCPs are upregulated in the tumor microenvironment to the formation of tumor-associated vessels in melanoma (268), and become key mediators of cell–ECM communication that in turn EMILIN1 exerts an oncosuppressive role in colon and skin (269, 270). promotes cellular proliferation, survival, and metastasis. The func- Clearly, there is still much to be discovered regarding the exquisite tional diversity of MCPs stems from their ability to interact with a spatiotemporal regulation of MCP expression patterns and functions variety of extracellular signaling molecules such as ECM components in the extracellular space during cancer tissue remodeling, similar to and growth factors. Moreover, as emphasized in this review, many the approach taken in fibrosis (17). In this respect, as more and more MCPs have been implicated in cancer development, and thus may knowledge accumulates, it should be possible to design appropriate certainly exert additive and/or antagonistic effects in this process. Our clinical studies that could firmly establish MCPs as useful biomarkers current understanding of MCP pathways gives an impression of and therapeutic targets in cancer. redundancy, and so a primary aim in the ECM field is to elucidate the precise manner in which MCPs mechanistically converge, both Disclosure of Potential Conflicts of Interest functionally and temporally, to remodel the tumor microenvironment A. Leask has ownership interest in Fibrogen. No potential conflicts of interest were and orchestrate critical neoplastic processes. disclosed by the other authors. This overarching goal highlights a major challenge, that of devel- oping experimental systems that better model the physical state of Acknowledgments This work was supported by the Operating Grant Funding Program 24347 (co- the native interstitial ECM. The usefulness of various existing models, funded by Cancer Research Society and the Kidney Cancer Research Network of including 2D monolayers (261), 3D (262), and tissue- Canada) and start-up funds from Hopital^ Maisonneuve-Rosemont Foundation (all to extracted ECM (263), is limited because these models fall well short C. Gerarduzzi). C. Gerarduzzi is a recipient of the Kidney Research Scientist Core of fully recapitulating the complexities of tissue ECM in vivo. This Education and National Training (KRESCENT) Program New Investigator Award inadequacy may underlie some of the discrepancies in the literature KRES180003 (co-funded by the Kidney Foundation of Canada, Canadian Society of regarding MCP functionality in cancer. Furthermore, the identifica- Nephrology, and Canadian Institutes of Health Research) and the Cole Foundation Early Career Transition Award. tion of naturally occurring protein–protein interactions and post- translational modifications among MCPs in the ECM have been Received July 10, 2018; revised December 4, 2019; accepted March 17, 2020; difficult to characterize. Overall, as concisely reviewed elsewhere (264), published first March 19, 2020.

References 1. Bornstein P. Matricellular proteins: an overview. Matrix Biol 2000;19:555–6. 6. Frangogiannis NG. Matricellular proteins in cardiac and disease. 2. Bornstein P. Matricellular proteins: an overview. J Cell Commun Signal 2009;3: Physiol Rev 2012;92:635–88. 163–5. 7. Lu P, Weaver VM, Werb Z. The extracellular matrix: a dynamic niche in cancer 3. Roberts DD. Emerging functions of matricellular proteins. Cell Mol Life Sci progression. J Cell Biol 2012;196:395–406. 2011;68:3133–6. 8. Chiodoni C, Colombo MP, Sangaletti S. Matricellular proteins: from homeo- 4. Matsui Y, Morimoto J, Uede T. Role of matricellular proteins in cardiac stasis to inflammation, cancer, and metastasis. Cancer Metastasis Rev 2010;29: tissue remodeling after myocardial . World J Biol Chem 2010;1: 295–307. 69–80. 9. Sawyer AJ, Kyriakides TR. Matricellular proteins in drug delivery: therapeutic 5. Wong GS, Rustgi AK. Matricellular proteins: priming the tumour microenvi- targets, active agents, and therapeutic localization. Adv Drug Deliv Rev 2016;97: ronment for cancer development and metastasis. Br J Cancer 2013;108:755–61. 56–68.

AACRJournals.org Cancer Res; 80(13) July 1, 2020 2711

Downloaded from cancerres.aacrjournals.org on October 3, 2021. © 2020 American Association for Cancer Research. Published OnlineFirst March 19, 2020; DOI: 10.1158/0008-5472.CAN-18-2098

Gerarduzzi et al.

