The Matrix Revolution: Matricellular Proteins and Restructuring of … · The Matrix Revolution: Matricellular Proteins and Restructuring of the Cancer Microenvironment A C Casimiro

CANCER RESEARCH | REVIEW

The Matrix Revolution: Matricellular Proteins andRestructuring of the Cancer Microenvironment A CCasimiro Gerarduzzi1,2, Ursula Hartmann3, Andrew Leask4, and Elliot Drobetsky1,2

ABSTRACT◥

The extracellular matrix (ECM) surrounding cells is indis-pensable for regulating their behavior. The dynamics of ECMsignaling are tightly controlled throughout growth and develop-ment. During tissue remodeling, matricellular proteins (MCP)are secreted into the ECM. These factors do not serve classicalstructural roles, but rather regulate matrix proteins and cell–matrix interactions to influence normal cellular functions. In thetumor microenvironment, it is becoming increasingly clear that

aberrantly expressed MCPs can support multiple hallmarks ofcarcinogenesis by interacting with various cellular componentsthat are coupled to an array of downstream signals. Moreover,MCPs also reorganize the biomechanical properties of the ECMto accommodate metastasis and tumor colonization. This real-ization is stimulating new research on MCPs as reliable andaccessible biomarkers in cancer, as well as effective and selectivetherapeutic targets.

IntroductionThe behavior of individual cells is influenced by a plethora of signals

originating from the surrounding microenvironment, which includesthe extracellular matrix (ECM). Previously regarded as merely a staticscaffold for cell/tissue organization, the ECM is now viewed as a criticalniche contributing to the regulation of cellular survival, proliferation,and migration. This realization has positioned the ECM at the centerstage of normal physiologic processes such as development, tissuehomeostasis, and tissue remodeling.

The dynamic nature of ECM signaling is determined by a secretedsubset of nonstructuralmatricellular proteins (MCP; ref. 1), in contrastto the structural roles of “classical” ECM proteins such as collagen andfibronectin (2). MCP functional versatility is achieved by its multipledomains that either (i) bind ECM proteins and/or cell surface recep-tors, (ii) bind and regulate the activity or accessibility of extracellularsignalingmolecules such as growth factors, proteases, chemokines, andcytokines, or (iii) mediate intrinsic enzymatic activities to preciselyorchestrate the assembly, degradation, and organization of the ECM.MCPs are tightly controlled, with expression promptly occurring incontext-specific scenarios. Typically, they are highly expressed duringearly development, ultimately subsiding in adult tissues under phys-iologic conditions. However, transient reexpression is observed duringinjury repair, and can also be sustained in chronic pathologies such ascancer (2–7). Indeed, chronic unscheduled expression of variousMCPs, either by tumor cells or the surrounding stromal cells (8),leads to abnormal ECM remodeling and stimulation of mitogenic

pathways essential for cancer progression. This may underlie thecorrelation between the upregulation of many MCPs and poorprognosis in cancer patients (9) and, moreover, provide rationalefor exploring the utility of MCPs as cancer biomarkers and ther-apeutic targets.

This review will focus on the burgeoning roles of the MCP familiesSPARC, CCN, SIBLING, tenascin, and Gla-containing proteins inboth cancer development, and detection and treatment. Certainly,members of these particular families are aberrantly expressed invarious tumor types, and moreover exhibit biochemical, biomechan-ical, and metastatic properties influencing cancer progression.

Normal Physiologic Roles of MCPsThe ever-growing number of newly discovered MCPs has neces-

sitated their classification into families. Members are grouped on thebasis of shared domains, which in turn reflect the functional diversitybetween families.

The SPARC protein (secreted protein acidic and rich in cysteine;hereafter alternative protein names are included in parentheses; BM40,osteonectin), one of the original MCPs to be characterized, is consid-ered prototypical due to its simple structure and rich functionality. Thesubsequent discovery of otherMCPswith structural similarity revealeda broader family of SPARC-related proteins (10). Such SPARC familymembers share follistatin-like and extracellular calcium-binding (EC)domains, and are classified into five distinct groups based on sequencehomology 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, influencecytokine activity, inhibit cell adhesion and cell-cycle progression,regulate cell differentiation, and activate matrix metalloproteinases(MMP; ref. 10). While most SPARC members exhibit ubiquitousexpression throughout early development, in adults, expression islargely limited to tissues that are diseased or undergoing woundrepair/remodeling.

The vertebrate CCN (centralized coordination network) family iscomposed of six homologous cysteine-rich members (11): CCN1(CYR61), CCN2 (CTGF), CCN3 (NOV), CCN4 (WISP-1), CCN5(WISP-2), and CCN6 (WISP-3). Each is comprised of an N-terminalsecretory peptide and four functional domains: insulin-like growthfactor-binding protein domain (IGFBP), Von Willebrand factortype C domain (VWC), thrombospondin type-1 repeat module (TSR),

1Centre de Recherche de l'Hôpital Maisonneuve-Rosemont, Montr�eal, Qu�ebec,Canada. 2D�epartement de M�edecine, Universit�e de Montr�eal, Montr�eal, Qu�ebec,Canada. 3Center for Biochemistry, Medical Faculty, University of Cologne,Cologne, Germany. 4College of Dentistry, University of Saskatchewan, Saska-toon, Saskatchewan, Canada.

