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Biological Characteristics of CCN Proteins in Tumor Development Stephany C CCN proteins in tumor development JBUON 2016; 21(6): 1359-1367 ISSN: 1107-0625, online ISSN: 2241-6293 • www.jbuon.com E-mail: [email protected] REVIEW ARTICLE Biological characteristics of CCN proteins in tumor development Stephany C. Barreto, Amitabha Ray, Page AG. Edgar Saint James School of Medicine, Anguilla, British West Indies Summary The extracellular matrix (ECM) is no longer regarded as teins are capable of modulating a variety of biological pro- inert, rather it has multiple versatile physiologic functions. cesses in health as well as in disease conditions. In tumor Its diverse composition is implicated in each step of cancer development and in tumor microenvironment, CCN proteins progression including inflammation, angiogenesis, tumor can influence multiple facets of pathophysiological process- invasion and metastasis. In addition to structural proteins, es including cellular proliferation, invasion and metastasis. the ECM also contains a family of non-structural proteins This review has attempted a cohesive look at the CCN family called matricellular proteins. The six secreted CCN proteins, protein functions in a tumor-specific manner. which belong to the matricellular protein family, include the following: Cyr61 (CCN1), CTGF (CCN2), Nov (CCN3), WISP- Key words: cancer, CCN proteins, cell signaling, extracel- 1 (CCN4), WISP-2 (CCN5) and WISP-3(CCN6). These pro- lular matrix, matricellular proteins Introduction The extracellular matrix (ECM) consists of or CCN1), connective tissue growth factor (CTGF diverse groups of proteins including matricellu- or CCN2), nephroblastoma overexpressed protein lar proteins, which are a family of non-structural (Nov or CCN3), Wnt-inducible secreted protein-1 matrix proteins capable of modulating a variety (WISP-1 or CCN4), WISP-2 (CCN5) and WISP- of biological processes. Members of this family 3 (CCN6). A growing body of evidence suggests include a large number of structurally unrelated that the CCN proteins are involved in different proteins such as thrombospondins, osteopontin, aspects of cancer development [2-5]. It has been and the CCN proteins. Overall, they play a high- shown that CCN proteins can modulate the sig- ly complex role in health and disease conditions nals of several proteins including integrins, Wnt, [1]. It is expected that these proteins are critical and transforming growth factor-β (TGF-β); many for the development of an appropriate tumor mi- of the functions of these proteins are also related croenvironment by establishing complex inter- to tumor growth [2,3]. actions/crosstalk among cancer cells and various Studies have revealed a link between CCN components of the surrounding stroma such as proteins and various cancer risk factors. One such different ECM constituents, inflammatory cells, important risk factor is chronic inflammation. Re- and numerous molecules of signaling pathways. cent reports documented that CCN proteins have The CCN (Cyr61-CTGF-Nov) family consists been strongly implicated in the inflammatory pro- of six members: cysteine-rich protein 61 (Cyr61 cess [6,7]. Expression of CCN has been shown to Correspondence to: Page Edgar, MD. Faculty of Basic Sciences, Saint James School of Medicine, Albert Lake Drive, The Quarter, AI 2640 Anguilla, British West Indies. Tel: +1 264 235 4166, Fax: +773 897 3393, E-mail: [email protected] Received: 01/06/2016 ; Accepted: 17/06/2016 CCN proteins in tumor development 1360 CCN proteins in tumor development be regulated by diverse inflammatory mediators [23-25]. The available data on melanoma suggests including TGF-β, prostaglandins, and extracellu- that Cyr61 can act as a tumor-suppressor gene; lar matrix enzymes [8]. It has been hypothesized Dobroff et al. [26] found that Cyr61 reduced tu- that the CCN family proteins may play a central mor growth and metastases, decreased angiogen- role in signaling the tumor microenvironment of esis and matrix metalloproteinase-2 (MMP-2) ex- hepatocellular carcinoma (HCC) [9]. In general, pression, as well as stimulated apoptosis in vivo. HCC takes place in inflammatory conditions that Cyr61 may also decrease the metastatic ability of could be associated, for example, with infection melanoma cells by altering vascular cell adhesion by hepatitis B virus (HBV) or hepatitis C virus molecule 1 (VCAM-1) activity [27]. (HCV). Other agents that have associated etiolog- Overexpressed Cyr61 has been associated ical roles in HCC are alcohol intake, obesity and with more invasive breast cancer phenotypes, cigarette smoking - all of which can generate a due to increased cell growth stimulated invasion chronic inflammatory environment [10]. Interest- and metastases, partly via up-regulated VEGF and ingly, CCN1 expression level