A structural approach to the role of CCN (CYR61/CTGF/NOV) proteins in tumourigenesis

Cancer Cell International

Bernard Perbal¹  Nathalie Planque¹ 

[1] Laboratoire d'Oncologie Virale et Moléculaire, UFR de Biochimie, Université Paris 7 – D. Diderot, 2 Place Jussieu- 75 005 PARIS – France

关键词: cancer;    growth control;    development;    tumourigenesis;    differentiation;    NOVH;    CTGF;    CYR61;    CCN1-6;   

Others  :  796068
DOI  :  10.1186/1475-2867-3-15

 received in 2003-05-12, accepted in 2003-08-22,  发布年份 2003

【 摘 要 】

The CCN (CYR61 [Cystein-rich61]/CTGF [connective tissue growth factor]/NOV [Nephroblastoma overexpressed]) proteins constitute a family of regulatory factors involved in many aspects of cell proliferation and differentiation. An increasing body of evidence indicates that abnormal expression of the CCN proteins is associated to tumourgenesis. The multimodular architecture of the CCN proteins, and the production of truncated isoforms in tumours, raise interesting questions regarding the participation of each individual module to the various biological properties of these proteins. In this article, we review the current data regarding the involvement of CCN proteins in tumourigenesis. We also attempt to provide structural basis for the stimulatory and inhibitory functions of the full length and truncated CCN proteins that are expressed in various tumour tissues.

【 授权许可】

   
2003 Planque and Perbal; licensee BioMed Central Ltd. This is an Open Access article: verbatim copying and redistribution of this article are permitted in all media for any purpose, provided this notice is preserved along with the article's original URL.