10. Bradshaw AD. Diverse biological functions of the SPARC family of proteins. 37. Forsberg E, Hirsch E, Frohlich L, Meyer M, Ekblom P, Aszodi A, et al. Skin Int J Biochem Cell Biol 2012;44:480–8. and severed heal normally in mice lacking tenascin-C. Proc Natl 11. Jun JI, Lau LF. Taking aim at the extracellular matrix: CCN proteins as emerging Acad Sci U S A 1996;93:6594–9. therapeutic targets. Nat Rev Drug Discov 2011;10:945–63. 38. Saga Y, Yagi T, Ikawa Y, Sakakura T, Aizawa S. Mice develop normally without 12. Lau LF. Cell surface receptors for CCN proteins. J Cell Commun Signal 2016;10: tenascin. Dev 1992;6:1821–31. 121–7. 39. Nagao T, Okura T, Irita J, Jotoku M, Enomoto D, Desilva VR, et al. Osteopontin 13. Quesnel K, Shi-wen X, Hutchenreuther J, Xiao Y, Liu S, Peidl A, et al. CCN1 plays a critical role in interstitial fibrosis but not glomerular sclerosis in diabetic expression by fibroblasts is required for bleomycin-induced skin fibrosis. nephropathy. Extra 2012;2:87–103. Matrix Biology Plus 2019;3:100009. 40. Franzen A, Hultenby K, Reinholt FP, Onnerfjord P, Heinegard D. Altered 14. Chiovaro F, Chiquet-Ehrismann R, Chiquet M. Transcriptional regulation of osteoclast development and function in osteopontin deficient mice. J Orthop tenascin genes. Cell Adh Migr 2015;9:34–47. Res 2008;26:721–8. 15. Chiquet-Ehrismann R, Tucker RP. Tenascins and the importance of adhesion 41. Rittling SR, Matsumoto HN, McKee MD, Nanci A, An XR, Novick KE, et al. modulation. Cold Spring Harb Perspect Biol 2011;3:pii: a004960. Mice lacking osteopontin show normal development and bone structure but 16. Kruger TE, Miller AH, Godwin AK, Wang J. Bone sialoprotein and osteopontin display altered osteoclast formation in vitro. J Bone Miner Res 1998;13: in of osteotropic cancers. Crit Rev Oncol Hematol 2014;89: 1101–11. 330–41. 42. Liaw L, Birk DE, Ballas CB, Whitsitt JS, Davidson JM, Hogan BL. Altered wound 17. Feng D, Ngov C, Henley N, Boufaied N, Gerarduzzi C. Characterization of in mice lacking a functional osteopontin gene (spp1). J Clin Invest 1998; matricellular protein expression signatures in mechanistically diverse mouse 101:1468–78. models of kidney injury. Sci Rep 2019;9:16736. 43. Bozyk PD, Bentley JK, Popova AP, Anyanwu AC, Linn MD, Goldsmith AM, 18. Jiang C, Zurick K, Qin C, Bernards MT. Probing the influence of SIBLING et al. Neonatal periostin knockout mice are protected from hyperoxia-induced proteins on collagen-I fibrillogenesis and denaturation. Connect Tissue Res alveolar simplication. PLoS One 2012;7:e31336. 2018;59:274–86. 44. Elliott CG, Wang J, Guo X, Xu SW, Eastwood M, Guan J, et al. Periostin 19. Luo X, Ruhland MK, Pazolli E, Lind AC, Stewart SA. Osteopontin stimulates modulates myofibroblast differentiation during full-thickness cutaneous preneoplastic cellular proliferation through activation of the MAPK pathway. wound repair. J Cell Sci 2012;125:121–32. Mol Cancer Res 2011;9:1018–29. 45. Rios H, Koushik SV, Wang H, Wang J, Zhou HM, Lindsley A, et al. periostin 20. Fedarko NS, Jain A, Karadag A, Fisher LW. Three small integrin binding ligand null mice exhibit dwarfism, incisor enamel defects, and an early-onset peri- N-linked (SIBLINGs) bind and activate specific matrix metallo- odontal disease-like phenotype. Mol Cell Biol 2005;25:11131–44. proteinases. FASEB J 2004;18:734–6. 46. Ivkovic S, Yoon BS, Popoff SN, Safadi FF, Libuda DE, Stephenson RC, et al. 21. Vermeer C. : the effect on health beyond coagulation - an overview. Connective tissue coordinates chondrogenesis and angiogenesis Food Nutr Res 2012;56:10.3402/fnr.v56i0.5329. during skeletal development. Development 2003;130:2779–91. 22. Gonzalez-Gonzalez L, Alonso J. Periostin: a matricellular protein with multiple 47. Mo FE, Muntean AG, Chen CC, Stolz DB, Watkins SC, Lau LF. CYR61 (CCN1) functions in cancer development and progression. Front Oncol 2018;8:225. is essential for placental development and vascular integrity. Mol Cell Biol 2002; 23. Nishimoto SK, Nishimoto M. binds to fibronectin and 22:8709–20. enhances cell attachment and spreading on fibronectin. Int J Cell Biol 2014; 48. Marulanda J, Eimar H, McKee MD, Berkvens M, Nelea V, Roman H, et al. 2014:807013. Matrix Gla protein deficiency impairs nasal septum growth, causing midface 24. Kudo A. Periostin in fibrillogenesis for tissue regeneration: periostin actions hypoplasia. J Biol Chem 2017;292:11400–12. inside and outside the cell. Cell Mol Life Sci 2011;68:3201–7. 49. Yao Y, Yao J, Radparvar M, Blazquez-Medela AM, Guihard PJ, Jumabay M, 25. Zhu S, Barbe MF, Liu C, Hadjiargyrou M, Popoff SN, Rani S, et al. Periostin- et al. Reducing Jagged 1 and 2 levels prevents cerebral arteriovenous mal- like-factor in osteogenesis. J Cell Physiol 2009;218:584–92. formations in matrix Gla protein deficiency. Proc Natl Acad Sci U S A 2013;110: 26. Kuhn B, del Monte F, Hajjar RJ, Chang YS, Lebeche D, Arab S, et al. Periostin 19071–6. induces proliferation of differentiated cardiomyocytes and promotes cardiac 50. Luo G, Ducy P, McKee MD, Pinero GJ, Loyer E, Behringer RR, et al. Spon- repair. Nat Med 2007;13:962–9. taneous calcification of and in mice lacking matrix GLA 27. Bostrom K, Zebboudj AF, Yao Y, Lin TS, Torres A. Matrix GLA protein protein. Nature 1997;386:78–81. stimulates VEGF expression through increased transforming growth factor- 51. Viloria K, Hill NJ. Embracing the complexity of matricellular proteins: the beta1 activity in endothelial cells. J Biol Chem 2004;279:52904–13. functional and clinical significance of splice variation. Biomol Concepts 2016;7: 28. Gheorghe SR, Craciun AM. Matrix Gla protein in tumoral pathology. 117–32. Clujul Med 2016;89:319–21. 52. Wu T, Ouyang G. Matricellular proteins: multifaceted extracellular regulators 29. Gerarduzzi C, Kumar RK, Trivedi P, Ajay AK, Iyer A, Boswell S, et al. Silencing in tumor dormancy. Protein Cell 2014;5:249–52. SMOC2 ameliorates kidney fibrosis by inhibiting fibroblast to myofibroblast 53. Shi D, Jiang K, Fu Y, Fang R, Liu XI, Chen J. Overexpression of SPARC transformation. JCI Insight 2017;2:pii: 90299. correlates with poor prognosis in patients with cervical carcinoma and 30. Hartmann U, Hulsmann H, Seul J, Roll S, Midani H, Breloy I, et al. Testican-3: a regulates cancer cell epithelial-mesenchymal transition. Oncol Lett 2016;11: brain-specific member of the BM-40/SPARC/osteonectin family. 3251–8. J Neurochem 2013;125:399–409. 54. Botti G, Scognamiglio G, Marra L, Collina F, Di Bonito M, Cerrone M, et al. 31. Roll S, Seul J, Paulsson M, Hartmann U. Testican-1 is dispensable for mouse SPARC/osteonectin is involved in metastatic process to the lung during development. Matrix Biol 2006;25:373–81. melanoma progression. Virchows Arch 2014;465:331–8. 32. Bradshaw AD, Puolakkainen P, Dasgupta J, Davidson JM, Wight TN, Helene 55. Hsiao YH, Lien HC, Hwa HL, Kuo WH, Chang KJ, Hsieh FJ. SPARC Sage E. SPARC-null mice display abnormalities in the characterized by (osteonectin) in breast tumors of different histologic types and its role in the decreased collagen fibril diameter and reduced tensile strength. J Invest Der- outcome of invasive ductal carcinoma. Breast J 2010;16:305–8. matol 2003;120:949–55. 56. Seno T, Harada H, Kohno S, Teraoka M, Inoue A, Ohnishi T. Downregulation 33. Bradshaw AD, Sage EH. SPARC, a matricellular protein that functions in of SPARC expression inhibits and invasion in malignant gliomas. cellular differentiation and tissue response to injury. J Clin Invest 2001;107: Int J Oncol 2009;34:707–15. 1049–54. 57. Nagaraju GP, Dontula R, El-Rayes BF, Lakka SS. Molecular mechanisms 34. McKinnon PJ, McLaughlin SK, Kapsetaki M, Margolskee RF. Extracellular underlying the divergent roles of SPARC in human carcinogenesis. Carcino- matrix-associated protein Sc1 is not essential for mouse development. Mol Cell genesis 2014;35:967–73. Biol 2000;20:656–60. 58. Chan QK, Ngan HY, Ip PP, Liu VW, Xue WC, Cheung AN. Tumor suppressor 35. Maeda A, Ono M, Holmbeck K, Li L, Kilts TM, Kram V, et al. WNT1-induced effect of follistatin-like 1 in ovarian and endometrial carcinogenesis: a differ- secreted protein-1 (WISP1), a novel regulator of bone turnover and Wnt ential expression and functional analysis. Carcinogenesis 2009;30:114–21. signaling. J Biol Chem 2015;290:14004–18. 59. Singh M, Venugopal C, Tokar T, Brown KR, McFarlane N, Bakhshinyan D, et al. 36. Midwood KS, Hussenet T, Langlois B, Orend G. Advances in tenascin-C RNAi screen identifies essential regulators of human brain metastasis-initiating biology. Cell Mol Life Sci 2011;68:3175–99. cells. Acta Neuropathol 2017;134:923–40.

2712 Cancer Res; 80(13) July 1, 2020 CANCER RESEARCH

Downloaded from cancerres.aacrjournals.org on October 3, 2021. © 2020 American Association for Cancer Research. Published OnlineFirst March 19, 2020; DOI: 10.1158/0008-5472.CAN-18-2098

