Author Manuscript Published OnlineFirst on March 19, 2020; DOI: 10.1158/0008-5472.CAN-18-2098 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. 1 The Matrix Revolution: Matricellular Proteins and Restructuring of the 2 Cancer Microenvironment 3 4 Casimiro Gerarduzzi1,2,*,#, Ursula Hartmann3, Andrew Leask4 and Elliot Drobetsky1,2 5 6 7 1Centre de Recherche de l'Hôpital Maisonneuve-Rosemont, Montréal, Québec H1T 2M4, Canada 8 2Département de Médecine, Université de Montréal, Montréal, Québec H3T 1J4, Canada 9 3Center for Biochemistry, Medical Faculty, University of Cologne, Cologne, Germany 10 4College of Dentistry, University of Saskatchewan, 105 Wiggins Rd, Saskatoon SK S7N 5E4, Canada 11 12 13 *To whom correspondence should be addressed: Casimiro Gerarduzzi, PhD, Maisonneuve-Rosemont 14 Hospital Research Center, Division of Nephrology, 5415, boul. de l'Assomption, Montreal, Quebec, 15 Canada, H1T 2M4. Phone: (514) 252-3400 ext.2813, email: [email protected] 16 #Senior Author 17 18 19 Running title: The Role of Matricellular Proteins in Cancer 20 Keywords: Matricellular Proteins, Extracellular Matrix, Microenvironment, Cancer Progression, 21 Biomarkers/Therapeutics 22 Number of Figures: 1 23 Conflict of interest: The authors declare no potential conflicts of interest. 1 Downloaded from cancerres.aacrjournals.org on October 2, 2021. © 2020 American Association for Cancer Research. Author Manuscript Published OnlineFirst on March 19, 2020; DOI: 10.1158/0008-5472.CAN-18-2098 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. 24 25 Abstract 26 The extracellular matrix (ECM) surrounding cells is indispensable for regulating their 27 behavior. The dynamics of ECM signaling are tightly controlled throughout growth and 28 development. During tissue remodeling, matricellular proteins (MCPs) are secreted into the 29 ECM. These factors do not serve classical structural roles, but rather regulate matrix proteins 30 and cell-matrix interactions to influence normal cellular functions. In the tumor 31 microenvironment, it is becoming increasingly clear that aberrantly expressed MCPs can 32 support multiple hallmarks of carcinogenesis by interacting with various cellular components 33 that are coupled to an array of downstream signals. Moreover, MCPs also reorganize the 34 biomechanical properties of the ECM to accommodate metastasis and tumor colonization. This 35 realization is stimulating new research on MCPs as reliable and accessible biomarkers in cancer, 36 as well as effective and selective therapeutic targets. 37 2 Downloaded from cancerres.aacrjournals.org on October 2, 2021. © 2020 American Association for Cancer Research. Author Manuscript Published OnlineFirst on March 19, 2020; DOI: 10.1158/0008-5472.CAN-18-2098 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. 38 Introduction 39 The behavior of individual cells is influenced by a plethora of signals originating from the 40 surrounding microenvironment, which includes the extracellular matrix (ECM). Previously 41 regarded as merely a static scaffold for cell/tissue organization, the ECM is now viewed as a 42 critical niche contributing to the regulation of cellular survival, proliferation and migration. This 43 realization has positioned the ECM at the center stage of normal physiological processes such 44 as development, tissue homeostasis and tissue remodeling. 45 The dynamic nature of ECM signaling is determined by a secreted subset of non- 46 structural matricellular proteins (MCPs) (1), in contrast to the structural roles of “classical” ECM 47 proteins such as collagen and fibronectin (2). MCP functional versatility is achieved by its 48 multiple domains that either (i) bind ECM proteins and/or cell surface receptors, (ii) bind and 49 regulate the activity or accessibility of extracellular signaling molecules such as growth factors, 50 proteases, chemokines, and cytokines, or (iii) mediate intrinsic enzymatic activities to precisely 51 orchestrate the assembly, degradation, and organization of the ECM. MCPs are tightly 52 controlled, with expression promptly occurring in context-specific scenarios. Typically, they are 53 highly expressed during early development, ultimately subsiding in adult tissues under 54 physiological conditions. However, transient re-expression is observed during injury repair, and 55 can also be sustained in chronic pathologies such as cancer (2-7). Indeed, chronic unscheduled 56 expression of various MCPs, either by tumor cells or the surrounding stroma (8), leads to 57 abnormal ECM remodeling and stimulation of mitogenic pathways essential for cancer 58 progression. This may underlie the correlation between the upregulation of many MCPs and 3 Downloaded from cancerres.aacrjournals.org on October 2, 2021. © 2020 American Association for Cancer Research. Author Manuscript Published OnlineFirst on March 19, 2020; DOI: 10.1158/0008-5472.CAN-18-2098 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. 