Abstract
The Cellular communication network (CCN) family of growth regulatory factors comprises six secreted matricellular proteins that promote signal transduction through cell-cell or cell-matrix interaction. The diversity of functionality between each protein is specific to the many aspects of healthy and cancer biology. For example, CCN family proteins modulate cell adhesion, proliferation, migration, invasiveness, apoptosis, and survival. In addition, the expression of each protein regulates many biological and pathobiological processes within its microenvironment to regulate angiogenesis, inflammatory response, chondrogenesis, fibrosis, and mitochondrial integrity. The collective range of CCN operation remains fully comprehended; however, understanding each protein’s microenvironment may draw more conclusions about the abundance of interactions and signaling cascades occurring within such issues. This review observes and distinguishes the various roles a CCN protein may execute within distinct tumor microenvironments and the biological associations among them. Finally. We also review how CCN-family proteins can be used in nano-based therapeutic implications.
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Ahmed KA, Hasib TA, Paul SK, Saddam M, Mimi A, Saikat ASM, Faruque HA, Rahman MA, Uddin MJ, Kim B (2021) Potential role of CCN proteins in breast cancer: therapeutic advances and perspectives. Curr Oncol 28:4972–4985. https://doi.org/10.3390/curroncol28060417
Babic AM, Kireeva ML, Kolesnikova TV, Lau LF (1998) CYR61, a product of a growth factor-inducible immediate early gene, promotes angiogenesis and tumor growth. Proc Natl Acad Sci USA 95:6355–6360. https://doi.org/10.1073/pnas.95.11.6355
Baguma-Nibasheka M, Kablar B (2008) Pulmonary hypoplasia in the connective tissue growth factor (CTGF) null mouse. Dev Dyn 237:485–493. https://doi.org/10.1002/dvdy.21433
Banerjee SK, Banerjee S (2012) CCN5/WISP-2: a micromanager of breast cancer progression. J Cell Commun Signal 6:63–71. https://doi.org/10.1007/s12079-012-0158-2
Banerjee S, Dhar G, Haque I, Kambhampati S, Mehta S, Sengupta K, Tawfik O, Phillips TA, Banerjee SK (2008) CCN5/WISP-2 expression in breast adenocarcinoma is associated with less frequent progression of the disease and suppresses the invasive phenotypes of tumor cells. Cancer Res 68:7606–7612. https://doi.org/10.1158/0008-5472.CAN-08-1461
Banerjee S, Ghosh A, VonHoff DD, Banerjee SK (2019) Cyr61/CCN1 targets for chemosensitization in pancreatic cancer. Oncotarget 10:3579–3580. https://doi.org/10.18632/oncotarget.26986
Banerjee SK, Maity G, Haque I, Ghosh A, Sarkar S, Gupta V, Campbell DR, Von Hoff D, Banerjee S (2016) Human pancreatic cancer progression: an anarchy among CCN-siblings. J Cell Commun Signal 10:207–216. https://doi.org/10.1007/s12079-016-0343-9
Banerjee S, Saxena N, Sengupta K, Tawfik O, Mayo MS, Banerjee SK (2003) WISP-2 gene in human breast cancer: estrogen and progesterone inducible expression and regulation of tumor cell proliferation. Neoplasia 5:63–73. https://doi.org/10.1016/s1476-5586(03)80018-0
Benini S, Perbal B, Zambelli D, Colombo MP, Manara MC, Serra M, Parenza M, Martinez V, Picci P, Scotlandi K (2005) In Ewing’s sarcoma CCN3(NOV) inhibits proliferation while promoting migration and invasion of the same cell type. Oncogene 24:4349–4361. https://doi.org/10.1038/sj.onc.1208620