The Role of Matricellular Proteins in Cancer

60. Perurena N, Zandueta C, Martinez-Canarias S, Moreno H, Vicent S, Almeida 84. Wang L, Song L, Li J, Wang Y, Yang C, Kou X, et al. Bone sialoprotein-avb3 AS, et al. EPCR promotes breast cancer progression by altering SPOCK1/ integrin axis promotes breast cancer metastasis to the bone. Cancer Sci 2019; testican 1-mediated 3D growth. J Hematol Oncol 2017;10:23. 110:3157–72. 61. Ma LJ, Wu WJ, Wang YH, Wu TF, Liang PI, Chang IW, et al. SPOCK1 85. Cho WY, Hong SH, Singh B, Islam MA, Lee S, Lee AY, et al. Suppression of overexpression confers a poor prognosis in urothelial carcinoma. J Cancer 2016; tumor growth in lung cancer xenograft model mice by poly(sorbitol-co-PEI)- 7:467–76. mediated delivery of osteopontin siRNA. Eur J Pharm Biopharm 2015;94: 62. Nakada M, Miyamori H, Yamashita J, Sato H. Testican 2 abrogates inhibition of 450–62. membrane-type matrix metalloproteinases by other testican family proteins. 86. Zhang L, Pu D, Liu D, Wang Y, Luo W, Tang H, et al. Identification and Cancer Res 2003;63:3364–9. validation of novel circulating biomarkers for early diagnosis of lung cancer. 63. Lu H, Ju DD, Yang GD, Zhu LY, Yang XM, Li J, et al. Targeting cancer stem cell Lung Cancer 2019;135:130–7. signature gene SMOC-2 Overcomes chemoresistance and inhibits cell prolif- 87. Fedarko NS, Jain A, Karadag A, Van Eman MR, Fisher LW. Elevated serum eration of endometrial carcinoma. EBioMedicine 2019;40:276–89. bone sialoprotein and osteopontin in colon, breast, prostate, and lung cancer. 64. Su JR, Kuai JH, Li YQ. Smoc2 potentiates proliferation of hepatocellular Clin Cancer Res 2001;7:4060–6. carcinoma cells via promotion of cell cycle progression. World J Gastroenterol 88. Sun T, Li P, Sun D, Bu Q, Li G. Prognostic value of osteopontin in patients with 2016;22:10053–63. hepatocellular carcinoma: a systematic review and meta-analysis. Medicine 65. Shvab A, Haase G, Ben-Shmuel A, Gavert N, Brabletz T, Dedhar S, et al. 2018;97:e12954. Induction of the intestinal stem cell signature gene SMOC-2 is required for L1- 89. Loosen SH, Hoening P, Puethe N, Luedde M, Spehlmann M, Ulmer TF, et al. mediated colon cancer progression. Oncogene 2016;35:549–57. Elevated serum levels of bone sialoprotein (BSP) predict long-term mortality in 66. Brellier F, Ruggiero S, Zwolanek D, Martina E, Hess D, Brown-Luedi M, et al. patients with pancreatic adenocarcinoma. Sci Rep 2019;9:1489. SMOC1 is a tenascin-C interacting protein over-expressed in brain tumors. 90. Ng L, Wan T, Chow A, Iyer D, Man J, Chen G, et al. Osteopontin overexpression Matrix Biol 2011;30:225–33. induced tumor progression and chemoresistance to oxaliplatin through induc- 67. Haque I, Mehta S, Majumder M, Dhar K, De A, McGregor D, et al. Cyr61/CCN1 tion of stem-like properties in human colorectal cancer. Stem Cells Int 2015; signaling is critical for epithelial-mesenchymal transition and stemness and 2015:247892. promotes pancreatic carcinogenesis. Mol Cancer 2011;10:8. 91. Weber GF, Lett GS, Haubein NC. Categorical meta-analysis of osteopontin as a 68. Goodwin CR, Lal B, Zhou X, Ho S, Xia S, Taeger A, et al. Cyr61 mediates clinical cancer marker. Oncol Rep 2011;25:433–41. growth factor-dependent tumor cell growth, migration, and Akt 92. Anderberg C, Li H, Fredriksson L, Andrae J, Betsholtz C, Li X, et al. Paracrine activation. Cancer Res 2010;70:2932–41. signaling by -derived growth factor-CC promotes tumor growth by 69. Lv H, Fan E, Sun S, Ma X, Zhang X, Han DM, et al. Cyr61 is up-regulated in recruitment of cancer-associated fibroblasts. Cancer Res 2009;69:369–78. prostate cancer and associated with the p53 gene status. J Cell Biochem 2009; 93. Caiado H, Conceicao N, Tiago D, Marreiros A, Vicente S, Enriquez JL, et al. 106:738–44. Evaluation of MGP in colorectal cancer. Gene 2020;723: 70. Tsai MS, Bogart DF, Castaneda JM, Li P, Lupu R. Cyr61 promotes breast 144120. tumorigenesis and cancer progression. Oncogene 2002;21:8178–85. 94. Zandueta C, Ormazabal C, Perurena N, Martinez-Canarias S, Zalacain M, 71. Wells JE, Howlett M, Cole CH, Kees UR. Deregulated expression of connective Julian MS, et al. Matrix-Gla protein promotes osteosarcoma lung metastasis tissue growth factor (CTGF/CCN2) is linked to poor outcome in human cancer. and associates with poor prognosis. J Pathol 2016;239:438–49. Int J Cancer 2015;137:504–11. 95. Mertsch S, Schurgers LJ, Weber K, Paulus W, Senner V. Matrix gla protein 72. Mao Z, Ma X, Rong Y, Cui L, Wang X, Wu W, et al. Connective tissue growth (MGP): an overexpressed and migration-promoting mesenchymal component factor enhances the migration of gastric cancer through downregulation of E- in glioblastoma. BMC Cancer 2009;9:302. cadherin via the NF-kB pathway. Cancer Sci 2011;102:104–10. 96. Yoshimura K, Takeuchi K, Nagasaki K, Ogishima S, Tanaka H, Iwase T, et al. 73. Bennewith KL, Huang X, Ham CM, Graves EE, Erler JT, Kambham N, et al. The Prognostic value of matrix Gla protein in breast cancer. Mol Med Rep 2009;2: role of tumor cell-derived connective tissue growth factor (CTGF/CCN2) in 549–53. pancreatic tumor growth. Cancer Res 2009;69:775–84. 97. Chen Y, Miller C, Mosher R, Zhao X, Deeds J, Morrissey M, et al. Identification 74. Hutchenreuther J, Vincent KM, Carter DE, Postovit LM, Leask A. CCN2 of cervical cancer markers by cDNA and tissue microarrays. Cancer Res 2003; expression by tumor stroma is required for melanoma metastasis. J Invest 63:1927–35. Dermatol 2015;135:2805–13. 98. Takada Y, Ye X, Simon S. The integrins. Genome Biol 2007;8:215. 75. Nallet-Staub F, Marsaud V, Li L, Gilbert C, Dodier S, Bataille V, et al. Pro- 99. Chong HC, Tan CK, Huang RL, Tan NS. Matricellular proteins: a sticky affair invasive activity of the Hippo pathway effectors YAP and TAZ in cutaneous with cancers. J Oncol 2012;2012:351089. melanoma. J Invest Dermatol 2014;134:123–32. 100. Bellahcene A, Castronovo V, Ogbureke KU, Fisher LW, Fedarko NS. Small 76. Wang MY, Chen PS, Prakash E, Hsu HC, Huang HY, Lin MT, et al. Connective integrin-binding ligand N-linked glycoproteins (SIBLINGs): multifunctional tissue growth factor confers drug resistance in breast cancer through concom- proteins in cancer. Nat Rev Cancer 2008;8:212–26. itant up-regulation of Bcl-xL and cIAP1. Cancer Res 2009;69:3482–91. 101. Murphy-Ullrich JE, Sage EH. Revisiting the matricellular concept. Matrix Biol 77. Sahai E, Astsaturov I, Cukierman E, DeNardo DG, Egeblad M, Evans RM, et al. 2014;37:1–14. A framework for advancing our understanding of cancer-associated fibroblasts. 102. Tseng C, Kolonin MG. Proteolytic isoforms of SPARC induce adipose stromal Nat Rev Cancer 2020;20:174–86. cell mobilization in obesity. Stem Cells 2016;34:174–90. 78. Hutchenreuther J, Vincent K, Norley C, Racanelli M, Gruber SB, Johnson TM, 103. Nie J, Chang B, Traktuev DO, Sun J, March K, Chan L, et al. IFATS collection: et al. Activation of cancer-associated fibroblasts is required for tumor neo- combinatorial identify alpha5beta1 integrin as a receptor for the vascularization in a murine model of melanoma. Matrix Biol 2018;74:52–61. matricellular protein SPARC on adipose stromal cells. Stem Cells 2008;26: 79. Erez N, Truitt M, Olson P, Arron ST, Hanahan D. Cancer-associated fibroblasts 2735–45. are activated in incipient neoplasia to orchestrate tumor-promoting inflam- 104. Shi Q, Bao S, Song L, Wu Q, Bigner DD, Hjelmeland AB, et al. Targeting SPARC mation in an NF-kappaB-dependent manner. Cancer Cell 2010;17:135–47. expression decreases glioma cellular survival and invasion associated with 80. Chen CC, Kim KH, Lau LF. The matricellular protein CCN1 suppresses reduced activities of FAK and ILK kinases. Oncogene 2007;26:4084–94. hepatocarcinogenesis by inhibiting compensatory proliferation. Oncogene 105. De S, Chen J, Narizhneva NV, Heston W, Brainard J, Sage EH, et al. Molecular 2016;35:1314–23. pathway for cancer metastasis to bone. J Biol Chem 2003;278:39044–50. 81. Chang CC, Yang MH, Lin BR, Chen ST, Pan SH, Hsiao M, et al. CCN2 inhibits 106. Sun W, Feng J, Yi Q, Xu X, Chen Y, Tang L. SPARC acts as a mediator of TGF- lung cancer metastasis through promoting DAPK-dependent anoikis and beta1 in promoting epithelial-to-mesenchymal transition in A549 and H1299 inducing EGFR degradation. Cell Death Differ 2013;20:443–55. lung cancer cells. Biofactors 2018;44:453–64. 82. Li J, Ye L, Owen S, Weeks HP, Zhang Z, Jiang WG. Emerging role of CCN family 107. Tumbarello DA, Andrews MR, Brenton JD. SPARC Regulates transforming proteins in tumorigenesis and cancer metastasis (review). Int J Mol Med 2015; growth factor beta induced (TGFBI) extracellular matrix deposition and 36:1451–63. paclitaxel response in ovarian cancer cells. PLoS One 2016;11:e0162698. 83. Sharon Y, Raz Y, Cohen N, Ben-Shmuel A, Schwartz H, Geiger T, et al. Tumor- 108. Chandrasekaran V, Ambati J, Ambati BK, Taylor EW. Molecular docking and derived osteopontin reprograms normal mammary fibroblasts to promote analysis of interactions between vascular endothelial growth factor (VEGF) and inflammation and tumor growth in breast cancer. Cancer Res 2015;75:963–73. SPARC protein. J Mol Graph Model 2007;26:775–82.