59 poor prognosis in cancer patients (9) and, moreover, provide rationale for exploring the utility 60 of MCPs as cancer biomarkers and therapeutic targets. 61 This review will focus on the burgeoning roles of the MCP families SPARC, CCN, SIBLING, 62 Tenascin and Gla-containing proteins in both cancer development, detection and treatment. 63 Certainly, members of these particular families are aberrantly expressed in various tumor types, 64 and moreover exhibit biochemical, biomechanical and metastatic properties influencing cancer 65 progression. 66 67 Normal physiological roles of MCPs 68 The ever-growing number of newly-discovered MCPs has necessitated their 69 classification into families. Members are grouped based on shared domains, which in turn 70 reflect the functional diversity between families. 71 The SPARC protein (Secreted Protein Acidic and Rich in Cysteine; hereafter alternative 72 protein names are included in parentheses; BM40, osteonectin), one of the original MCPs to be 73 characterized, is considered prototypical due to its simple structure and rich functionality. The 74 subsequent discovery of other MCPs with structural similarity revealed a broader family of 75 SPARC-related proteins (10). Such SPARC family members share follistatin-like and extracellular 76 calcium-binding (EC) domains, and are classified into five distinct groups based on sequence 77 homology of their EC domains (10): SPARCs, SPARCL1, SMOCs, SPOCKs and Follistatin-like 78 protein-1 (FSTL1). SPARC family members were shown to regulate ECM assembly and 79 deposition, influence cytokine activity, inhibit cell adhesion and cell cycle progression, regulate 80 cell differentiation and activate matrix metalloproteinases (10). While most SPARC members 4 Downloaded from cancerres.aacrjournals.org on October 2, 2021. © 2020 American Association for Cancer Research. Author Manuscript Published OnlineFirst on March 19, 2020; DOI: 10.1158/0008-5472.CAN-18-2098 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. 81 exhibit ubiquitous expression throughout early development, in adults, expression is largely 82 limited to tissues that are diseased or undergoing wound repair/remodeling. 83 The vertebrate CCN (Centralized Coordination Network) family is composed of six 84 homologous cysteine-rich members (11): CCN1 (CYR61), CCN2 (CTGF), CCN3 (NOV), CCN4 85 (WISP-1), CCN5 (WISP-2) and CCN6 (WISP-3). Each is comprised of an N-terminal secretory 86 peptide and four functional domains: insulin-like growth factor-binding protein domain (IGFBP), 87 Von Willebrand factor domain (VWR), thrombospondin type-1 repeat module (TSR) and 88 carboxy-terminal cysteine-knot (CT) motif (11). In response to tissue remodeling, CCN proteins 89 are expressed, principally in mesenchymal cells, during development and in connective tissue 90 pathologies (12). The postnatal role of CCN proteins is known for promoting collagen stability or 91 organization (13). 92 Tenascins (TNs) comprise a family of four large extracellular matrix glycoproteins, i.e., 93 TN-C, -R, -W and -X, which exist as either trimers or hexamers (14). TNs share a characteristic 94 modular structure composed of tandem epidermal growth factor (EGF)-like domains, 95 fibronectin-type III domains and a C-terminal fibrinogen related domain (FReD). Consequently, 96 TNs share functions in modulating cellular responses to the ECM and growth factors, specifically 97 regulating growth, differentiation, adhesion and migration during tissue remodeling events 98 (15). However, each member has distinct spatial and temporal expression. TN-C expression is 99 typically present in all organs during fetal development and mechanical stress, whereas TN-W 100 expression is restricted to developing/remodeling bone and certain stem cell niches (14). TN-R 101 is expressed exclusively in the developing and adult nervous system, while TN-X represents a 5 Downloaded from cancerres.aacrjournals.org on October 2, 2021. © 2020 American Association for Cancer Research. Author Manuscript Published OnlineFirst on March 19, 2020; DOI: 10.1158/0008-5472.CAN-18-2098 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. 102 constitutive ECM component of most connective tissues, being hardly influenced by external 103 factors (14). 104 The SIBLING (Small Integrin-Binding