Brown BA, Connolly GM, Mill CEJ, Williams H, Angelini GD, Johnson JL, George SJ (2019) Aging differentially modulates the Wnt pro-survival signalling pathways in vascular smooth muscle cells. Aging Cell 18:e12844. https://doi.org/10.1111/acel.12844
Bussard KM, Mutkus L, Stumpf K, Gomez-Manzano C, Marini FC (2016) Tumor-associated stromal cells as key contributors to the tumor microenvironment. Breast Cancer Res 18:84. https://doi.org/10.1186/s13058-016-0740-2
Chen PC, Cheng HC, Yang SF, Lin CW, Tang CH (2014) The CCN family proteins: modulators of bone development and novel targets in bone-associated tumors. Biomed Res Int 2014:437096. https://doi.org/10.1155/2014/437096
Chen R, Masuo K, Yogo A, Yokoyama S, Sugiyama A, Seno H, Yoshizawa A, Takaishi S (2021) SNAIL regulates gastric carcinogenesis through CCN3 and NEFL. Carcinogenesis 42:190–201. https://doi.org/10.1093/carcin/bgaa133
Delmolino LM, Stearns NA, Castellot JJ Jr (2001) COP-1, a member of the CCN family, is a heparin-induced growth arrest specific gene in vascular smooth muscle cells. J Cell Physiol 188:45–55. https://doi.org/10.1002/jcp.1100
Dhar K, Banerjee S, Dhar G, Sengupta K, Banerjee SK (2007b) Insulin-like growth factor-1 (IGF-1) induces WISP-2/CCN5 via multiple molecular cross-talks and is essential for mitogenic switch by IGF-1 axis in estrogen receptor-positive breast tumor cells. Cancer Res 67:1520–1526. https://doi.org/10.1158/0008-5472.CAN-06-3753
Dhar G, Banerjee S, Dhar K, Tawfik O, Mayo MS, Vanveldhuizen PJ, Banerjee SK (2008) Gain of oncogenic function of p53 mutants induces invasive phenotypes in human breast cancer cells by silencing CCN5/WISP-2. Cancer Res 68:4580–4587. https://doi.org/10.1158/0008-5472.CAN-08-0316
Dhar G, Mehta S, Banerjee S, Gardner A, McCarty BM, Mathur SC, Campbell DR, Kambhampati S, Banerjee SK (2007a) Loss of WISP-2/CCN5 signaling in human pancreatic cancer: a potential mechanism for epithelial-mesenchymal-transition. Cancer Lett 254:63–70. https://doi.org/10.1016/j.canlet.2007.02.012
Egeblad M, Nakasone ES, Werb Z (2010) Tumors as organs: complex tissues that interface with the entire organism. Dev Cell 18:884–901. https://doi.org/10.1016/j.devcel.2010.05.012
Gascard P, Tlsty TD (2016) Carcinoma-associated fibroblasts: orchestrating the composition of malignancy. Genes Dev 30:1002–1019. https://doi.org/10.1101/gad.279737.116
Giusti V, Scotlandi K (2021) CCN proteins in the musculoskeletal system: current understanding and challenges in physiology and pathology. J Cell Commun Signal 15:545–566. https://doi.org/10.1007/s12079-021-00631-5
Gupta V, Bhavanasi S, Quadir M, Singh K, Ghosh G, Vasamreddy K, Ghosh A, Siahaan TJ, Banerjee S, Banerjee SK (2019) Protein PEGylation for cancer therapy: bench to bedside. J Cell Commun Signal 13:319–330. https://doi.org/10.1007/s12079-018-0492-0
Gurbuz I, Chiquet-Ehrismann R (2015) CCN4/WISP1 (WNT1 inducible signaling pathway protein 1): a focus on its role in cancer. Int J Biochem Cell Biol 62:142–146. https://doi.org/10.1016/j.biocel.2015.03.007
Haque I, Banerjee S, De A, Maity G, Sarkar S, Majumdar M, Jha SS, McGragor D, Banerjee SK (2014) CCN5/WISP-2 promotes growth arrest of triple-negative breast cancer cells through accumulation and trafficking of p27 via Skp2 and FOXO3a regulation. Oncogene. https://doi.org/10.1038/onc.2014.250
