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Review Research Published OnlineFirst September 16, 2013; DOI: 10.1158/1541-7786.MCR-12-0662 Molecular Cancer Review Research Collagen XV: Exploring Its Structure and Role within the Tumor Microenvironment Anthony George Clementz1,2 and Ann Harris1,2,3 Abstract The extracellular matrix (ECM) is a critical component of stroma-to-cell interactions that subsequently activate intracellular signaling cascades, many of which are associated with tumor invasion and metastasis. The ECM contains a wide range of proteins with multiple functions, including cytokines, cleaved cell-surface receptors, secreted epithelial cell proteins, and structural scaffolding. Fibrillar collagens, abundant in the normal ECM, surround cellular structures and provide structural integrity. However during the initial stages of invasive cancers, the ECM is among the first compartments to be compromised. Also present in the normal ECM is the nonfibrillar collagen XV, which is seen in the basement membrane zone but is lost prior to tumor metastasis in several organs. In contrast, the tumor microenvironment often exhibits increased synthesis of fibrillar collagen I and collagen IV, which are associated with fibrosis. The unique localization of collagen XV and its disappearance prior to tumor invasion suggests a fundamental role in maintaining basement membrane integrity and preventing the migration of tumor cells across this barrier. This review examines the structure of collagen XV, its functional domains, and its involvement in cell-surface receptor–mediated signaling pathways, thus providing further insight into its critical role in the suppression of malignancy. Mol Cancer Res; 11(12); 1481–6. Ó2013 AACR. Introduction fibril bundles, whereas nonfibrillar collagens generate dif- fi Collagen XV was first isolated from a human placental ferent structures. Collagen XV is a non brillar collagen and has multiple interruptions within its collagenous domain, cDNA library in a clone that encoded a different sequence fl and structure from collagen I to XIV types, which were enabling more structural exibility (4, 5). Collagen XV and identified previously. The gene encoding human collagen collagen XVIII (multiplexins) show some N- and C-terminal XV (COL15A1) is located on chromosome 9q21 (1). The sequence homology. Collagen XV is a secreted 1,388 amino gene spans 145 kilobases of genomic DNA and contains 42 acid residue protein that exists as 250 or 225 kDa polypep- exons (2). The corresponding homologous mouse collagen tides, which differ in their C-terminal domain (6, 7). The XV gene is found on chromosome 4. collagen XV protein has four main functional parts: a The hypothesis that collagen XV might be a tumor putative signaling peptide, a N-terminal noncollagenous suppressor was first proposed in 2003 (3), on the basis of domain, an interrupted collagenous domain, and a C-ter- cytogenetic analysis of tumorigenic segregants of somatic cell minal noncollagenous domain (Fig. 1). hybrids in which malignancy was suppressed. Reversion of Collagen XV: structural considerations malignancy was accompanied by consistent loss of a small Putative signaling peptide. The N-terminal region of region of mouse chromosome 4 and disappearance of a collagen XV begins with a series of hydrophobic amino acids collagenous extracellular matrix (ECM). The chromosome with homology to the signal peptides of other secreted ECM 4 fragment was subsequently shown to encompass the mouse Col15a1 proteoglycans (8). These 25 amino acids within collagen XV gene and to be syntenic with a region of human contain a leucine at position 23 and an alanine at position 25, chromosome 9. which indicate a signaling peptide (4, 9). Hence, although it Collagens are divided into two subfamilies on the basis of fi fi has not been experimentally veri ed, it is probable that the N- structural features: brillar collagens form classic collagen terminal 25–27 amino acid residues of collagen XV direct the polypeptide to secretory pathways that take it to the ECM. N-terminal noncollagenous domain. The N-terminal Authors' Affiliations: 1Human Molecular Genetics Program, Lurie Chil- noncollagenous domain consists of 530 amino acids and dren's Research Center, 2Department of Pediatrics, and 3Robert H Lurie Comprehensive Cancer Center, Northwestern University Feinberg School contains two cysteines at residues 179 and 235 (4). This of Medicine, Chicago, Illinois domain also contains eight sites for attachment of glycosa- Corresponding Author: Ann Harris, Human Molecular Genetics Program, minoglycans (GAG), long unbranched disaccharide chains Lurie Children's Research Center, 2430 North Halsted Street, Chicago, IL consisting of either N-acetylgalactosamine (GalNAc) or N- 60614. E-mail: [email protected] acetylglucosamine and