C. Gerarduzzi is senior author of this article.

Corresponding Author: Casimiro Gerarduzzi, Centre de Recherche de l'HôpitalMaisonneuve-Rosemont, Universit�e de Montr�eal, 5415, boul. de l'Assomption,Montr�eal, Qu�ebec H1T 2M4, Canada. Phone: 514-252-3400, ext. 2813; Fax: 514-252-3430; E-mail: [email protected]

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and carboxy-terminal cysteine-knot (CT) motif (11). In response totissue remodeling, CCN proteins are expressed principally in mesen-chymal cells during development and in connective tissue patholo-gies (12). The postnatal role of CCN proteins is known for promotingcollagen stability or organization (13).

Tenascins (TN) comprise a family of four large ECM glyco-proteins, that is, TNC, -R, -W, and -X, which exist as either trimersor hexamers (14). Tenascins share a characteristic modular structurecomposed of tandem EGF-like domains, fibronectin-type III domains,and a C-terminal fibrinogen-related domain (FReD). Consequently,tenascins share functions in modulating cellular responses to theECM and growth factors, specifically regulating growth, differentia-tion, adhesion, and migration during tissue remodeling events (15).However, each member has distinct spatial and temporal expression.TNC expression is typically present in all organs during fetal devel-opment andmechanical stress, whereas TN-W expression is restrictedto developing/remodeling bone and certain stem cell niches (14).TN-R is expressed exclusively in the developing and adult nervoussystem, while TN-X represents a constitutive ECMcomponent ofmostconnective tissues, being hardly influenced by external factors (14).

The SIBLING (small integrin-binding ligand N-linked glycopro-tein) family includes bone sialoprotein (BSP), osteopontin (SPP1, alsoknown as OPN), dentin sialophosphoprotein (DSPP), matrix extra-cellular phosphoglycoprotein (MEPE), and dentin matrix protein-1(DMP1). These proteins are primarily implicated in bone morpho-genesis and biomineralization, and were thus thought to be exclusivelylocalized to mineralized tissue such as bone and teeth (16). However,apart from these traditional functions, SIBLING members were alsoshown to influence cellular proliferation/survival pathways, collagenfibrillogenesis, MMPs activities, and response to injury (17–20).

The Gla-protein family members contain vitamin K–dependentg-carboxyglutamic acid residues (21), which have high affinity forcalcium ions, thus conferring important roles in coagulation and bonehomeostasis (22). Among the 17 Gla-protein members, periostin(POSTN) and matrix Gla-protein (MGP) are known to affect ECMcross-linking and various cellular behaviors, such as migration, adhe-sion, and proliferation in epithelial, endothelial, fibroblast, osteoblast,and myocyte cells (23–27). POSTN is expressed in osteoblast, mesan-gial, fibroblast, mesenchymal, and vascular smooth muscle cells (22),while MGP is typically secreted and localized in the surrounding ECMof chondrocytes or endothelial cells (28).

Considering that MCP expression is context dependent, MCP-knockout mouse models generally lack any postnatal phenotypeunless challenged by injury or disease, in which case they exhibit animpaired yet subtle response [see references for further details: SPARCfamily (29–34); CCN family (11, 35); tenascin family (36–38);SIBLING family (39–42); and POSTN (43–45)]. However, some MCPmouse knockouts are characterized by severe complications. Forexample, FSTL1- and CCN2-null mice die shortly after birth, whileCCN1 and CCN5 whole-body knockouts are embryonic lethal, show-ing that these proteins are essential for development (11, 46, 47). Asfor MGP-knockout mice, they show severe vascular calcification,arteriovenous malformation, and craniofacial anomalies, and diewithin 8 weeks after birth (48–50).

Expression of MCPs in CancerMCP overexpression is characteristic of tissue remodeling process-

es, including those occurring during carcinogenesis, as opposed to low/undetectable levels in normal tissue. Tumor cells and the surroundingactivated stromal cells are the major cell types that aberrantly secrete

MCPs into the tumor microenvironment, in turn promotingcancer development (5, 51). Nonetheless, we note there are certaincases where MCP expression has been shown to oppose cancerdevelopment (51, 52).

SPARC protein is highly expressed in cancer cells and thestroma of certain cancers, including glioma, breast, and cervicalmelanoma (53–56), where it exhibits oncogenic roles in cell growth,invasion, and apoptosis. Interestingly, SPARC has also been associatedwith tumor suppression by influencing these same processes (57). Thisdiscrepancy might be explained by cancer type and stage, and/or theconcentration of SPARC in the tumor microenvironment (57). LikeSPARC, the role of FSTL1 in carcinogenesis has generated significantcontroversy. Endometrial and ovarian cancers exhibit low FSTL1levels; moreover, ectopic FSTL1 expression exerts antineoplastic activ-ity by inducing apoptosis (58). Among SPOCK isoforms (SPOCK1–3),SPOCK1 is upregulated in different tumor types, and its expressionpositively correlates with invasive/metastatic potential and hence poorprognosis (59–61). However, in brain tumors, expression of all SPOCKfamily members decreases with increasing tumor grade (62). SMOC2was shown to be upregulated in hepatocellular, endometrial, andcolorectal cancers where it modulated proliferation, chemoresistance,andmetastasis, respectively (63–65). Very little is known regarding anyrole for SMOC1 in carcinogenesis, although its expression is increasedin brain tumors, where it interacts with TNC to counteract the chemo-attractive effect of the latter on glioma cells in vitro (66).