Harris J, Chess R (2003) Effect of pegylation on pharmaceuticals. Nat Rev Drug Discovery 2:214–221. https://doi.org/10.1038/nrd1033
Huang J, Bonduelle C, Thévenot J, Lecommandoux S, Heise A (2012) Biologically active polymersomes from amphiphilic glycopeptides. J Am Chem Soc 134:119–122. https://doi.org/10.1021/ja209676p
Huang A, Li H, Zeng C, Chen W, Wei L, Liu Y, Qi X (2020) Endogenous CCN5 participates in angiotensin II/TGF-beta1 networking of cardiac fibrosis in high angiotensin II-induced hypertensive heart failure. Front Pharmacol 11:1235. https://doi.org/10.3389/fphar.2020.01235
Huang W, Zhang Y, Varambally S, Chinnaiyan AM, Banerjee M, Merajver SD, Kleer CG (2008) Inhibition of CCN6 (Wnt-1-induced signaling protein 3) down-regulates E-cadherin in the breast epithelium through induction of snail and ZEB1. Am J Pathol 172:893–904. https://doi.org/10.2353/ajpath.2008.070899
Hutchenreuther J, Vincent KM, Carter DE, Postovit LM, Leask A (2015) CCN2 expression by tumor stroma is required for melanoma metastasis. J Invest Dermatol 135:2805–2813. https://doi.org/10.1038/jid.2015.279
Hutchenreuther J, Vincent K, Norley C, Racanelli M, Gruber SB, Johnson TM, Fullen DR, Raskin L, Perbal B, Holdsworth DW et al (2018) Activation of cancer-associated fibroblasts is required for tumor neovascularization in a murine model of melanoma. Matrix Biol 74:52–61. https://doi.org/10.1016/j.matbio.2018.06.003
Itaka K, Yamauchi K, Harada A, Nakamura K, Kawaguchi H, Kataoka K (2003) Polyion complex micelles from plasmid DNA and poly(ethylene glycol)-poly(L-lysine) block copolymer as serum-tolerable polyplex system: physicochemical properties of micelles relevant to gene transfection efficiency. Biomaterials 24:4495–4506
Ivkovic S, Yoon BS, Popoff SN, Safadi FF, Libuda DE, Stephenson RC, Daluiski A, Lyons KM (2003) Connective tissue growth factor coordinates chondrogenesis and angiogenesis during skeletal development. Development 130:2779–2791. https://doi.org/10.1242/dev.00505
Jeong D, Lee MA, Li Y, Yang DK, Kho C, Oh JG, Hong G, Lee A, Song MH, LaRocca TJ et al (2016) Matricellular protein CCN5 reverses established cardiac fibrosis. J Am Coll Cardiol 67:1556–1568. https://doi.org/10.1016/j.jacc.2016.01.030
Jia Q, Xu B, Zhang Y, Ali A, Liao X (2021) CCN family proteins in cancer: insight into their structures and coordination role in tumor microenvironment. Front Genet 12:649387. https://doi.org/10.3389/fgene.2021.649387
Joliot V, Martinerie C, Dambrine G, Plassiart G, Brisac M, Crochet J, Perbal B (1992) Proviral rearrangements and overexpression of a new cellular gene (nov) in myeloblastosis-associated virus type 1-induced nephroblastomas. Mol Cell Biol 12:10–21. https://doi.org/10.1128/mcb.12.1.10-21.1992
Kalluri R (2016) The biology and function of fibroblasts in cancer. Nat Rev Cancer 16:582–598. https://doi.org/10.1038/nrc.2016.73
Kim H, Son S, Shin I (2018a) Role of the CCN protein family in cancer. BMB Rep 51:486–492
Kim KH, Won JH, Cheng N, Lau LF (2018b) The matricellular protein CCN1 in tissue injury repair. J Cell Commun Signal 12:273–279. https://doi.org/10.1007/s12079-018-0450-x
Kozlowski A, Harris J (2001) Improvements in protein PEGylation: pegylated interferons for treatment of hepatitis C. J Controlled Release 72:217–224. https://doi.org/10.1016/S0168-3659(01)00277-2