AACRJournals.org Cancer Res; 80(13) July 1, 2020 2713

Downloaded from cancerres.aacrjournals.org on October 3, 2021. © 2020 American Association for Cancer Research. Published OnlineFirst March 19, 2020; DOI: 10.1158/0008-5472.CAN-18-2098

Gerarduzzi et al.

109. Raines EW, Lane TF, Iruela-Arispe ML, Ross R, Sage EH. The extracellular enhances prostate cancer metastasis by down-regulating miR-126. Oncotarget SPARC interacts with platelet-derived growth factor (PDGF)-AB 2014;5:7589–98. and -BB and inhibits the binding of PDGF to its receptors. Proc Natl Acad 130. Chang AC, Chen PC, Lin YF, Su CM, Liu JF, Lin TH, et al. Osteoblast-secreted Sci U S A 1992;89:1281–5. WISP-1 promotes adherence of prostate cancer cells to bone via the VCAM-1/ 110. Miao L, Wang Y, Xia H, Yao C, Cai H, Song Y. SPOCK1 is a novel transforming integrin alpha4beta1 system. Cancer Lett 2018;426:47–56. growth factor-beta target gene that regulates lung cancer cell epithelial- 131. Tsai HC, Tzeng HE, Huang CY, Huang YL, Tsai CH, Wang SW, et al. WISP-1 mesenchymal transition. Biochem Biophys Res Commun 2013;440:792–7. positively regulates angiogenesis by controlling VEGF-A expression in human 111. Zhao P, Guan HT, Dai ZJ, Ma YG, Liu XX, Wang XJ. Knockdown of SPOCK1 osteosarcoma. Cell Death Dis 2017;8:e2750. inhibits the proliferation and invasion in colorectal cancer cells by suppressing 132. Lin CC, Chen PC, Lein MY, Tsao CW, Huang CC, Wang SW, et al. WISP-1 the PI3K/Akt pathway. Oncol Res 2016;24:437–45. promotes VEGF-C-dependent lymphangiogenesis by inhibiting miR-300 in 112. ShuYJ,WengH,YeYY,HuYP,BaoRF,CaoY,etal.SPOCK1asapotential human oral squamous cell carcinoma cells. Oncotarget 2016;7:9993–10005. cancer prognostic marker promotes the proliferation and metastasis of 133. Shao H, Cai L, Moller M, Issac B, Zhang L, Owyong M, et al. Notch1-WISP-1 gallbladder cancer cells by activating the PI3K/AKT pathway. Mol Cancer axis determines the regulatory role of -derived stromal 2015;14:12. fibroblasts in melanoma metastasis. Oncotarget 2016;7:79262–73. 113. Liu P, Lu J, Cardoso WV, Vaziri C. The SPARC-related factor SMOC-2 134. Soon LL, Yie TA, Shvarts A, Levine AJ, Su F, Tchou-Wong KM. Overexpression promotes growth factor-induced cyclin D1 expression and DNA synthesis via of WISP-1 down-regulated motility and invasion of lung cancer cells through integrin-linked kinase. Mol Biol Cell 2008;19:248–61. inhibition of Rac activation. J Biol Chem 2003;278:11465–70. 114. Zheng CC, Hu HF, Hong P, Zhang QH, Xu WW, He QY, et al. Significance of 135. Orend G, Chiquet-Ehrismann R. Tenascin-C induced signaling in cancer. integrin-linked kinase (ILK) in tumorigenesis and its potential implication as a Cancer Lett 2006;244:143–63. biomarker and therapeutic target for human cancer. Am J Cancer Res 2019;9: 136. Fiorilli P, Partridge D, Staniszewska I, Wang JY, Grabacka M, So K, et al. 186–97. Integrins mediate adhesion of medulloblastoma cells to tenascin and 115. Maier S, Paulsson M, Hartmann U. The widely expressed extracellular matrix activate pathways associated with survival and proliferation. Lab Invest protein SMOC-2 promotes keratinocyte attachment and migration. Exp Cell 2008;88:1143–56. Res 2008;314:2477–87. 137. Yokosaki Y, Monis H, Chen J, Sheppard D. Differential effects of the integrins 116. Thakur R, Mishra DP. Matrix reloaded: CCN, tenascin and SIBLING group of alpha9beta1, alphavbeta3, and alphavbeta6 on cell proliferative responses to matricellular proteins in orchestrating cancer hallmark capabilities. tenascin. Roles of the beta subunit extracellular and cytoplasmic domains. J Biol Pharmacol Ther 2016;168:61–74. Chem 1996;271:24144–50. 117. Haque I, De A, Majumder M, Mehta S, McGregor D, Banerjee SK, et al. The 138. San Martin R, Pathak R, Jain A, Jung SY, Hilsenbeck SG, Pina-Barba MC, et al. matricellular protein CCN1/Cyr61 is a critical regulator of Sonic Hedgehog in Tenascin-C and integrin a9 mediate interactions of prostate cancer with the pancreatic carcinogenesis. J Biol Chem 2012;287:38569–79. bone microenvironment. Cancer Res 2017;77:5977–88. 118. Huang YT, Lan Q, Ponsonnet L, Blanquet M, Christofori G, Zaric J, et al. The 139. Huang W, Chiquet-Ehrismann R, Moyano JV, Garcia-Pardo A, Orend G. matricellular protein CYR61 interferes with normal pancreatic islets architec- Interference of tenascin-C with syndecan-4 binding to fibronectin blocks ture and promotes pancreatic neuroendocrine tumor progression. Oncotarget cell adhesion and stimulates tumor cell proliferation. Cancer Res 2001;61: 2016;7:1663–74. 8586–94. 119. Xie D, Yin D, Tong X, O'Kelly J, Mori A, Miller C, et al. Cyr61 is overexpressed 140. Alcaraz LB, Exposito JY, Chuvin N, Pommier RM, Cluzel C, Martel S, et al. in gliomas and involved in integrin-linked kinase-mediated Akt and beta- Tenascin-X promotes epithelial-to-mesenchymal transition by activating latent catenin-TCF/Lef signaling pathways. Cancer Res 2004;64:1987–96. TGF-b. J Cell Biol 2014;205:409–28. 120. Huang YT, Lan Q, Lorusso G, Duffey N, Ruegg C. The matricellular protein 141. Chuanyu S, Yuqing Z, Chong X, Guowei X, Xiaojun Z. Periostin promotes CYR61 promotes breast cancer lung metastasis by facilitating tumor cell migration and invasion of renal cell carcinoma through the integrin/focal extravasation and suppressing anoikis. Oncotarget 2017;8:9200–15. adhesion kinase/c-Jun N-terminal kinase pathway. Tumour Biol 2017;39: 121. Menendez JA, Vellon L, Mehmi I, Teng PK, Griggs DW, Lupu R. A novel 1010428317694549. CYR61-triggered 'CYR61-alphavbeta3 integrin loop' regulates breast cancer cell 142. Orecchia P, Conte R, Balza E, Castellani P, Borsi L, Zardi L, et al. Identification survival and chemosensitivity through activation of ERK1/ERK2 MAPK of a novel cell binding site of periostin involved in tumour growth. Eur J Cancer signaling pathway. Oncogene 2005;24:761–79. 2011;47:2221–9. 122. Chien W, O'Kelly J, Lu D, Leiter A, Sohn J, Yin D, et al. Expression of connective 143. Bao S, Ouyang G, Bai X, Huang Z, Ma C, Liu M, et al. Periostin potently tissue growth factor (CTGF/CCN2) in breast cancer cells is associated with promotes metastatic growth of colon cancer by augmenting cell survival via the increased migration and angiogenesis. Int J Oncol 2011;38:1741–7. Akt/PKB pathway. Cancer Cell 2004;5:329–39. 123. Stephens S, Palmer J, Konstantinova I, Pearce A, Jarai G, Day E. A functional 144. Michaylira CZ, Wong GS, Miller CG, Gutierrez CM, Nakagawa H, Hammond analysis of Wnt inducible signalling pathway protein -1 (WISP-1/CCN4). J Cell R, et al. Periostin, a cell adhesion molecule, facilitates invasion in the tumor Commun Signal 2015;9:63–72. microenvironment and annotates a novel tumor-invasive signature in esoph- 124. Haque I, Banerjee S, De A, Maity G, Sarkar S, Majumdar M, et al. CCN5/WISP- ageal cancer. Cancer Res 2010;70:5281–92. 2 promotes growth arrest of triple-negative breast cancer cells through accu- 145. Yao Y, Zebboudj AF, Shao E, Perez M, Bostrom K. Regulation of bone mulation and trafficking of p27(Kip1) via Skp2 and FOXO3a regulation. morphogenetic protein-4 by matrix GLA protein in vascular endothelial cells Oncogene 2015;34:3152–63. involves activin-like kinase receptor 1. J Biol Chem 2006;281:33921–30. 125. Kaasboll OJ, Gadicherla AK, Wang JH, Monsen VT, Hagelin EMV, Dong MQ, 146. Nam JS, Suchar AM, Kang MJ, Stuelten CH, Tang B, Michalowska AM, et al. et al. Connective tissue growth factor (CCN2) is a matricellular preproprotein Bone sialoprotein mediates the tumor cell-targeted prometastatic activity of controlled by proteolytic activation. J Biol Chem 2018;293:17953–70. transforming growth factor beta in a mouse model of breast cancer. Cancer Res 126. Brigstock DR, Steffen CL, Kim GY, Vegunta RK, Diehl JR, Harding PA. 2006;66:6327–35. Purification and characterization of novel -binding growth factors in 147. Sung V, Stubbs JT III, Fisher L, Aaron AD, Thompson EW. Bone sialoprotein uterine secretory fluids. Identification as heparin-regulated Mr 10,000 forms of supports breast cancer cell adhesion proliferation and migration through connective tissue growth factor. J Biol Chem 1997;272:20275–82. differential usage of the alpha(v)beta3 and alpha(v)beta5 integrins. J Cell 127. Li J, Ye L, Sun PH, Zheng F, Ruge F, Satherley LK, et al. Reduced NOV Physiol 1998;176:482–94. expression correlates with disease progression in colorectal cancer and is 148. Zhao H, Chen Q, Alam A, Cui J, Suen KC, Soo AP, et al. The role of osteopontin associated with survival, invasion and chemoresistance of cancer cells. Onco- in the progression of solid tumour. Cell Death Dis 2018;9:356. target 2017;8:26231–44. 149. Gimba ERP, Brum MCM, Nestal De Moraes G. Full-length osteopontin and its 128. Chen PC, Cheng HC, Tang CH. CCN3 promotes prostate cancer bone splice variants as modulators of chemoresistance and radioresistance (review). metastasis by modulating the tumor-bone microenvironment through Int J Oncol 2019;54:420–30. RANKL-dependent pathway. Carcinogenesis 2013;34:1669–79. 150. Shirasaki T, Honda M, Yamashita T, Nio K, Shimakami T, Shimizu R, et al. The 129. Tai HC, Chang AC, Yu HJ, Huang CY, Tsai YC, Lai YW, et al. Osteoblast- osteopontin-CD44 axis in hepatic cancer stem cells regulates IFN signaling and derived WNT-induced secreted protein 1 increases VCAM-1 expression and HCV replication. Sci Rep 2018;8:13143.