Among the CCN family, CCN1 and CCN2 are the most studied incancer (11). Specifically, CCN1 expression is elevated in many tumortypes including brain, breast, prostate, and pancreas (67–70); similarly,CCN2 upregulation is implicated in proliferation, apoptosis, andmigration for numerous cancers (71), including gastric (72), pancre-atic (73), melanoma (74, 75), and breast (76). In addition to cancercells, a potential origin of these MCPs may be cancer-associatedfibroblasts (CAF; ref. 77), and indeed this cell type was shown to bethe source of CCN1/CCN2 expression in murine models of skincancer (78, 79). Although unscheduled expression of CCN1 andCCN2are generally associated with tumor promotion, in some cases theseproteins were reported to inhibit cancer development (80, 81). LikeCCN1/2, CCN3, and CCN4 exhibit a mixture of pro- versus anti-tumorigenic effects, whereas CCN5 and CCN6 are predominantlyregarded as tumor suppressors (11, 82).

Each tenascin family member differs substantially in spatial (tissuespecificity) and temporal expression patterns (14). In the case of TNCand TN-W, de novo expression is prominent in tumors versus healthytissue, where they promote tumor progression on multiple levels, thatis, proliferation, invasion, metastasis, and angiogenesis. TNC is recov-ered in the stroma of most solid cancers, while TN-W is primarilyrestricted to brain, colon, kidney, and lung cancers (14). In contrast,TN-R and TN-X are constitutively expressed and largely unaffected bytumorigenic signals, that is, to date have not been reported to play asubstantial role in carcinogenesis (14).

Among SIBLING proteins, SPP1 and BSP have been the mostextensively studied in the context of cancer (16). Consistent withtheir roles in osteogenesis, SPP1 and BSP have been implicatedin bone malignancy (16). However, while these proteins wereinitially thought to be expressed only during bone morphogenesis,both were subsequently shown to be broadly expressed in humanepithelial carcinomas, including but not limited to breast (83, 84),lung (85, 86), prostate (87), liver (88), pancreas (89), and colon (87, 90),where their pathophysiologic roles have recently been thoroughlyreviewed (16, 91). Furthermore, CAFs have been shown to produceand secrete SPP1, which contributes to melanoma tumor growth (92).

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POSTN, the most well-characterized Gla-protein family member,was shown to be a major determinant in proliferation for a number ofaggressive, advanced solid tumors with poor prognosis (22). MGP ismuch less understood than POSTN, but is gradually emerging as adeterminant in cancer progression, exhibiting increased expression incolorectal, glioblastoma, breast, cervical, osteosarcoma, and skin can-cers with unfavorable prognosis (93–97).

In general, MCPs are capable of regulating a variety of mechan-isms necessary for tumorigenesis, such as survival, proliferation,migration, matrix stiffness, and development of a signal reservoir

and metastatic microenvironment. These versatile functions dependon the diverse biochemical, biomechanical, and metastatic nicheeffects induced by MCPs (Fig. 1), as discussed in more detailimmediately below.

MCP Biochemical EffectsMuch evidence has shown that MCPs possess biochemical

properties essential for regulating various cellular behaviors, includingones implicated in tumor development. These properties mainly

POSTN

Myosin

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MMPMMP MMP

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Increased matrix organizationCollagen cross-linkingDeregulation of enzymes (i.e. LOX)

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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 thatabnormally secrete MCPs into the microenvironment to affect cellular behavior and ECM remodeling. A, Biochemical pathways. MCPs can activate an array of cellsurface receptors. Most MCPs can bind and signal through integrins, with a specific heterodimer signature accounting for signaling diversity (see text for details). Inaddition, it has been shown that CCN and TNC can bind and signal through syndecans, while osteopontin (SPP1)mediates its effects through CD44.B,Biomechanicalpathways. MCPs are able to increase the stiffness of the normal ECM tension by influencing matrix organization and collagen cross-linking, as well as deregulatingenzymatic activity. Stiffness is convertedby integrins into biochemical signals that can influence pathways inA. In addition,matrix stiffness can lead to thematurationof integrin and the actin cytoskeleton into focal adhesions and stress fibers, respectively. This occurs by activating the integrin–RhoA–ROCK–myosin axis, which isreviewed in detail elsewhere (158, 159). C, Metastatic niche. Various MCPs prepare cancer cells and the local and secondary tumor sites for metastasis throughnumerous steps. MCPs stimulate cancer cells into amotile phenotype through the EMTbut also to promote invadopodia formation at the invasion site. Formetastaticcells to exit the embedded state for intravasation, MCPs can break down the ECMbasementmembrane throughMMPs and guide cells out of their embedded state bycross-linking collagens intomigration tracks. At the secondary site, MCPs once again activateMMPs to remodel the ECM for colonization after invasion. At the distantsite, 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/).

The Role of Matricellular Proteins in Cancer

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pertain to the ability of MCPs to activate a number of cell surfacereceptors and elicit their downstream signaling (Fig. 1A). Most MCPsare well-known to directly bind integrins, which are ab heterodimerscomposed of 18 a subunits and 8 b subunits (98). Integrins arecommonly bound by members of the SPARC, CCN, SIBLING, tenas-cin, and Gla-protein families (99–101), each bound to varying hetero-dimer combinations. Other than integrins, members of CCN andtenascin families can also bind syndecans, while SPP1 is reported toalso bind CD44 receptors (99, 100). In addition, MCPs can actindirectly by binding a variety of ligands (i.e., growth factors and cyto-kines), thereby affecting ligand distribution and accessibility, and/orcoactivating or inhibiting their function (101).

