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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 Matrix Revolution: Matricellular Proteins and Restructuring of the Cancer Microenvironment A C Casimiro Gerarduzzi1,2, Ursula Hartmann3, Andrew Leask4, and Elliot Drobetsky1,2 ABSTRACT ◥ The extracellular matrix (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 tissue 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 metastasis and tumor colonization. This real- structural roles, but rather regulate matrix proteins and cell– 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 tumor microenvironment, 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, tenascin, 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 tissue remodeling. various tumor types, and moreover exhibit biochemical, biomechan- The dynamic nature 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 collagen 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, proteases, 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 protein (secreted protein acidic and rich in cysteine; 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 osteonectin), 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 structure 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 calcium-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 cell adhesion and cell-cycle progression, Canada. 2Departement de Medecine, Universite de Montreal, Montreal, Quebec, regulate cell differentiation, and activate matrix metalloproteinases Canada. 3Center for Biochemistry, 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 wound repair/remodeling. ^ Corresponding Author: Casimiro Gerarduzzi, Centre de Recherche de l'Hopital The vertebrate 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 peptide and four functional domains: insulin-like growth doi: 10.1158/0008-5472.CAN-18-2098 factor-binding protein domain (IGFBP), Von Willebrand factor Ó2020 American Association for Cancer Research. type C domain (VWC), thrombospondin 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 connective tissue 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 Tenascins (TN) comprise a family of four large ECM glyco- stroma of certain cancers, including glioma, breast, 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 invasion, and apoptosis. 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 bone and certain stem cell 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 integrin-binding ligand N-linked glycopro- colorectal cancers where it modulated proliferation, chemoresistance, tein) family includes bone sialoprotein (BSP), osteopontin (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-
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