2714 Cancer Res; 80(13) July 1, 2020 CANCER RESEARCH

Downloaded from cancerres.aacrjournals.org on October 3, 2021. © 2020 American Association for Cancer Research. Published OnlineFirst March 19, 2020; DOI: 10.1158/0008-5472.CAN-18-2098

The Role of Matricellular Proteins in Cancer

151. Pietras A, Katz AM, Ekstrom EJ, Wee B, Halliday JJ, Pitter KL, et al. Osteo- 176. Jia H, Janjanam J, Wu SC, Wang R, Pano G, Celestine M, et al. The tumor cell- pontin-CD44 signaling in the glioma perivascular niche enhances cancer stem secreted matricellular protein WISP1 drives pro-metastatic collagen lineariza- cell phenotypes and promotes aggressive tumor growth. Cell Stem Cell 2014;14: tion. EMBO J 2019;38:e101302. 357–69. 177. Thiery JP, Acloque H, Huang RY, Nieto MA. Epithelial-mesenchymal transi- 152. Rao G, Wang H, Li B, Huang L, Xue D, Wang X, et al. Reciprocal interactions tions in development and disease. Cell 2009;139:871–90. between tumor-associated and CD44-positive cancer cells via 178. Walker C, Mojares E, Del Rio Hernandez A. Role of extracellular matrix in osteopontin/CD44 promote tumorigenicity in colorectal cancer. Clin Cancer development and cancer progression. Int J Mol Sci 2018;19:pii: E3028. Res 2013;19:785–97. 179. Lu W, Kang Y. Epithelial-mesenchymal plasticity in cancer progression and 153. Tajima K, Ohashi R, Sekido Y, Hida T, Nara T, Hashimoto M, et al. Osteo- metastasis. Dev Cell 2019;49:361–74. pontin-mediated enhanced hyaluronan binding induces multidrug resistance 180. Brady JJ, Chuang CH, Greenside PG, Rogers ZN, Murray CW, Caswell DR, et al. in mesothelioma cells. Oncogene 2010;29:1941–51. An Arntl2-driven secretome enables lung adenocarcinoma metastatic self- 154. Pickup MW, Mouw JK, Weaver VM. The extracellular matrix modulates the sufficiency. Cancer Cell 2016;29:697–710. hallmarks of cancer. EMBO Rep 2014;15:1243–53. 181. Kim HP, Han SW, Song SH, Jeong EG, Lee MY, Hwang D, et al. Testican-1- 155. Fiorino S, Di Saverio S, Leandri P, Tura A, Birtolo C, Silingardi M, et al. The role mediated epithelial-mesenchymal transition signaling confers acquired resis- of matricellular proteins and tissue stiffness in breast cancer: a systematic tance to lapatinib in HER2-positive gastric cancer. Oncogene 2014;33:3334–41. review. Future Oncol 2018;14:1601–27. 182. Chang CH, Yen MC, Liao SH, Hsu YL, Lai CS, Chang KP, et al. Secreted protein 156. Sangaletti S, Colombo MP. Matricellular proteins at the crossroad of inflam- acidic and rich in cysteine (SPARC) enhances cell proliferation, migration, and mation and cancer. Cancer Lett 2008;267:245–53. epithelial mesenchymal transition, and SPARC expression is associated with 157. Zhu X, Zhong J, Zhao Z, Sheng J, Wang J, Liu J, et al. Epithelial derived CTGF tumor grade in head and neck cancer. Int J Mol Sci 2017;18:pii: E1556. promotes breast tumor progression via inducing EMT and collagen I fibers 183. Sangaletti S, Di Carlo E, Gariboldi S, Miotti S, Cappetti B, Parenza M, et al. deposition. Oncotarget 2015;6:25320–38. -derived SPARC bridges tumor cell-extracellular matrix interac- 158. Legate KR, Wickstrom SA, Fassler R. Genetic and cell biological analysis of tions toward metastasis. Cancer Res 2008;68:9050–9. integrin outside-in signaling. Genes Dev 2009;23:397–418. 184. Robert G, Gaggioli C, Bailet O, Chavey C, Abbe P, Aberdam E, et al. SPARC 159. Lee S, Kumar S. Actomyosin stress fiber mechanosensing in 2D and 3D. represses E-cadherin and induces mesenchymal transition during melanoma F1000Res 2016;5:pii: F1000 Faculty Rev-2261. development. Cancer Res 2006;66:7516–23. 160. Bradshaw AD. The role of SPARC in extracellular matrix assembly. J Cell 185. Hou CH, Lin FL, Hou SM, Liu JF. Cyr61 promotes epithelial-mesenchymal Commun Signal 2009;3:239–46. transition and tumor metastasis of osteosarcoma by Raf-1/MEK/ERK/Elk-1/ 161. Martinek N, Shahab J, Sodek J, Ringuette M. Is SPARC an evolutionarily TWIST-1 signaling pathway. Mol Cancer 2014;13:236. conserved collagen chaperone? J Dent Res 2007;86:296–305. 186. Habel N, Stefanovska B, Carene D, Patino-Garcia A, Lecanda F, Fromigue O. 162. Brekken RA, Puolakkainen P, Graves DC, Workman G, Lubkin SR, Sage EH. CYR61 triggers osteosarcoma metastatic spreading via an IGF1Rbeta- Enhanced growth of tumors in SPARC null mice is associated with changes in dependent EMT-like process. BMC Cancer 2019;19:62. the ECM. J Clin Invest 2003;111:487–95. 187. Das A, Dhar K, Maity G, Sarkar S, Ghosh A, Haque I, et al. Deficiency of CCN5/ 163. Bradshaw AD, Baicu CF, Rentz TJ, Van Laer AO, Boggs J, Lacy JM, et al. WISP-2-driven program in breast cancer promotes cancer epithelial cells to overload-induced alterations in fibrillar collagen content and myo- mesenchymal stem cells and breast cancer growth. Sci Rep 2017;7:1220. cardial diastolic function: role of secreted protein acidic and rich in cysteine 188. Haque I, Ghosh A, Acup S, Banerjee S, Dhar K, Ray A, et al. -induced (SPARC) in post-synthetic procollagen processing. Circulation 2009;119: ER-alpha-positive breast cancer cell viability and migration is mediated 269–80. by suppressing CCN5-signaling via activating JAK/AKT/STAT-pathway. 