SPARC has been reported to mediate a variety of signaling path-ways. For example, SPARC can bind directly to integrin receptors(avb1, avb3, and avb5), resulting in the activation of the proximalintracellular kinases Akt, focal adhesion kinase (FAK), and integrin-linked kinase (ILK; refs. 102–105). These kinases were associated withSPARC-mediated invasion and survival of glioma cells (105). SPARCmay also directly interact with the TGFb1 receptor to mediate Smadsignaling, as shown in lung cancer cells (106). Recently, SPARC wasreported to bind TGFb1 to regulate its deposition in the ECM (107). Inaddition, SPARC may bind other growth factors but with unknowneffects (108, 109). Interestingly, SPOCK1 was identified as a down-stream target of TGFb1 and a key player in lung cancer metastasis andproliferation (110), as well as in antiapoptosis via activation of thePI3K/Akt pathway (111, 112). SMOC2 acts to maintain ILK activityduring G1-phase, which in turn influences cell-cycle progression bymodulating cyclin D1 expression and DNA synthesis (113). Thispossibly involves ILK interaction with integrin b1 and b3 cytoplasmicdomains, which also leads to inhibition of anoikis and apoptosisthrough activation of PI3K/Akt signaling (114). Studies by Maier andcolleagues suggested that SMOC2 can bind directly to integrins aVb1and aVb6 (115), consistent with recent data showing that SMOC2binds integrin b1 to activate FAK in kidney fibroblasts (29).

CCNs act through multiple mechanisms to regulate a plethora ofdynamic cellular processes (11, 101, 116). In particular, these proteinsactivate ILK/Akt, MAPK, and associated growth-promoting pathwaysin cancer, with each CCN member exerting distinct effects andtemporal expression profiles. For example, CCN1 signals throughintegrin aVb3/Sonic hedgehog to promote motility in vitro andtumorigenic growth in vivo (117), as well as integrin a6b1-mediatedinvasion (118), in pancreatic cancer. In glioma, CCN1 overexpressionenhances tumorigenicity through integrin aVb3- and aVb1-linkedILK-mediated activation of Akt, b-catenin-TCF/Lef, and associatedsurvival and proliferation pathways (119). In breast cancer cells, CCN1can promote (i) resistance to anoikis, partly via integrin b1 (120), aswell as (ii) proliferation, survival, and apoptosis resistance through theavb3-activated ERK1/2 pathway (121). Similar to CCN1, ectopicexpression of CCN2 (i) promotes migration and angiogenesis (122),and (ii) confers apoptosis resistance through integrin avb3/ERK1/2upregulation of antiapoptotic Bcl-xL and cIAP (76) in breast cancercells. Although most CCNs act primarily through binding variousintegrin heterodimer combinations, they also bind several otherreceptors (11, 101, 123, 124), for example syndecan-4 and Notch inthe case of CCN1/2 and CCN3, respectively. Interestingly, CCNproteins may be activated by proteolytic cleavage (125, 126).

The opposing effects of CCN3 and CCN4 in different cancers raisethe question of which biochemical pathways are responsible for theirsignaling diversity. In colorectal cancer cells, CCN3 inhibits survival byregulating caspase-3/-8 while inhibiting JNK-mediated migra-tion (127). On the contrary, CCN3 promotes osteoclastogenesis

through the FAK/Akt/p38/NF-kB pathway (128). CCN4 also pro-motes FAKand p38 signaling throughavb1 integrin in prostate cancercells; however, this pathway specifically induces migration and vas-cular cell adhesion molecule-1 (VCAM-1) expression by downregu-lating miR-126 (129). Furthermore, osteoblast-derived CCN4 plays akey role in prostate cancer cell adhesion to bone through VCAM-1/integrin a4b1 (130). CCN4 also promotes lymphangiogenesis in oralsquamous cell carcinoma (SCC) via integrin avb3/Akt signaling andupregulation ofVEGFC expression, as well as promotes integrinavb3/FAK/JNK signaling to induce VEGFA activation of angiogenesis inosteosarcoma cells (131, 132). Conversely, CCN4 inhibits migration inmelanoma and lung cancer cells by inactivating the family of Rho-likeGTPases (133, 134).

TNC has been shown to stimulate proliferation and survival in avariety of cancers by activating several pathways downstream ofintegrins and syndecans (135), including integrin a9b1 activation ofAkt and MAPK (136) and avb3 activation of FAK and paxillin (137).However, a recent study showed that TNC signaling through integrina2b1, but nota9b1 oravb3, induced autocrine growth in brain tumorcells (138). Through an indirect mechanism of tumorigenesis, TNC isable to compete with syndecan-4 binding to fibronectin, therebyinterfere with fibronectin inhibition of proliferation (139). Instead,the FReD domain of TN-X was reported to convert latent TGFb1 intoits biologically active form to indirectly control mesenchymaldifferentiation (140).