【 图 表 】

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【 参考文献 】

• [1]Bork P: The modular architecture of a new family of growth regulators related to connective tissue growth factor. FEBS Lett 1993, 327:125-130.
• [2]Brigstock DR: The connective tissue growth factor/cysteine-rich 61/nephroblastoma overexpressed (CCN) family. Endocr Rev 1999, 20:189-206.
• [3]Lau LF, Lam SC: The CCN family of angiogenic regulators: the integrin connection. Exp Cell Res 1999, 248:44-57.
• [4]Perbal B: NOV (nephroblastoma overexpressed) and the CCN family of genes: structural and functional issues. Mol Pathol 2001, 54:57-79.
• [5]Joliot V, Martinerie C, Dambrine G, Plassiart G, Brisac M, Crochet J, Perbal B: Proviral rearrangements and overexpression of a new cellular gene (nov) in myeloblastosis-associated virus type 1-induced nephroblastomas. Mol Cell Biol 1992, 12:10-21.
• [6]Brigstock DR, Steffen CL, Kim GY, Vegunta RK, Diehl JR, Harding PA: Purification and characterization of novel heparin-binding growth factors in uterine secretory fluids. Identification as heparin-regulated Mr 10,000 forms of connective tissue growth factor. J Biol Chem 1997, 272:20275-20282.
• [7]Su BY, Cai WQ, Zhang CG, Martinez V, Lombet A, Perbal B: The expression of ccn3 (nov) RNA and protein in the rat central nervous system is developmentally regulated. Mol Pathol 2001, 54:184-191.
• [8]Planque N, Perbal B: The CCN proteins: a new family of cell growth regulators. In In Recent Research Developments in Human Pathology. Edited by Pandalai SG. Research Signpost; in press.
• [9]Perbal B, Brigstock DR, Lau L: Report of the second international workshop on the CCN family of genes. Mol Pathol 2003, 56:80-85.
• [10]Babic A, Kireeva M, Kolesnikova T, Lau L: CYR61, a product of a growth factor-inducible immediate early gene, promotes angiogenesis and tumour growth. Proc Natl Acad Sci 1998, 95:6355-6360.
• [11]Xie D, Nakachi K, Wang H, Elashoff R, Koeffler HP: Elevated levels of ccn1, ccn2 and ccn4 in primary breast cancers associated with more advanced features. Cancer Res 2001, 61:8917-8923.
• [12]Sampath D, Winneker RC, Zhang Z: The angiogenic factor Cyr61 is induced by the progestin R5020 and is necessary for mammary adenocarcinoma cell growth. Endocrine 2002, 18:147-159.
• [13]Tsai MS, Hornby AE, Lakins J, Lupu R: Expression and function of CYR61, an angiogenic factor, in breast cancer cell lines and tumour biopsies. Cancer Res 2000, 60:5603-5607.
• [14]Tsai MS, Bogart DF, Castaneda JM, Li P, Lupu R: Cyr61 promotes breast tumourigenesis and cancer progression. Oncogene 2002, 21:8178-8185.
• [15]Xie D, Miller CW, O'Kelly J, Nakachi K, Sakashita A, Said JW, Gornbein J, Koeffler HP: Breast cancer. Cyr61 is overexpressed, estrogen-inducible, and associated with more advanced disease. J Biol Chem 2001, 276:14187-14194.
• [16]Wenger C, Gress TM: CCN-family members in pancreatic diseases [abstract]. Mol Pathol 2001, 54:119.
• [17]Frazier K, Grotendorst G: Expression of Connective Tissue Growth Factor mRNA in the Fibrous Stroma of Mammary Tumours. Int J Biochem Cell Biol 1997, 29:153-161.
• [18]Igarashi A, Hayashi N, Nashiro K, Takehara K: Differential expression of connective tissue growth factor gene in cutuneous fibrohistiocytic and vascular tumour. J Cutan Pathol 1998, 25:143-148.
• [19]Wenger C, Ellenrieder V, Alber B, Lacher U, Menke A, Hameister H, Wilda M, Iwamura T, Beger HG, Adler G, Gress TM: Expression and differential regulation of connective tissue growth factor in pancreatic cancer cells. Oncogene 1999, 18:1073-1080.
• [20]Shakunaga T, Ozaki T, Ohara N, Asaumi K, Doi T, Nishida K, Kawai A, Nakanishi T, Takigawa M, Inoue H: Expression of connective tissue growth factor in cartilaginous tumours. Cancer 2000, 89:1466-1473.
• [21]Pan LH, Beppu T, Kurose A, Yamauchi K, Sugawara A, Suzuki M, Ogawa A, Sawai T: Neoplastic cells and proliferating endothelial cells express connective tissue growth factor (CTGF) in glioblastoma. Neurol Res 2002, 24:677-683.
• [22]Rubenstein J, Shen A, Haqq C, Ginziger D, Hyun W, Brigstock D, Shuman M: Connective tissue growth factor is expressed in malignant astrocytic tumors and is involved in cell-cycle regulation [abstract]. Mol Pathol 2003, 56:72.