164. Chioran A, Duncan S, Catalano A, Brown TJ, Ringuette MJ. Collagen IV BMC Cancer 2018;18:99. trafficking: the inside-out and beyond story. Dev Biol 2017;431:124–33. 189. Huang W, Martin EE, Burman B, Gonzalez ME, Kleer CG. The matricellular 165. Chlenski A, Cohn SL. Modulation of matrix remodeling by SPARC in neo- protein CCN6 (WISP3) decreases Notch1 and suppresses breast cancer initi- progression. Semin Cell Dev Biol 2010;21:55–65. ating cells. Oncotarget 2016;7:25180–93. 166. Kehlet SN, Manon-Jensen T, Sun S, Brix S, Leeming DJ, Karsdal MA, et al. A 190. Tran MN, Kleer CG. Matricellular CCN6 (WISP3) protein: a tumor suppressor fragment of SPARC reflecting increased collagen affinity shows pathological for mammary metaplastic carcinomas. J Cell Commun Signal 2018;12:13–9. relevance in lung cancer - implications of a new collagen chaperone function of 191. Qin X, Yan M, Zhang J, Wang X, Shen Z, Lv Z, et al. TGFb3-mediated induction SPARC. Cancer Biol Ther 2018;19:904–12. of Periostin facilitates head and neck cancer growth and is associated with 167. Tomko LA, Hill RC, Barrett A, Szulczewski JM, Conklin MW, Eliceiri KW, et al. metastasis. Sci Rep 2016;6:20587. Targeted matrisome analysis identifies thrombospondin-2 and tenascin-C in 192. Wu G, Wang X, Zhang X. Clinical implications of periostin in the liver aligned collagen stroma from invasive breast carcinoma. Sci Rep 2018;8:12941. metastasis of colorectal cancer. Cancer Biother Radiopharm 2013;28:298–302. 168. Provenzano PP, Eliceiri KW, Campbell JM, Inman DR, White JG, Keely PJ. 193. Kudo Y, Ogawa I, Kitajima S, Kitagawa M, Kawai H, Gaffney PM, et al. Periostin Collagen reorganization at the tumor-stromal interface facilitates local inva- promotes invasion and anchorage-independent growth in the metastatic sion. BMC Med 2006;4:38. process of head and neck cancer. Cancer Res 2006;66:6928–35. 169. Kubow KE, Vukmirovic R, Zhe L, Klotzsch E, Smith ML, Gourdon D, et al. 194. Insua-Rodriguez J, Pein M, Hongu T, Meier J, Descot A, Lowy CM, et al. Stress Mechanical forces regulate the interactions of fibronectin and collagen I in signaling in breast cancer cells induces matrix components that promote extracellular matrix. Nat Commun 2015;6:8026. chemoresistant metastasis. EMBO Mol Med 2018;10:pii: e9003. 170. Kadler KE, Hill A, Canty-Laird EG. Collagen fibrillogenesis: fibronectin, 195. Murakami T, Kikuchi H, Ishimatsu H, Iino I, Hirotsu A, Matsumoto T, et al. integrins, and minor collagens as organizers and nucleators. Curr Opin Cell in colorectal cancer stroma is a predictive marker for liver Biol 2008;20:495–501. metastasis and is a potent target of miR-198 as identified by microRNA 171. Sottile J, Shi F, Rublyevska I, Chiang HY, Lust J, Chandler J. - analysis. Br J Cancer 2017;117:1360–70. dependent collagen I deposition modulates the cell response to fibronectin. 196. Yang Z, Zhang C, Qi W, Cui C, Cui Y, Xuan Y. Tenascin-C as a prognostic Am J Physiol Cell Physiol 2007;293:C1934–46. determinant of colorectal cancer through induction of epithelial-to- 172. Maruhashi T, Kii I, Saito M, Kudo A. Interaction between periostin and BMP-1 mesenchymal transition and proliferation. Exp Mol Pathol 2018;105:216–22. promotes proteolytic activation of . J Biol Chem 2010;285: 197. Yoneura N, Takano S, Yoshitomi H, Nakata Y, Shimazaki R, Kagawa S, et al. 13294–303. Expression of II and stromal tenascin C promotes epithelial to 173. Garnero P. The contribution of collagen crosslinks to bone strength. mesenchymal transition and correlates with distant metastasis in pancreatic Bonekey Rep 2012;1:182. cancer. Int J Mol Med 2018;42:821–30. 174. Gineyts E, Bonnet N, Ferrari S, Garnero P. Periostin, a matricellular glutamic- 198. Chen L, Tian X, Gong W, Sun B, Li G, Liu D, et al. Periostin mediates epithelial- acid protein influences crosslinking of bone collagen. Osteoporosis Int 2011; mesenchymal transition through the MAPK/ERK pathway in hepatoblastoma. 22:43. Cancer Biol Med 2019;16:89–100. 175. Ibbetson SJ, Pyne NT, Pollard AN, Olson MF, Samuel MS. Mechanotransduc- 199. Hu WW, Chen PC, Chen JM, Wu YM, Liu PY, Lu CH, et al. Periostin promotes tion pathways promoting tumor progression are activated in invasive human epithelial-mesenchymal transition via the MAPK/miR-381 axis in lung cancer. squamous cell carcinoma. Am J Pathol 2013;183:930–7. Oncotarget 2017;8:62248–60.

AACRJournals.org Cancer Res; 80(13) July 1, 2020 2715

Downloaded from cancerres.aacrjournals.org on October 3, 2021. © 2020 American Association for Cancer Research. Published OnlineFirst March 19, 2020; DOI: 10.1158/0008-5472.CAN-18-2098

Gerarduzzi et al.