was reported to be increased tumor vascularization in a VEGF-inde- correlated with smoking in non-small cell lung pendent manner [28-30]. Interestingly, Sarkissyan cancer (NSCLC) [11]. et al. [31] showed that IGF-1 can induce Cyr61 ex- Obesity-related inflammation has been linked pression, resulting in reduced E-cadherin expres- with a number of health problems such as cardio- sion in breast cancer. Zhang et al. [32] provided ev- vascular disorders, insulin resistance/type 2 dia- idence that 17β-estradiol exposure induced Cyr61 betes, and certain cancers. In different obesity-re- synthesis in MCF-7 breast cancer cells. Epidermal lated diseases, many components of matricellular growth factor (EGF) can also up-regulate Cyr61 in proteins including CCN have been shown to be MCF-7 cells, suggesting a synergistic regulation altered and influence the pathological processes. of Cyr61 in carcinogenesis [33]. In addition, Cyr61 For instance, CCN1 can cause endothelial cell dys- can induce estrogen-independence and anti-estro- function in atherosclerosis [12]; CCN2 may play gen resistance to bring about an aggressive breast an important role in diabetic pathology [13,14]; cancer phenotype [28]. In concordance, Lin et al. and all CCN proteins probably affect breast cancer [34] observed that over-expressed Cyr61 in MCF- development [2,15]. Intriguingly, reports show a 7 cells had a remarkable resistance to apoptosis close connection between different CCN proteins against chemotherapeutic agents. and tumor-associated biochemical risk factors, Abnormal expression of Cyr61 has been e.g., estrogenic influence [16], pro-inflammatory demonstrated to be associated with osteosarco- adipokines such as tumor necrosis factor alpha ma progression; Cyr61 can promote osteogene- (TNFα) and leptin [12,17], as well as enhanced ac- sis by increasing osteoblast differentiation and tivity of growth factors, for instance insulin-like impeding osteoclast formation [35]. Enticingly, growth factor-1 (IGF-1) and vascular endothelial Cyr61 levels correlated with a poor prognosis re- growth factor (VEGF) [5,16,18]. Obviously, high- gardless of metastasis [36]. In addition, Hou et al. er VEGF action promotes increased angiogenesis [35] showed that in osteosarcoma the abnormal and/or lymphangiogenesis, which is supportive expression of Cyr61 induced mesenchymal tran- for cell proliferation and tumor growth. In this re- sition and promoted lung metastases, via ανβ5 in- view article, an attempt has been made to focus tegrin, Raf-1, mitogen-activated protein kinase ki- on CCN proteins’ functions in the tumor microen- nase (MEK), extracellular signal-regulated kinase vironment. (ERK), and Elk-1 signal transduction pathways. They also demonstrated that the knockdown of CCN1: Cyr61 Cyr61 inhibited in vitro tumor cell invasion and migration, along with in vivo lung metastases. In certain cancers Cyr61 can induce tumori- genesis, cancer progression and/or invasion, such CCN2: CTGF as in gliomas, ovarian carcinoma, and prostate cancer [19-21]. In other cancers, including NSCLC, Increased levels of CTGF have been linked Cyr61 promoted apoptosis and impeded tumor with an advanced aggressive state of breast can- growth [22]. Astonishingly, elevated expressions cer, esophageal cancer, gastric cancer, osteosar- of Cyr61 have been found in colorectal cancer, coma, hepatocellular carcinoma and glioblasto- gastric cancer, and HCC; however its levels de- ma [37-42]. In a breast cancer cell line, Chien et clined when these cancers became more advanced al. [43] demonstrated that forced overexpression JBUON 2016; 21(6): 1360 CCN proteins in tumor development CCN proteins in tumor development 1361 Figure 1. General structure of CCN proteins. The general structure of the CCN proteins consists of the signal peptide (SP), insulin-like growth factor binding domain (IGFBP), von Willebrand factor type C domain (vWF-C), thrombospondin type-1 repeat (TSP-1), and a carboxy-terminal domain (CT) which contains a cysteine knot (not depicted). CCN5 (WISP-2) lacks CT domain. Listed above each domain, are some of the corresponding known binding partners. Underneath each domain are the corresponding known or suspected roles. Thought-provoking- ly, more than one domain can bind to the same protein, thus the interactions of the full-length protein may be needed to bring about certain functions. A hinge region exists, which is susceptible to cleavage by matrix metal- loproteases -1, -2, -3, -7, -9, -13, as well as by elastase and plasmin. IGFs: Insulin like growth factors, BMP: bone morphogenic protein, TGF: transforming growth factor, LRP-1: LDL receptor protein-1, GAGs: glycosaminogly- cans, VEGF: vascular endothelial growth factor, HSPGs: heparin sulphated proteoglycans, PDGF: platelet-derived growth factor, Rbp 7: Retinol
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