• [23]Vorwerk P, Wex H, Hohmann B, Mohnike K, Schmidt U, Mittler U: Expression of components of the IGF signalling system in childhood acute lymphoblastic leukaemia. Mol Pathol 2002, 55:40-45.
• [24]Maillard M, Cadot B, Ball RY, Sethia K, Edwards D, Perbal B, Tatoud R: Differential expression of novH proto-oncogene in human prostate cell lines and tissues. Mol Pathol 2001, 54:275-280.
• [25]Glukhova L, Angevin E, Lavialle C, Cadot B, Terrier M, Lacombe J, Perbal B, Bernheim A, Goguel AF: Specific Genomic Alterations Associated With Poor Prognosis In High Grade Renal Cell Carcinomas. Cancer Genet Cytogenet 2001, 130:105-110.
• [26]Manara MC, Perbal B, Benini S, Strammiello R, Cerisano V, Perdichizzi S, Serra M, Astolfi A, Bertoni F, Alami J, Yeger H, Picci P, Scotlandi K: The expression of ccn3(nov) gene in musculoskeletal tumours. Am J Pathol 2002, 160:849-859.
• [27]Hu Y, Ippolito JE, Garabedian EM, Humphrey PA, Gordon JI: Molecular characterization of a metastatic neuroendocrine cell cancer arising in the prostates of transgenic mice. J Biol Chem 2002, 277:44462-44474.
• [28]Lopez-Bermejo A, Buckway CK, Devi GR, Hwa V, Plymate SR, Oh Y, Rosenfeld RG: Characterization of insulin-like growth factor-binding protein-related proteins (IGFBP-rPs) 1, 2, and 3 in human prostate epithelial cells: potential roles for IGFBP-rP1 and 2 in senescence of the prostatic epithelium. Endocrinology 2000, 141:4072-4080.
• [29]Scotlandi K, Benini S, Manara MC, Cerisano V, Perdichizzi S, Strammiello R, Perbal B: Biological role of NOVH in Ewing's sarcomac cells [abstract]. Mol Pathol 2003, 56:73.
• [30]Pennica D, Swanson TA, Welsh JW, Roy M, Lawrence D, Lee J, Brush J, Taneyhill L, Deuel B, Lew M, Watanabe C, Cohen R, Melhem M, Finley G, Quirke P, Goddard A, Hillan K, Gurney A, Botstein D, Levine A: WISP genes are members of the connective tissue growth factor family that are up-regulated in Wnt-1-transformed cells and aberrantly expressed in human colon tumours. Proc Natl Acad Sci USA 1998, 95:14717-14722.
• [31]Perbal B: Contribution of MAV-1-induced nephroblastoma to the study of genes involved in human Wilms' tumour development. Critical Reviews in Oncogenesis 1994, 5:589-613.
• [32]Beckwith JB, Kiviat NB, Bonadio JF: Nephrogenic rests, nephroblastomatosis, and the pathogenesis of Wilms' tumour. Pediatric Pathology 1990, 10:1-36.
• [33]Martinerie C, Huff V, Joubert I, Badzioch M, Saunders G, Strong L, Perbal B: Structural analysis of the human nov proto-oncogene and expression in Wilms tumour. Oncogene 1994, 9:2729-2732.
• [34]Martinerie C, Chevalier G, Rauscher FJ 3rd, Perbal B: Regulation of nov by WT1: a potential role for nov in nephrogenesis. Oncogene 1996, 12:1479-1492.
• [35]Chevalier G, Yeger H, Martinerie C, Laurent M, Alami J, Schofield P, Perbal B: NovH: Differential Expression in Developing Kidney and Wilms' Tumours. Am J Pathol 1998, 152:1563-1575.
• [36]Stanhope-Baker P, Williams BR: Identification of connective tissue growth factor as a target of WT1 transcriptional regulation. J Biol Chem 2000, 275:38139-38150.
• [37]Le AT, Yu C, Yeger H, Perbal B, Alman BA: NOV (CCN3) regulation in the growth plate and CCN family member expression in cartilage neoplasia. Journal of Pathology, in press.
• [38]Kocialkowski S, Yeger H, Kingdom J, Perbal B, Schofield P: Expression of the human nov gene in first trimester fetal tissues. Anat Embryol 2001, 203:417-427.
• [39]Gilmour L, Price S, Whetton AD, Perbal B, Irvine AE: Deregulation of nov expression in chronic myeloid leukaemia [abstract]. Mol Pathol 2003, 56:73.
• [40]Sampath D, Zhu Y, Winneker RC, Zhang Z: Aberrant expression of Cyr61, a member of the CCN (CTGF/Cyr61/Cef10/NOVH) family, and dysregulation by 17 beta-estradiol and basic fibroblast growth factor in human uterine leiomyomas. J Clin Endocrinol Metab 2001, 86:1707-1715.
• [41]Genini M, Schwalbe P, Scholl FA, Schufer BW: Isolation of genes differentially expressed in human primary myoblasts and embryonal rhabdomyosarcoma. Int J Cancer 1996, 66:571-577.
• [42]Pilarsky CP, Schmidt U, Eissrich C, Stade J, Froschermaier SE, Haase M, Faller G, Kirchner TW, Wirth MP: Expression of the extracellular matrix signaling molecule Cyr61 is downregulated in prostate cancer. Prostate 1998, 36:85-91.