POSTN is primarily known for binding integrins avb3 and avb5to elicit activation of FAK/JNK and PI3-K/Akt signaling pathwayscontrolling cell proliferation, survival, or migration in various cancers(141–143). POSTN may also signal through EGFR to influencemigration in esophageal SCC (144), potentially through cross-talkwith integrin avb5. Unlike POSTN, little is known regarding themechanism of MGP in cancer development, although the latter caninfluence the TGFb superfamily, including activation of TGFb1receptor and inhibition of the bone morphogenetic proteins BMP-2and BMP-4 (27, 145).

The SIBLING family members BSP and SPP1 exhibit similaractivities in cancer development. BSP supports adhesion, proliferation,and migration through avb3 and avb5, and the prometastatic activityof TGFb1 in breast cancer cells (146, 147). SPP1 can interact withseveral integrin receptors (avb1, 3, and 5, a8b1, a9b1 and 4, anda4b1) to regulate cell proliferation, angiogenesis, adhesion, andmigration (116, 148). SPP1 can also signal through CD44 (149) toactivate HIF2a-induced stemness in hepatocellular carcinoma andglioblastoma cells (150, 151), and Akt-mediated cell survival inmesothelioma and colorectal cancer cells (152, 153).

MCP Biomechanical EffectsRemodeling of the ECM is an integral process in cancer develop-

ment that accommodates the structural architecture of the tumor andprovides necessary physical changes such as increased matrix andtissue stiffness to promote and sustain neoplastic transformation (154).Mechanotransduction is a process in which perturbations in ECMmechanical stiffness are transduced into biochemical signals. ECMstiffness can communicate with cells through mechano-responsiveintegrins (98). In a normal setting, the ECM forms a structuralmicroenvironment of relaxed nonoriented fibrils that exertshomeostatic stiffness on embedded cells. In cancer, disruptionof this local ECM structure can occur through MCP-mediatedremodeling (5, 8, 155–157), which results in structures that are oftenstiffer, more highly linearized, and have a different orientation relative

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to normal stroma (7). In response to this, matrix bound integrinstructures convert these physical mechanical signals into conventionalintegrin biochemical signals to influence survival, proliferation, andgrowth (158). Moreover, integrin and their associated intracellularcytoskeleton mature into reinforced focal adhesions and stress fibers,respectively, to compensate for changes in ECM stiffness (Fig. 1B).Stress fibers are formed from the bundling of actin, and generate acounter-force, both of which are regulated by phosphoactivatingmyosin through the stiffness-induced integrin–RhoA–ROCKaxis (159). Some of the biomechanical processes regulated by MCPsthat affect ECM stiffness include increased matrix organization,collagen cross-linking, and deregulation of enzymatic activity.

SPARC is well-known to be implicated in rearranging the matrixthrough collagen cross-linking. SPARC binds to several fibrillarcollagens (I, II, III, and V) as well as to collagen IV, a prominentconstituent of basement membranes (160, 161), and is critical fororganization of collagenous ECMs. SPARC-knockout mice manifestsignificant changes in collagen fibril morphology, as well as a sub-stantial decrease in adult tissue concentrations of collagen (32).SPARC also influences the response of host tissue to implanted tumorcells and a lack of endogenous SPARC engenders decreased capacity toencapsulate the tumor, as well as a reduction in the deposition ofcollagen (162). SPARC exerts at least two roles in collagen fibrilassembly, that is, by modulating interactions of collagen with cellsurface receptors and directly regulating collagen incorporation intofibrils (163). Loss of SPARC also disrupts the homeostasis of basementmembranes and alters tissue biomechanics and physiologic func-tion (164). Finally, SPARC can act as an extracellular chaperone forcollagens that enhance the tumorigenic environment (164–166).

In a recent study, TNC significantly colocalized with alignedcollagen fibers in patients with breast cancer, compared with the wavyand randomly organized layout of collagen (167) typically observed innormal tissue (168). TNC contains multiple ECM-binding partners,including collagen; however, its involvement in collagen alignmentmay bemediated through binding tofibronectin, which serves to directcollagen organization (169–171). Similarly, POSTN plays a mecha-nistic role in intermatrix interactions through formation of a POSTN–BMP-1–LOX complex, where BMP-1 promotes LOX activity forcollagen cross-linking (172, 173). In fact, POSTN-knockout animalmodels exhibit aberrant collagen fibrillogenesis (174). Furthermore,the mechanotransduction pathways of both ROCK in SCC and thetranscription factor TWIST from variousmechanical stressmodels areknown to increase POSTN deposition (24, 175). The POSTN familymemberMGPwas recently shown to be incorporated into cross-linkedmultimers of fibronectin, which enhanced cancer cell attachment tofibronectin (23). As for the CCN family, recent studies have shownCCN1, CCN2, and CCN4 to promote alignment and stability ofcollagen fibers (13, 157, 176).

MCP Influence on the Metastatic NicheThe matrix environment needs to achieve a level of plasticity for

cellular displacement during metastasis. To disseminate, cancer cellsrequire a local ECM niche to support cellular differentiation andintravasation, and an ECM at the secondary metastatic site to permitinvasion and colonization (Fig. 1C). There are various ways in whichMCPs are able to establish a metastatic niche by influencing the ECMand its embedded cells. First, MCPs induce cancer cells to undergo anepithelial-to-mesenchymal transition (EMT), a genetic program thatpromotes metastatic dissemination of cancer cells from primaryepithelial tumors (177). Second, MCPs reorganize the ECM architec-

ture and integrity to promote cancer cell accessibility into intactstructures, that is, basement membrane (178). MCPs can also affectphysical properties of the ECM, including spatial arrangement, ori-entation, rigidity, permeability, and solubility, in such a way as to alteranchorage sites and create motility tracks suitable for metastasis (178).