Lake AC, Castellot Jr JJ (2003) CCN5 modulates the antiproliferative effect of heparin and regulates cell motility in vascular smooth muscle cells. Cell Commun Signal 1:5. https://doi.org/10.1186/1478-811X-1-5
Leask A (2020a) A centralized communication network: recent insights into the role of the cancer associated fibroblast in the development of drug resistance in tumors. Semin Cell Dev Biol 101:111–114. https://doi.org/10.1016/j.semcdb.2019.10.016
Leask A (2020b) Conjunction junction, what’s the function? CCN proteins as targets in fibrosis and cancers. Am J Physiol Cell Physiol 318:C1046. https://doi.org/10.1152/ajpcell.00028.2020
Lee Y, Fukushima S, Bae Y, Hiki S, Ishii T, Kataoka K (2007) A protein nanocarrier from charge-conversion polymer in response to endosomal pH. J Am Chem Soc 129:5362–. https://doi.org/10.1021/ja071090b
Lee MA, Raad N, Song MH, Yoo J, Lee M, Jang SP, Kwak TH, Kook H, Choi EK, Cha TJ et al (2020) The matricellular protein CCN5 prevents adverse atrial structural and electrical remodelling. J Cell Mol Med 24:11768–11778. https://doi.org/10.1111/jcmm.15789
Leguit RJ, Raymakers RAP, Hebeda KM, Goldschmeding R (2021) CCN2 (cellular communication network factor 2) in the bone marrow microenvironment, normal and malignant hematopoiesis. J Cell Commun Signal 15:25–56. https://doi.org/10.1007/s12079-020-00602-2
Leu SJ, Liu Y, Chen N, Chen CC, Lam SC, Lau LF (2003) Identification of a novel integrin alpha 6 beta 1 binding site in the angiogenic inducer CCN1 (CYR61). J Biol Chem 278:33801–33808. https://doi.org/10.1074/jbc.M305862200
Liang H, Ward WF (2006) PGC-1alpha: a key regulator of energy metabolism. Adv Physiol Educ 30:145–151. https://doi.org/10.1152/advan.00052.2006
Liao X, Bu Y, Chang F, Jia F, Song G, Xiao X, Zhang M, Ning P, Jia Q (2019a) Remodeling of hepatic stellate cells orchestrated the stroma-derived oxaliplatin-resistance through CCN3 paracrine in hepatocellular carcinoma. BMC Cancer 19:1192. https://doi.org/10.1186/s12885-019-6362-1
Liao X, Bu Y, Jiang S, Chang F, Jia F, Xiao X, Song G, Zhang M, Ning P, Jia Q (2019b) CCN2-MAPK-Id-1 loop feedback amplification is involved in maintaining stemness in oxaliplatin-resistant hepatocellular carcinoma. Hepatol Int 13:440–453. https://doi.org/10.1007/s12072-019-09960-5
Liu H, Dong W, Lin Z, Lu J, Wan H, Zhou Z, Liu Z (2013) CCN4 regulates vascular smooth muscle cell migration and proliferation. Mol Cells 36:112–118. https://doi.org/10.1007/s10059-013-0012-2
Lorenzatti G, Huang W, Pal A, Cabanillas AM, Kleer CG (2011) CCN6 (WISP3) decreases ZEB1-mediated EMT and invasion by attenuation of IGF-1 receptor signaling in breast cancer. J Cell Sci 124:1752–1758. https://doi.org/10.1242/jcs.084194
Maity G, Ghosh A, Gupta V, Haque I, Sarkar S, Das A, Dhar K, Bhavanasi S, Gunewardena SS, Von Hoff DD et al (2019) CYR61/CCN1 regulates dCK and CTGF and causes gemcitabine-resistant phenotype in pancreatic ductal adenocarcinoma. Mol Cancer Ther 18:788–800. https://doi.org/10.1158/1535-7163.MCT-18-0899
Maity G, Mehta S, Haque I, Dhar K, Sarkar S, Banerjee SK, Banerjee S (2014) Pancreatic tumor cell secreted CCN1/Cyr61 promotes endothelial cell migration and aberrant neovascularization. Sci Rep 4:4995. https://doi.org/10.1038/srep04995