• [43]Tong X, Xie D, O'Kelly J, Miller CW, Muller-Tidow C, Koeffler HP: Cyr61, a member of CCN family, is a tumour suppressor in non-small cell lung cancer. J Biol Chem 2001, 276:47709-47714.
• [44]Freemantle SJ, Kerley JS, Olsen SL, Gross RH, Spinella MJ: Developmentally-related candidate retinoic acid target genes regulated early during neuronal differentiation of human embryonal carcinoma. Oncogene 2002, 21:2880-2889.
• [45]Banerjee S, Saxena N, Sengupta K, Tawfik O, Mayo MS, Banerjee SK: WISP-2 gene in human breast cancer: role of estrogen and progesterone [abstract]. Mol Pathol 2003, 56:71.
• [46]Kleer CG, Zhang Y, Pan Q, van Golen KL, Wu Z-F, Merajver SD: WISP3 is a novel tumor suppressor gene for inflammatory breast cancer [abstract]. Mol Pathol 2003, 56:72.
• [47]Hurvitz JR, Suwairi WM, Van Hul W, El-Shanti H, Superti-Furga A, Roudier J, Holderbaum D, Pauli RM, Herd JK, Van Hul EV, Rezai-Delui H, Legius E, Le Merrer M, Al-Alami J, Bahabri SA, Warman ML: Mutations in the CCN gene family member WISP3 cause progressive pseudorheumatoid dysplasia. Nat Genet 1999, 23:94-98.
• [48]Li WX, Martinerie C, Zumkeller W, Westphal M, Perbal B: Differential expression of nov H and CTGF in human glioma cell lines. Mol Pathol 1996, 49:91-97.
• [49]Gupta N, Wang H, McLeod TL, Naus CC, Kyurkchiev S, Advani S, Yu J, Perbal B, Weichselbaum RR: Inhibition of glioma cell growth and tumourigenic potential by CCN3 (NOV). Mol Pathol 2001, 54:293-99.
• [50]Gellhaus A, Propson S, Gabriel H-D, Gruemmer R, Duerig J, Klein-Hitpass BL, Maass K, Perbal B, Winterhager E: NOV is associated with CX43 but not with CX40 and TRCX43 in human choriocarcinoma transfectants: evidence for potential growth-regulatory functions [abstract]. Mol Pathol 2003, 56:75.
• [51]Soon LL, Yie TA, Shvarts A, Levine AJ, Su F, Tchou-Wong KM: Overexpression of WISP-1 downregulated motility and invasion of lung cancer cells through inhibition of Rac activation. J Biol Chem 2003, 278:11465-11470.
• [52]Zhang R, Averboukh L, Zhu W, Zhang H, Jo H, Dempsey PJ, Coffey RJ, Pardee AB, Liang P: Identification of rCop-1, a New Member of the CCN Protein Family, as a Negative Regulator for Cell Transformation. Mol Cell Biol 1998, 18:6131-6141.
• [53]Mason HR, Nowak RA, Castellot JJ Jr: CCN5 inhibits the proliferation and motility of human myometrial and leiomyoma smooth muscle cells [abstract]. Mol Pathol 2003, 56:73.
• [54]Kleer CG, Zhang Y, Pan Q, van Golen KL, Wu ZF, Livant D, Merajver SD: WISP3 is a novel tumour suppressor gene of inflammatory breast cancer. Oncogene 2002, 21:3172-3180.
• [55]Brigstock DR: Angiogenesis: the shared role of CTGF and CYR61. CCN Newsletter 2002, 1:5-8.
• [56]Lin C, Leu SJ, Chen N, Tebeau C, Lin SX, Yeung CY, Lau L: CCN3 (NOV) is a novel angiogenic regulator of the CCN protein family. J Biol Chem, in press. Apr 13 2003
• [57]Perbal B, Martinerie C, Sainson R, Werner M, He B, Roizman B: The C-terminal domain of the regulatory proteinNOVH is sufficient to promote interaction with fibulin 1C: a clue for a role of NOVH in cell-adhesion signaling. Proc Natl Acad Sci U S A 1999, 96:869-874.
• [58]Sakamoto K, Yamaguchi S, Ando R, Miyawaki A, Kabasawa Y, Takagi M, Li CL, Perbal B, Katsube K: The nephroblastoma overexpressed gene (NOV/ccn3) protein associates with Notch1 extracellular domain and inhibits myoblast differentiation via Notch signaling pathway. J Biol Chem 2002, 277:29399-29405.
• [59]Li CL, Martinez V, He B, Lombet A, Perbal B: A role for CCN3 (NOV) in calcium signalling. Mol Pathol 2002, 55:250-261.
• [60]Perbal B: Nuclear localisation of NOV protein : a potential role for nov in the regulation of gene expression. Mol Pathol 1999, 52:84-91.
• [61]Thomopoulos GN, Kyurkchiev S, Perbal B: Immunocytochemical localisation of NOVH protein and ultrastructural characteristics of NCI-H295R cells. J Submicrosc Cytol Pathol 2001, 33:251-260.
• [62]Wahab NA, Brinkman H, Mason RM: Uptake and intracellular transport of the connective tissue growth factor. Biochem J 2001, 359:89-97.