Normally, epithelial cells maintain their polarity, intercellulartight junctions, and adherence to the basement membrane neces-sary for proper tissue architecture and function (179). DuringEMT, epithelial cells undergo reorganization of adhesion andcytoskeletal structures to acquire a mesenchymal morphology. Thisallows cells to detach, which, in conjunction with enhanced migra-tory capacity associated with the mesenchymal phenotype, stimu-lates metastasis (179).

SPARC family members promote EMT in a variety of cancers(Fig. 1C). Recently, SMOC2 was shown to participate in a prometa-static secretomemediated by the ARNTL2 transcription factor in lungadenocarcinoma (180), and SMOC2 induction is required for coloncancer invasion by stimulating EMT (65). Several studies also showthat SPOCK1 promotes EMT (110, 181). Among SPARC familymembers, SPARC is the most characterized for influencingEMT (106, 182, 183): (i) in lung cancer cell lines, TGFb1 activationofmigration and EMT is in part through SPARC (106), (ii) in head andneck cancer cells, SPARC enhances EMT signaling via activation ofAkt (182), and (iii) overexpression of SPARC in melanoma cellsincreases invasiveness mediated by phosphorylation of FAK and Snailrepression of E-cadherin promoter activity (184).

The CCN family exerts varying effects on EMT. An early studyusing pancreatic cancer cells reported that CCN1 promotes EMTand stemness, and that silencing this MCP forestalled aggressivetumor cell behavior by reversing the EMT phenotype (67). Recentstudies have continued to dissect CCN1 signaling leading to EMT. Inosteosarcoma, pharmacologic or gene knockdown of integrin avb5/Raf-1/MEK/ERK signaling components inhibited CCN1-inducedEMT (185), as well as CCN1-mediated expression of EMT markersand cell spreading through an IGF1Rb-JNK–dependent path-way (186). In contrast, CCN5 and CCN6 exert opposing effects onEMT. In triple-negative breast cancer cells, CCN5 activates the Bcl-2/Bax apoptotic pathway and inhibits both EMT and migration (187),while activation of the JAK/Akt/STAT pathway reverses such CCN5-mediated events (188). Similarly, CCN6 reversed the EMT features andinhibited metastasis of breast cancer cells in vivo, but through a Slugsignaling axis that regulates Notch1 activation (189). Another mech-anism involves CCN6-BMP-4 binding in breast cancer cells, whichreduces BMP-4 signaling through p38/TAK1 and subsequent down-stream activation of invasion and migration (190).

TNC and POSTN have also been associated withmetastasis (191–195). While the influence of TNC (196, 197) andPOSTN (198, 199) can be exerted through the EMT process, inter-estingly, these MCPs are also capable of remodeling the ECM to formmigratory tracks that support rapid dissemination of cancer cells(Fig. 1C). TNC is frequently observed to be expressed along theborder of matrix tracks in skin (200), pulmonary (201), colorec-tal (202), and breast (203) cancers. In fact, TNC assembles into matrixtracks with ECM molecules such as fibronectin, laminins, and severalcollagens (200, 204), which are also linked to metastatic poten-tial (200, 205, 206). Evidence reveals that these TNC matrix trackshave a functional purpose in metastasis. In coculture experiments,leading fibroblasts were able to create matrix tracks composed of TNCand fibronectin, which were left behind for the movement of SCCcells (207). For fibronectin and TNC to coassemble into such tracks,POSTN is responsible for incorporating TNC into the meshwork






architecture (208). While integrating TNC, it is possible that POSTNcould also serve as a scaffold for BMP-1, LOX-1, and collagen toaccelerate collagen cross-linking into migratory tracks during metas-tasis (172). Mechanistically, track mobility involves TNC competingfor syndecan-4 binding to fibronectin, which blocks integrin a5b1–mediated cell adhesion for detachment (139), followed by TNCpromotion of migration through integrin a9b1 following YAP inac-tivation (209). As previously discussed, TNC and POSTN can bindmultiple ECM proteins (i.e., fibronectin and various collagens) andenzymes (i.e., LOX) to serve as scaffolds of collagen cross-linkingneeded for cancer cell proliferation and survival. This is a similarprocess that comes into play when TNC and POSTN interact to buildECM scaffolds for migration tracks (24, 167, 204, 208, 210).

Finally, for metastatic cells to exit the embedded state for intra-vasation, and then return into the ECM for colonization after invasionat a distant site, a degree of matrix plasticity is required. Such ECMremodeling is achieved by the degradative activity of extracellularproteases (Fig. 1C), in particular MMPs. Like several other MCPs,SIBLINGs bind and activate MMPs to promote metastasis. SPP1binds CD44 to activate MMP-3 while BSP binds to integrin avb3 toactivate MMP-2 to increase invasiveness in various cancer celltypes (20, 211). Furthermore, SPP1 and BSP bind and activateMMP-3 and MMP-2, respectively (20). Early studies reported thatSPARC upregulates the expression and activity of MMP-2 and MMP-14 in glioma cells and MMP-2 in breast cancer cells (212, 213). Onthe other hand, the SPARC family member SPOCK2 was recentlyshown to inhibit the expression of MMP-2 and MMP14, and activa-tion of MMP-2 in endometrial cancer cells (214, 215). TNC may alsoinfluence the invasion of chondrosarcoma, colon cancer, and gliomacells by interacting with and upregulating MMP-1, -2/9, and -12,respectively (216, 217).