Martinez-Outschoorn UE, Bartrons M, Bartrons R (2019) Editorial: cancer ecosystems. Front Oncol 9:718. https://doi.org/10.3389/fonc.2019.00718
Meurette O, Mehlen P (2018) Notch signaling in the tumor microenvironment. Cancer Cell 34:536–548. https://doi.org/10.1016/j.ccell.2018.07.009
Nel AE, Mädler L, Velegol D, Xia T, Hoek EM, Somasundaran P, Klaessig F, Castranova V, Thompson M (2009) Understanding biophysicochemical interactions at the nano-bio interface. Nat Mater 8:543–557. https://doi.org/10.1038/nmat2442
Neophytou CM, Panagi M, Stylianopoulos T, Papageorgis P (2021) The role of tumor microenvironment in cancer metastasis: molecular mechanisms and therapeutic opportunities. Cancers (Basel). https://doi.org/10.3390/cancers13092053
Nivison MP, Meier KE (2018) The role of CCN4/WISP-1 in the cancerous phenotype. Cancer Manag Res 10:2893–2903. https://doi.org/10.2147/CMAR.S133915
Oba M, Miyata K, Osada K, Christie RJ, Sanjoh M, Li W, Fukushima S, Ishii T, Kano MR, Nishiyama N et al (2011) Polyplex micelles prepared from ω-cholesteryl PEG-polycation block copolymers for systemic gene delivery. Biomaterials 32:652–663. https://doi.org/10.1016/j.biomaterials.2010.09.022
Park MH, Kim AK, Manandhar S, Oh SY, Jang GH, Kang L, Lee DW, Hyeon DY, Lee SH, Lee HE et al (2019) CCN1 interlinks integrin and hippo pathway to autoregulate tip cell activity. Elife 8. https://doi.org/10.7554/eLife.46012
Patra M, Mahata SK, Padhan DK, Sen M (2016) CCN6 regulates mitochondrial function. J Cell Sci 129:2841–2851. https://doi.org/10.1242/jcs.186247
Peng L, Wei Y, Shao Y, Li Y, Liu N, Duan L (2021) The emerging roles of CCN3 protein in immune-related diseases. Mediators Inflamm 2021:5576059. https://doi.org/10.1155/2021/5576059
Perbal B (2001) NOV (nephroblastoma overexpressed) and the CCN family of genes: structural and functional issues. Mol Pathol 54:57–79. https://doi.org/10.1136/mp.54.2.57
Perbal B (2009) Alternative splicing of CCN mRNAs … it has been upon us. J Cell Commun Signal 3:153–157. https://doi.org/10.1007/s12079-009-0051-9
Ping Q, Yan R, Cheng X, Wang W, Zhong Y, Hou Z, Shi Y, Wang C, Li R (2021) Cancer-associated fibroblasts: overview, progress, challenges, and directions. Cancer Gene Ther 28:984–999. https://doi.org/10.1038/s41417-021-00318-4
Poon Z, Chang D, Zhao X, Hammond PT (2011) Layer-by-layer nanoparticles with a pH-sheddable layer for in vivo targeting of tumor hypoxia. ACS Nano 5:4284–4292. https://doi.org/10.1021/nn200876f
Ren X, Kang B, Zhang Z (2018) Understanding tumor ecosystems by single-cell sequencing: promises and limitations. Genome Biol 19:211. https://doi.org/10.1186/s13059-018-1593-z
Roberts M, Bentley M, Harris J (2002) Chemistry for peptide and protein PEGylation. Adv Drug Deliv Rev 54:459–476. https://doi.org/10.1016/S0169-409X(02)00022-4
Sabbah M, Prunier C, Ferrand N, Megalophonos V, Lambein K, De Wever O, Nazaret N, Lachuer J, Dumont S, Redeuilh G (2011) CCN5, a novel transcriptional repressor of the transforming growth factor beta signaling pathway. Mol Cell Biol 31:1459–1469. https://doi.org/10.1128/MCB.01316-10
Sahai E, Astsaturov I, Cukierman E, DeNardo DG, Egeblad M, Evans RM, Fearon D, Greten FR, Hingorani SR, Hunter T et al (2020) A framework for advancing our understanding of cancer-associated fibroblasts. Nat Rev Cancer 20:174–186. https://doi.org/10.1038/s41568-019-0238-1