glucuronic acid (GlcA; reviewed in doi: 10.1158/1541-7786.MCR-12-0662 ref. 10). Thus, collagen XV is a true proteoglycan. Native Ó2013 American Association for Cancer Research. collagen XV contains chrondroitin sulfate modifications on www.aacrjournals.org 1481 Downloaded from mcr.aacrjournals.org on September 28, 2021. © 2013 American Association for Cancer Research. Published OnlineFirst September 16, 2013; DOI: 10.1158/1541-7786.MCR-12-0662 Clementz and Harris GAG(s) 1 1,388 H2N RESTIN COOH c c c ccc c c 25 530 577 256 Putative N-Terminal Collagenous C-Terminal signaling non-collagenous domain non-collagenous peptide domain domain Figure 1. Schematic representation of the structure of collagen XV. Collagen XV is a secreted 1,388 amino acid protein with a putative signaling domain, N-terminal noncollagenous domain with glycosaminoglycan chains (GAGs), a central interrupted collagenous domain, and the C-terminal restin domain. Cysteine residues (C) are shown and those critical for intermolecular disulfide interactions marked (Ã). Modified from Amenta and colleagues, 2005 (25). its glycosaminoglycan chains, with differential sulfation known as an endostatin-related fragment or restin domain specifically on unbranched GalNAc and/or GlcA residues (4, 17, 18). Restin has 61% sequence homology with (7). These sites may interact with other components of the endostatin but the two peptides have divergent properties, ECM and with cell-surface receptors, cytokines, and growth as endostatin, unlike restin, has been implicated as an factors. These types of interactions are critical to stromal and antiangiogenic polypeptide fragment (17, 19). Moreover, cellular cross-talk within the tumor microenvironment (11). in experiments to test the hypothesis that collagen XV is a In comparison with other collagens, the N-terminal domain dose-dependent suppressor of tumorigenicity, the restin of collagen XV and collagen XVIII are similar, demonstrat- domain alone was shown not to be involved, whereas the ing 45% homology. This domain has extensive sequence N-terminal portion of the protein (without the C-terminal homology with thrombospondin, suggesting a role in medi- restin peptide) retained the function (14, 20). Specifically, ating cell-to-cell and cell-to-matrix interactions (4, 12). the ability of COLXV to enhance adherence of D98 AP2 Consistent with this prediction, overexpression of a collagen cells to a collagen I substrate and to suppress the growth of XV cDNA (COLXV) inhibits invasion of BxPC-3 pancre- tumors arising from the same cells in nude mice was not atic adenocarcinoma cells through a collagen I gel (13). dependent on the restin fragment (14). The C-terminal Moreover, removal of all the GAG residues from COLXV, domain contains four cysteine residues at positions C1237, by site-directed mutagenesis, partially restored the ability of C1339, C1369, and C1377 (21). Two intramolecular these cells to invade (Clementz and colleagues; unpublished disulfide bridges can form between C1237, C1369, and data). between C1339 and C1377, which are similar to the two Collagenous domain. The discontinuous collagenous disulfide bonds within endostatin (21, 22). However, domain encompasses 577 amino acids and contains nine despite some homology with the C-terminal peptide of collagenous domains with eight noncollagenous interruptions collagen XVIII, the restin domain seems to have different (4). This region contains two critical cysteine residues functional properties from endostatin. involved in intermolecular disulfide bonding. These cysteines are separated by 231 amino acids and are found in the Localization of collagen XV interruptions of the collagenous domain: one at the start of Collagen XV is expressed within the heart, in skeletal and a 31 amino acid interruption, and the other in the center of a smooth muscle tissue, and is abundant in the placenta. It is 34–amino acid interruption (7). Mutagenesis of just one of also found in kidney and in interstitial tissues in the pancreas the cysteine residues is sufficient to abolish the active con- where it is produced in part by fibroblasts within the ECM formation of COLXV as measured by its ability to enhance (23). Subsequently, collagen XV expression was also the adherence of D98 AP2 cervical cancer cells to a collagen I detected in testis, ovaries, small intestine, and colon (24). substrate (6, 14). The collagenous regions contain the classic Ultrastructural studies have shown collagen XV to be local- Gly-X-Y motif, where X and Y are commonly hydroxylated ized to the distal side of basement membrane zones (the prolyl and lysyl residues, forming a homotrimeric a-helical outermost lamina densa) in association with banded collagen chain (4). The discontinuity between the collagenous regions fibers in
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