MCPs can also serve as a substrate for MMPs (218), that is, SPARCand SPP1 in the case ofMMP-2, -3, -7, -9, -12, and -14, andMMP-3, -7,-9, and -12, respectively. From the SPARC family, SPARCL1 andSPARC are cleaved by MMP-3 in gliomas (219) and cathepsin K inbone cancer (220), respectively, whose fragments could affect SPARCactivity. Recently,MMP-9 cleavage of SPARCwas reported to enhanceSPARC-collagen binding, preventing collagen degradation by MMPsin lung cancer (166). As for SPP1, thrombin and plasmin can cleave itsC-terminal, which increases adhesion of melanoma cells (221) andmigration of breast cancer cells (222), while cleavage of SPP1 byMMP-9 is essential for hepatocellular carcinoma invasion, which correlateswith metastatic potential (223).

Apart from targeting MMPs, the role of TNC in influencing theECM to promote invasion is multifaceted. In Ewing sarcoma, TNCexpression and Src activation cooperate to promote invadopodiaformation, an actin-rich protrusion of the plasmamembrane involvedin degradation of the ECM during cancer cell extravasation (224). Inorder for distant sites to accommodate disseminated tumor cells,MCPs are also required at the secondary target tissue to prime themetastatic niche for colonization. TNC has been shown to be involvedin metastatic colonization because loss of this MCP in breast cancer,melanoma, or metastatic niche stromal cells inhibited colonization inthe lungs (225–227). Gla-containing proteins have also been impli-cated in establishing a metastatic niche. Tumor-derived POSTN wasreported to form a microenvironmental niche supportive of breastcancer stem cells via the integrin avb3/ERK pathway (228). In variousmouse models, POSTN was responsible for metastatic colonization ofthe lung by breast and melanoma cells as evidenced by POSTN-neutralizing antibodies, antisense oligonucleotides, and knockoutmice, all independently inhibiting metastasis (229–231). Given their

significance for breast cancer cell dissemination to the lungs, it remainspossible that both POSTN and TNC are interdependent in promotingcolonization of the metastatic niche, because POSTN anchors TNC tothe ECM (208). MGP was also recently shown to influence themetastatic niche by promoting osteosarcoma adhesion, extravasation,and MMP activities in murine lung endothelium in vitro (94).

Future Clinical ApplicationsMCPs are generally expressed at low levels in adult tissues but highly

upregulated in various pathologies or injuries (4–6). This hasprompted researchers to elucidate the potential functions of differentMCPs in diseases such as cancer. As discussed throughout this review,numerous studies have shown that MCPs play critical roles in cancerdevelopment. In addition, the presence of certain MCPs in circulationas well as diseased tissue indicates their utility as noninvasive diag-nostic and prognostic cancer biomarkers. Furthermore, their extra-cellular location and involvement in cancer pathology indicate thatMCPs represent accessible and potentially effective therapeutic targets.In the following sections, we discuss various preclinical studies andclinical trials exploring the above possibilities.

MCPs as Cancer BiomarkersSPARC has been suggested as a prognostic biomarker for certain

cancers such as soft tissue sarcoma, esophageal SCC, and glioblastomabecause its expression correlates with poor survival (232–234). Inaddition, SPP1 may be prognostic for breast, lung, gastric, liver, andcolon cancers because it is associated with tumor progression anddecreased patient survival (235–238). Subsequently, a number ofongoing clinical trials have been established to validate their applica-tion. Recently, SPARC has been the subject of a clinical study probingits utility as a diagnostic marker for brain cancer [registered numberclinical trial (NCT) 01012609], given prior investigations correlatingincreased tumor vascular SPARC expression with decreased braincancer patient survival (239). Several groups have also reported thathigh plasma SPP1 concentrationsmight be predictive of poor outcomefor several cancers, including breast cancer (240). Consequently, oneclinical study is currently probing the relevance of SPP1 serum levelsfor diagnosis of breast cancer (NCT 02895178). Other MCP familiesawait successful clinical trials since the expression of several CCNfamily members in pancreatic, breast, oral, esophageal, and braincancers (241–245), TNC in colorectal, glioma, pancreatic, and bladdercancers (196, 246–248), and POSTN in various solid cancers (249)have all been touted as potential diagnostic and prognostic biomarkers.

MCPs as Therapeutic TargetsTargeting MCPs for therapeutic purposes has received relatively

little attention, primarily because of limited data concerning mechan-isms of action. The fact thatMCPs are located in the extracellular spaceduring cancer development renders them attractive as accessibletargets for drug delivery; moreover, their context-specific expressionimplies that targeting these proteins would result in minimum pleio-tropic side-effects. Neutralizing antibodies against MCPs have shownsuccess in various preclinical settings; however, translation to the clinichas been difficult. One group showed that an SPP1 mAb (AOM1)significantly inhibited tumor growth and metastasis in a mouse modelof non–small lung cancer (250). In addition, a commonly used mAbfor antagonizing CCN2 (FG-3019) has reportedly been used in pre-clinical models with success in both monotherapy and combination

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therapy for different tumor types, including pancreatic andmelanoma (251–256). With such progress, neutralizing antibodiestargeting MCPs have advanced to registered clinical trials. For exam-ple, FG-3019 is currently in phase III for CCN2-targeted treatment ofpancreatic cancer (LAPIS, NCT03941093).