• [63]Moritani NH, Kubota S, Nishida T, Kawaki H, Kondo S, Sugahara T, Takigawa M: Suppressive effect of overexpressed connective tissue growth factor on tumor cell growth in a human oral squamous cellcarcinoma-derived cell line. Cancer Lett 2003, 192:205-214.
• [64]Perbal B: Les protéines CCN: Quand multimodulaire rime avec multifonctionnel. Médecine/Sciences 2002, 18:745-756.
• [65]Grotendorst GR, Lau LF, Perbal B: CCN proteins are distinct from and should not be considered members of the insulin-like growth factor-binding protein superfamily. Endocrinology 2000, 141:2254-2256.
• [66]Kim HS, Nagalla SR, Oh Y, Wilson E, Roberts CT jr, Rosenfeld RG: Identification of a family of low-affinity insulin-like growth factor binding proteins (IGFBPs):characterisation of connective tissue growth factor as a member of the IGFBP super family. Proc Natl Acad Sci USA 1997, 94:12981-12986.
• [67]Burren C, Wilson E, Hwa V, Oh Y, Rosenfeld R: Binding Properties and Distribution of Insulin-Like Growth Factor Binding Protein-Related Protein 3 (IGFBP-rP3/NovH), an Additional Member of the IGFBP Superfamily. J Clin Endocri and Metab 1999, 84:1096-1103.
• [68]Hwa V, Oh Y, Rosenfeld RG: The insulin-like growth factor-binding protein (IGFBP) superfamily. Endocr Rev 1999, 20:761-787.
• [69]Tanaka S, Sugimachi K, Saeki H, Kinoshita J, Ohga T, Shimada M, Maehara Y, Sugimachi K: A novel variant of WISP1 lacking a Von Willebrand type C module overexpressed in scirrhous gastric carcinoma. Oncogene 2001, 20:5525-5532.
• [70]Holt GD, Pangburn MK, Ginsburg V: Properdin binds to sulfatide [Gal(3-SO4)beta 1–1 Cer] and has a sequence homology with other proteins that bind sulfated glycoconjugates. J Biol Chem 1990, 265:2852-2855.
• [71]Chen CC, Chen N, Lau LF: The angiogenic factors Cyr61 and connective tissue growth factor induce adhesive signaling in primary human skin fibroblasts. J Biol Chem 2001, 276:10443-10452.
• [72]Chen CC, Mo FE, Lau LF: The angiogenic factor Cyr61 activates a genetic program for wound healing in human skin fibroblasts. J Biol Chem 2001, 276:47329-47337.
• [73]Grzeszkiewicz TM, Kirschling DJ, Chen N, Lau LF: CYR61 stimulates human skin fibroblast migration through Integrin alpha vbeta 5 and enhances mitogenesis through integrin alpha vbeta 3, independent of its carboxyl-terminal domain. J Biol Chem 2001, 276:21943-21950.
• [74]Grzeszkiewicz TM, Lindner V, Chen N, Lam SC, Lau LF: The angiogenic factor cysteine-rich 61 (CYR61, CCN1) supports vascular smooth muscle cell adhesion and stimulates chemotaxis through integrin alpha(6)beta(1) and cell surface heparan sulfate proteoglycans. Endocrinology 2002, 143:1441-1450.
• [75]Desnoyers L, Arnott D, Pennica D: WISP-1 binds to decorin and biglycan. J Biol Chem 2001, 276:47599-47607.
• [76]Leng E, Malcom T, Gai G, Estable M, Saowski I: Organization and expression of the Cyr61 gene in normal human fibroblasts. J Biomed Sci 2002, 9:59-67.
• [77]Thorstensen L, Diep CB, Meling GI, Aagesen TH, Ahrens CH, Rognum TO, Lothe RA: WNT1 inducible signaling pathway protein 3, WISP-3, a novel target gene in colorectal carcinomas with microsatelliteinstability. Gastroenterology 2001, 121:1275-1280.
• [78]Tanaka S, Sugimachi K, Shimada M, Maehara Y, Sugimachi K: Variant WISPs as targets for gastrointestinal carcinomas. Gastroenterology 2002, 123:392-393.
• [79]Schlunegger MP, Grutter MG: Refined crystal structure of human transforming growth factor beta 2 at 1.95 A resolution. J Mol Biol 1993, 231:445-458.
• [80]Ball DK, Rachfal AW, Kemper SA, Brigstock DR: The heparin-binding 10 kDa fragment of connective tissue growth factor (CTGF) containing module 4 alone stimulates cell adhesion. J Endocrinol 2003, 176:R1-R7.
• [81]Kumar S, Hand AT, Connor JR, Dodds RA, Ryan PJ, Trill JJ, Fisher SM, Nuttall ME, Lipshutz DB, Zou C, Hwang SM, Votta BJ, James IE, Rieman DJ, Gowen M, Lee JC: Identification and cloning of a connective tissue growth factor-like cDNA from human osteoblasts encoding a novel regulator of osteoblast functions. J Biol Chem 1999, 274:17123-17131.
• [82]Brigstock DR, Goldschmeding R, Katsube KI, Lam SCT, Lau LF, Lyons K, Naus C, Perbal B, Riser B, Takigawa M, Yeger H: Proposal for a unified CCN nomenclature. Mol Pathol 2003, 56:127-128.