200. Kaariainen E, Nummela P, Soikkeli J, Yin M, Lukk M, Jahkola T, et al. Switch to 222. Mi Z, Oliver T, Guo H, Gao C, Kuo PC. Thrombin-cleaved COOH(-) terminal an invasive growth phase in melanoma is associated with tenascin-C, fibro- osteopontin peptide binds with cyclophilin C to CD147 in murine breast cancer nectin, and procollagen-I forming specific channel structures for invasion. cells. Cancer Res 2007;67:4088–97. J Pathol 2006;210:181–91. 223. Takafuji V, Forgues M, Unsworth E, Goldsmith P, Wang XW. An osteopontin 201. Sun Z, Velazquez-Quesada I, Murdamoothoo D, Ahowesso C, Yilmaz A, Spenle fragment is essential for tumor cell invasion in hepatocellular carcinoma. C, et al. Tenascin-C increases lung metastasis by impacting vessel Oncogene 2007;26:6361–71. invasions. Matrix Biol 2019;83:26–47. 224. Hawkins AG, Julian CM, Konzen S, Treichel S, Lawlor ER, Bailey KM. 202. Degen M, Brellier F, Schenk S, Driscoll R, Zaman K, Stupp R, et al. Tenascin-W, Microenvironmental factors drive tenascin C and Src cooperation to promote a new marker of cancer stroma, is elevated in sera of colon and breast cancer invadopodia formation in Ewing sarcoma. Neoplasia 2019;21:1063–72. patients. Int J Cancer 2008;122:2454–61. 225. O'Connell JT, Sugimoto H, Cooke VG, MacDonald BA, Mehta AI, LeBleu VS, 203. Shoji T, Kamiya T, Tsubura A, Hatano T, Sakakura T, Yamamoto M, et al. et al. VEGF-A and Tenascin-C produced by S100A4þ stromal cells are Immunohistochemical patterns of tenascin in invasive breast carci- important for metastatic colonization. Proc Natl Acad Sci U S A 2011;108: nomas. Virchows Arch A Pathol Anat Histopathol 1992;421:53–6. 16002–7. 204. Spenle C, Gasser I, Saupe F, Janssen KP, Arnold C, Klein A, et al. Spatial 226. Oskarsson T, Acharyya S, Zhang XH, Vanharanta S, Tavazoie SF, Morris PG, organization of the tenascin-C microenvironment in experimental and human et al. Breast cancer cells produce tenascin C as a metastatic niche component to cancer. Cell Adh Migr 2015;9:4–13. colonize the lungs. Nat Med 2011;17:867–74. 205. Saupe F, Schwenzer A, Jia Y, Gasser I, Spenle C, Langlois B, et al. Tenascin-C 227. Fukunaga-Kalabis M, Martinez G, Nguyen TK, Kim D, Santiago-Walker A, downregulates wnt inhibitor dickkopf-1, promoting tumorigenesis in a neu- Roesch A, et al. Tenascin-C promotes melanoma progression by maintaining roendocrine tumor model. Cell Rep 2013;5:482–92. the ABCB5-positive side population. Oncogene 2010;29:6115–24. 206. Midwood KS, Orend G. The role of tenascin-C in tissue injury and tumori- 228. Lambert AW, Wong CK, Ozturk S, Papageorgis P, Raghunathan R, Alekseyev genesis. J Cell Commun Signal 2009;3:287–310. Y, et al. Tumor cell-derived periostin regulates cytokines that maintain breast 207. Gaggioli C, Hooper S, Hidalgo-Carcedo C, Grosse R, Marshall JF, cancer stem cells. Mol Cancer Res 2016;14:103–13. Harrington K, et al. -led collective invasion of carcinoma cells 229. Semba T, Sugihara E, Kamoshita N, Ueno S, Fukuda K, Yoshino M, et al. with differing roles for RhoGTPases in leading and following cells. Nat Cell Periostin antisense oligonucleotide suppresses bleomycin-induced formation Biol 2007;9:1392–400. of a lung premetastatic niche for melanoma. Cancer Sci 2018;109:1447–54. 208. Kii I, Nishiyama T, Li M, Matsumoto K, Saito M, Amizuka N, et al. Incorpo- 230. Wang Z, Xiong S, Mao Y, Chen M, Ma X, Zhou X, et al. Periostin promotes ration of tenascin-C into the extracellular matrix by periostin underlies an immunosuppressive premetastatic niche formation to facilitate breast tumour extracellular meshwork architecture. J Biol Chem 2010;285:2028–39. metastasis. J Pathol 2016;239:484–95. 209. Sun Z, Schwenzer A, Rupp T, Murdamoothoo D, Vegliante R, Lefebvre O, et al. 231. Malanchi I, Santamaria-Martinez A, Susanto E, Peng H, Lehr HA, Delaloye JF, Tenascin-C promotes tumor cell migration and metastasis through integrin et al. Interactions between cancer stem cells and their niche govern metastatic alpha9beta1-mediated YAP inhibition. Cancer Res 2018;78:950–61. colonization. Nature 2011;481:85–9. 210. Kii I. Periostin functions as a scaffold for assembly of extracellular proteins. 232. Chen Y, Zhang Y, Tan Y, Liu Z. Clinical significance of SPARC in esophageal Adv Exp Med Biol 2019;1132:23–32. squamous cell carcinoma. Biochem Biophys Res Commun 2017;492:184–91. 211. Karadag A, Ogbureke KU, Fedarko NS, Fisher LW. Bone sialoprotein, matrix 233. Davis EJ, Zhao L, Lucas DR, Schuetze SM, Baker LH, Zalupski MM, et al. metalloproteinase 2, and alpha(v)beta3 integrin in osteotropic cancer cell SPARC expression in patients with high-risk localized soft tissue sarcoma invasion. J Natl Cancer Inst 2004;96:956–65. treated on a randomized phase II trial of neo/adjuvant chemotherapy. 212. McClung HM, Thomas SL, Osenkowski P, Toth M, Menon P, Raz A, et al. BMC Cancer 2016;16:663. SPARC upregulates MT1-MMP expression, MMP-2 activation, and the secre- 234. Rich JN, Hans C, Jones B, Iversen ES, McLendon RE, Rasheed BK, et al. Gene tion and cleavage of -3 in U87MG glioma cells. Neurosci Lett 2007;419: expression profiling and genetic markers in glioblastoma survival. Cancer Res 172–7. 2005;65:4051–8. 213. Gilles C, Bassuk JA, Pulyaeva H, Sage EH, Foidart JM, Thompson EW. SPARC/ 235. Cao DX, Li ZJ, Jiang XO, Lum YL, Khin E, Lee NP, et al. Osteopontin as osteonectin induces 2 activation in human breast potential biomarker and therapeutic target in gastric and liver cancers. World J cancer cell lines. Cancer Res 1998;58:5529–36. Gastroenterol 2012;18:3923–30. 214. Liu G, Ren F, Song Y. Upregulation of SPOCK2 inhibits the invasion and 236. Feng YH, Su YC, Lin SF, Lin PR, Wu CL, Tung CL, et al. Oct4 upregulates migration of prostate cancer cells by regulating the MT1-MMP/MMP2 path- osteopontin via Egr1 and is associated with poor outcome in human lung way. PeerJ 2019;7:e7163. cancer. BMC Cancer 2019;19:791. 215. Ren F, Wang D, Wang Y, Chen P, Guo C. SPOCK2 affects the biological 237. Wei R, Wong JPC, Lyu P, Xi X, Tong O, Zhang SD, et al. In vitro and clinical data behavior of endometrial cancer cells by regulation of MT1-MMP and MMP2. analysis of osteopontin as a prognostic indicator in colorectal cancer. J Cell Mol Reprod Sci 2019:1933719119834341. DOI: 10.1177/1933719119834341. Med 2018;22:4097–105. 216. Suzuki H, Sasada M, Kamiya S, Ito Y, Watanabe H, Okada Y, et al. The 238. Bramwell VH, Doig GS, Tuck AB, Wilson SM, Tonkin KS, Tomiak A, et al. promoting effect of the extracellular matrix peptide TNIIIA2 derived Serial plasma osteopontin levels have prognostic value in metastatic breast from tenascin-C in colon cancer cell infiltration. Int J Mol Sci 2017;18:pii: cancer. Clin Cancer Res 2006;12:3337–43. E181. 239. Capper D, Mittelbronn M, Goeppert B, Meyermann R, Schittenhelm J. Secreted 217. Sarkar S, Nuttall RK, Liu S, Edwards DR, Yong VW. Tenascin-C stimulates protein, acidic and rich in cysteine (SPARC) expression in astrocytic tumour glioma cell invasion through matrix metalloproteinase-12. Cancer Res 2006;66: cells negatively correlates with proliferation, while vascular SPARC expression 11771–80. is associated with patient survival. Neuropathol Appl Neurobiol 2010;36: 218. Khalil RA, editor. Matrix metalloproteinases and tissue remodeling in health 183–97. and disease: target tissues and therapy. 1st ed. Cambridge, MA: Academic Press, 240. Rittling SR, Chambers AF. Role of osteopontin in tumour progression. Br J Elsevier; 2017. Cancer 2004;90:1877–81. 219. Weaver M, Workman G, Schultz CR, Lemke N, Rempel SA, Sage EH. 241. Yang JY, Yang MW, Huo YM, Liu W, Liu DJ, Li J, et al. High expression of Proteolysis of the matricellular protein hevin by matrix metalloproteinase-3 WISP-1 correlates with poor prognosis in pancreatic ductal adenocarcinoma. produces a SPARC-like fragment (SLF) associated with neovasculature in a Am J Transl Res 2015;7:1621–8. murine glioma model. J Cell Biochem 2011;112:3093–102. 242. Xiao G, Tang Z, Yuan X, Yuan J, Zhao J, Zhang Z, et al. The expression 220. Podgorski I, Linebaugh BE, Koblinski JE, Rudy DL, Herroon MK, Olive MB, of Wnt-1 inducible signaling pathway protein-2 in astrocytoma: corre- et al. Bone marrow-derived cleaves SPARC in bone metastasis. lation between pathological grade and clinical outcome. Oncol Lett 2015; Am J Pathol 2009;175:1255–69. 9:235–40. 221. Christensen B, Klaning E, Nielsen MS, Andersen MH, Sorensen ES. C-terminal 243. Xie JJ, Xu LY, Wu ZY, Li LY, Xu XE, Wu JY, et al. Expression of cysteine-rich 61 modification of osteopontin inhibits interaction with the aVb3-integrin. J Biol is correlated with poor prognosis in patients with esophageal squamous cell Chem 2012;287:3788–97. carcinoma. Eur J Surg Oncol 2011;37:669–74.