Alternatively, MCPs could be targeted by inhibiting gene expres-sion in patients. In fact, one of the first studies using RNAi to treatcancer with promising results involved targeting TNC in 11patients with glioma (257). This was followed up with an inves-tigation of a larger cohort of 46 patients, which reported significantimprovement in overall survival (258). Other promising MCPtargets for posttranscriptional gene silencing include SPP1,POSTN, CCN1, and CCN2, where inhibition of RNA expressionwas shown to reduce cancer progression in various animal mod-els (68, 73, 229, 235). Another therapeutic approach involvesexploiting the high expression of MCP within the tumor environ-ment as a strategy to deliver therapeutic molecules. Using a highaffinity antibody to deliver radiotherapy (mAb 81C6), TNC wastargeted for treatment of glioma and lymphoma (259, 260), show-ing safe and promising antitumor benefit.

Conclusion and Future PerspectiveUpon perturbation of tissue homeostasis during multistage carci-

nogenesis, MCPs are upregulated in the tumor microenvironment tobecome key mediators of cell–ECM communication that in turnpromotes cellular proliferation, survival, and metastasis. The func-tional diversity of MCPs stems from their ability to interact with avariety of extracellular signaling molecules such as ECM componentsand growth factors. Moreover, as emphasized in this review, manyMCPs have been implicated in cancer development, and thus maycertainly exert additive and/or antagonistic effects in this process. Ourcurrent understanding of MCP pathways gives an impression ofredundancy, and so a primary aim in the ECM field is to elucidatethe precise manner in which MCPs mechanistically converge, bothfunctionally and temporally, to remodel the tumor microenvironmentand orchestrate critical neoplastic processes.

This overarching goal highlights a major challenge, that of devel-oping experimental systems that better model the physical state ofthe native interstitial ECM. The usefulness of various existing models,including 2D monolayers (261), 3D Matrigel (262), and tissue-extracted ECM (263), is limited because these models fall well shortof fully recapitulating the complexities of tissue ECM in vivo. Thisinadequacy may underlie some of the discrepancies in the literatureregarding MCP functionality in cancer. Furthermore, the identifica-tion of naturally occurring protein–protein interactions and post-translational modifications among MCPs in the ECM have beendifficult to characterize. Overall, as concisely reviewed elsewhere (264),

new approaches are clearly needed to dissect the daunting complexityof the ECM environment and its role in carcinogenesis.

While confronting the above challenges it remains important toconcomitantly work toward characterizing particular MCPs, aloneor in combination, as impactful diagnostic/prognostic cancer bio-markers and therapeutic targets. In fact, given their burgeoningroles in cancer development and extracellular accessibility, MCPshave long been regarded as potentially useful for diagnosing andtreating various pathologies such as fibrosis and cancer; nonethelessclinical data supporting this notion have been relatively scant.Toward addressing this knowledge gap, over the past decade,progress has been made in defining better the fundamental mechan-isms of MCPs, opening new questions that entice the generation ofthe next needed tools to understand sufficient detail for optimaltherapeutic design.

Herein we have summarized some important ways in which mis-regulation of MCP expression promotes cancer development, includ-ing perturbation of intracellular signaling and aberrant coordination ofECM remodeling. Although we focused on MCP families with themost well-characterized roles, others are emerging as potentiallyimportant players, such as the EMILIN and R-Spondin families.Recently, R-Spondin-1 and 2 were shown to promote liver, glioblas-toma, and ovarian cancer through their well-defined influence onWnt/b-catenin signaling (265–267). In addition, EMILIN2 promotesthe formation of tumor-associated vessels in melanoma (268), andEMILIN1 exerts an oncosuppressive role in colon and skin (269, 270).Clearly, there is still much to be discovered regarding the exquisitespatiotemporal regulation of MCP expression patterns and functionsin the extracellular space during cancer tissue remodeling, similar tothe approach taken in fibrosis (17). In this respect, as more and moreknowledge accumulates, it should be possible to design appropriateclinical studies that could firmly establish MCPs as useful biomarkersand therapeutic targets in cancer.

Disclosure of Potential Conflicts of InterestA. Leask has ownership interest in Fibrogen. No potential conflicts of interest were

disclosed by the other authors.

AcknowledgmentsThis work was supported by the Operating Grant Funding Program 24347 (co-

funded by Cancer Research Society and the Kidney Cancer Research Network ofCanada) and start-up funds fromHôpitalMaisonneuve-Rosemont Foundation (all toC. Gerarduzzi). C. Gerarduzzi is a recipient of the Kidney Research Scientist CoreEducation and National Training (KRESCENT) Program New Investigator AwardKRES180003 (co-funded by the Kidney Foundation of Canada, Canadian Society ofNephrology, and Canadian Institutes of Health Research) and the Cole FoundationEarly Career Transition Award.

Received July 10, 2018; revised December 4, 2019; accepted March 17, 2020;published first March 19, 2020.

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