2716 Cancer Res; 80(13) July 1, 2020 CANCER RESEARCH

Downloaded from cancerres.aacrjournals.org on October 3, 2021. © 2020 American Association for Cancer Research. Published OnlineFirst March 19, 2020; DOI: 10.1158/0008-5472.CAN-18-2098

The Role of Matricellular Proteins in Cancer

244. Kok SH, Chang HH, Tsai JY, Hung HC, Lin CY, Chiang CP, et al. Expression of 257. Zukiel R, Nowak S, Wyszko E, Rolle K, Gawronska I, Barciszewska MZ, et al. Cyr61 (CCN1) in human oral squamous cell carcinoma: an independent Suppression of human brain tumor with interference RNA specific for tenascin- marker for poor prognosis. Head Neck 2010;32:1665–73. C. Cancer Biol Ther 2006;5:1002–7. 245. Davies SR, Watkins G, Mansel RE, Jiang WG. Differential expression and 258. Wyszko E, Rolle K, Nowak S, Zukiel R, Nowak M, Piestrzeniewicz R, et al. A prognostic implications of the CCN family members WISP-1, WISP-2, and multivariate analysis of patients with brain tumors treated with ATN-RNA. WISP-3 in human breast cancer. Ann Surg Oncol 2007;14:1909–18. Acta Pol Pharm 2008;65:677–84. 246. Qi J, Esfahani DR, Huang T, Ozark P, Bartom E, Hashizume R, et al. 259. Zalutsky MR, Reardon DA, Akabani G, Coleman RE, Friedman AH, Friedman Tenascin-C expression contributes to pediatric brainstem glioma tumor HS, et al. Clinical experience with alpha-particle emitting 211At: treatment of phenotype and represents a novel biomarker of disease. Acta Neuropathol recurrent brain tumor patients with 211At-labeled chimeric antitenascin Commun 2019;7:75. monoclonal antibody 81C6. J Nucl Med 2008;49:30–8. 247. Guan Z, Zeng J, Wang Z, Xie H, Lv C, Ma Z, et al. Urine tenascinC is an 260. Rizzieri DA, Akabani G, Zalutsky MR, Coleman RE, Metzler SD, Bowsher JE, independent risk factor for bladder cancer patients. Mol Med Rep 2014;9: et al. Phase 1 trial study of 131I-labeled chimeric 81C6 monoclonal antibody 961–6. for the treatment of patients with non-Hodgkin lymphoma. Blood 2004;104: 248. Balasenthil S, Chen N, Lott ST, Chen J, Carter J, Grizzle WE, et al. A migration 642–8. signature and plasma biomarker panel for pancreatic adenocarcinoma. 261. Kuschel C, Steuer H, Maurer AN, Kanzok B, Stoop R, Angres B. Cell adhesion Cancer Prev Res 2011;4:137–49. profiling using extracellular matrix protein microarrays. BioTechniques 2006; 249. Yang T, Deng Z, Pan Z, Qian Y, Yao W, Wang J. Prognostic value of periostin in 40:523–31. multiple solid cancers: a systematic review with meta-analysis. J Cell Physiol 262. Kleinman HK, Martin GR. Matrigel: basement membrane matrix with bio- 2020;235:2800–8. logical activity. Semin Cancer Biol 2005;15:378–86. 250. Shojaei F, Scott N, Kang X, Lappin PB, Fitzgerald AA, Karlicek S, et al. 263. Rosso F, Marino G, Giordano A, Barbarisi M, Parmeggiani D, Barbarisi A. Osteopontin induces growth of metastatic tumors in a preclinical model of Smart materials as scaffolds for . J Cell Physiol 2005;203: non-small lung cancer. J Exp Clin Cancer Res 2012;31:26. 465–70. 251. Ohara Y, Chew SH, Misawa N, Wang S, Somiya D, Nakamura K, et al. 264. Madhusoodanan J. Matrix mimics shape cell studies. Nature 2019;566: Connective tissue growth factor-specific monoclonal antibody inhibits growth 563–5. of malignant mesothelioma in an orthotopic mouse model. Oncotarget 2018;9: 265. Conboy CB, Velez-Reyes GL, Tschida BR, Hu H, Kaufmann G, Koes N, et al. R- 18494–509. spondin 2 drives liver tumor development in a yes-associated protein- 252. Moran-Jones K, Gloss BS, Murali R, Chang DK, Colvin EK, Jones MD, et al. dependent manner. Hepatol Commun 2019;3:1496–509. Connective tissue growth factor as a novel therapeutic target in high grade 266. Liu Q, Zhao Y, Xing H, Li L, Li R, Dai J, et al. The role of R-spondin 1 through serous ovarian cancer. Oncotarget 2015;6:44551–62. activating Wnt/b-catenin in the growth, survival and migration of ovarian 253. Neesse A, Frese KK, Bapiro TE, Nakagawa T, Sternlicht MD, Seeley TW, et al. cancer cells. Gene 2019;689:124–30. CTGF antagonism with mAb FG-3019 enhances chemotherapy response 267. Liu S, U KP, Zhang J, Tsang LL, Huang J, Tu SP, et al. R-spodin2 enhances without increasing drug delivery in murine ductal pancreas cancer. canonical Wnt signaling to maintain the stemness of glioblastoma cells. Proc Natl Acad Sci U S A 2013;110:12325–30. Cancer Cell Int 2018;18:156. 254. Makino Y, Hikita H, Kodama T, Shigekawa M, Yamada R, Sakamori R, et al. 268. Paulitti A, Andreuzzi E, Bizzotto D, Pellicani R, Tarticchio G, Marastoni S, et al. CTGF mediates tumor-stroma interactions between hepatoma cells and hepatic The ablation of the matricellular protein EMILIN2 causes defective vascular- stellate cells to accelerate HCC progression. Cancer Res 2018;78:4902–14. ization due to impaired EGFR-dependent IL-8 production affecting tumor 255. Dornhofer N, Spong S, Bennewith K, Salim A, Klaus S, Kambham N, et al. growth. Oncogene 2018;37:3399–414. Connective tissue growth factor-specific monoclonal antibody therapy inhibits 269. Capuano A, Pivetta E, Sartori G, Bosisio G, Favero A, Cover E, et al. Abrogation pancreatic tumor growth and metastasis. Cancer Res 2006;66:5816–27. of EMILIN1-b1 integrin interaction promotes experimental colitis and colon 256. Aikawa T, Gunn J, Spong SM, Klaus SJ, Korc M. Connective tissue growth carcinogenesis. Matrix Biol 2019;83:97–115. factor-specific antibody attenuates tumor growth, metastasis, and angiogenesis 270. Danussi C, Petrucco A, Wassermann B, Modica TM, Pivetta E, Del Bel Belluz L, in an orthotopic mouse model of pancreatic cancer. Mol Cancer Ther 2006;5: et al. An EMILIN1-negative microenvironment promotes tumor cell prolifer- 1108–16. ation and invasion. Cancer Prev Res 2012;5:1131–43.

AACRJournals.org Cancer Res; 80(13) July 1, 2020 2717

Downloaded from cancerres.aacrjournals.org on October 3, 2021. © 2020 American Association for Cancer Research. Published OnlineFirst March 19, 2020; DOI: 10.1158/0008-5472.CAN-18-2098

The Matrix Revolution: Matricellular Proteins and Restructuring of the Cancer Microenvironment

Casimiro Gerarduzzi, Ursula Hartmann, Andrew Leask, et al.

Cancer Res 2020;80:2705-2717. Published OnlineFirst March 19, 2020.

Updated version Access the most recent version of this article at: doi:10.1158/0008-5472.CAN-18-2098

Cited articles This article cites 261 articles, 62 of which you can access for free at: http://cancerres.aacrjournals.org/content/80/13/2705.full#ref-list-1

Citing articles This article has been cited by 2 HighWire-hosted articles. Access the articles at: http://cancerres.aacrjournals.org/content/80/13/2705.full#related-urls

E-mail alerts Sign up to receive free email-alerts related to this article or journal.

Reprints and To order reprints of this article or to subscribe to the journal, contact the AACR Publications Department at Subscriptions [email protected].

Permissions To request permission to re-use all or part of this article, use this link http://cancerres.aacrjournals.org/content/80/13/2705. Click on "Request Permissions" which will take you to the Copyright Clearance Center's (CCC) Rightslink site.

Downloaded from cancerres.aacrjournals.org on October 3, 2021. © 2020 American Association for Cancer Research.

Top View