Sarkar S, Ghosh A, Banerjee S, Maity G, Das A, Larson MA, Gupta V, Haque I, Tawfik O, Banerjee SK (2017) CCN5/WISP-2 restores ER-proportional, variant in normal and neoplastic breast cells and sensitizes triple negative breast cancer cells to tamoxifen. Oncog 6:e340. https://doi.org/10.1038/oncsis.2017.43
Sengupta A, Padhan DK, Ganguly A, Sen M (2021) Ccn6 is required for mitochondrial integrity and skeletal muscle function in zebrafish. Front Cell Dev Biol 9:627409. https://doi.org/10.3389/fcell.2021.627409
Siddiqui S, Pandey V, Ali S, Singh A, Sharma D, Yadav M, Raikwar A (2021) CCN3 proteins as a diagnostic marker in osteosarcoma patients: a case control study. Cancer Treat Res Commun 28:100381. https://doi.org/10.1016/j.ctarc.2021.100381
Song MH, Jo Y, Kim YK, Kook H, Jeong D, Park WJ (2022) The TSP-1 domain of the matricellular protein CCN5 is essential for its nuclear localization and anti-fibrotic function. PLoS ONE 17:e0267629. https://doi.org/10.1371/journal.pone.0267629
Takigawa M (2018) An early history of CCN2/CTGF research: the road to CCN2 via hcs24, ctgf, ecogenin, and regenerin. J Cell Commun Signal 12:253–264. https://doi.org/10.1007/s12079-017-0414-6
Turley SJ, Cremasco V, Astarita JL (2015) Immunological hallmarks of stromal cells in the tumour microenvironment. Nat Rev Immunol 15:669–682. https://doi.org/10.1038/nri3902
Tzeng HE, Tang CH, Wu SH, Chen HT, Fong YC, Lu YC, Chen WC, Huang HD, Lin CY, Wang SW (2018) CCN6-mediated MMP-9 activation enhances metastatic potential of human chondrosarcoma. Cell Death Dis 9:955. https://doi.org/10.1038/s41419-018-1008-9
Wang M, Li XZ, Zhang MX, Ye QY, Chen YX, Chang X (2021) Atractylenolide-I sensitizes triple-negative breast cancer cells to paclitaxel by blocking CTGF expression and fibroblast activation. Front Oncol 11:738534. https://doi.org/10.3389/fonc.2021.738534
Whiteside TL (2008) The tumor microenvironment and its role in promoting tumor growth. Oncogene 27:5904–5912. https://doi.org/10.1038/onc.2008.271
Wilhelm S, Tavares A, Dai Q, Ohta S, Audet J, Dvorak H, Chan W (2016) Analysis of nanoparticle delivery to tumours. Nat Reviews Mater 1. https://doi.org/10.1038/natrevmats.2016.14
Yoshioka Y, Ono M, Maeda A, Kilts TM, Hara ES, Khattab H, Ueda J, Aoyama E, Oohashi T, Takigawa M et al (2016) CCN4/WISP-1 positively regulates chondrogenesis by controlling TGF-beta3 function. Bone 83:162–170. https://doi.org/10.1016/j.bone.2015.11.007
Zaykov V, Chaqour B (2021) The CCN2/CTGF interactome: an approach to understanding the versatility of CCN2/CTGF molecular activities. J Cell Commun Signal 15:567–580. https://doi.org/10.1007/s12079-021-00650-2
Zhang Y, Yu M, Dai M, Chen C, Tang Q, Jing W, Wang H, Tian W (2017) miR-450a-5p within rat adipose tissue exosome-like vesicles promotes adipogenic differentiation by targeting WISP2. J Cell Sci 130:1158–1168. https://doi.org/10.1242/jcs.197764
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We thank the members of the Kansas City VA Research Office and Midwest Biomedical Veteran’s Research Foundation. We greatly appreciate and recognize the developing research that propagates the complex understanding of the CCN family and its diverse role in oncology. Several graphs of this manuscript are created with BioRender.com
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Conceptualization, SKB and SB, writing and original draft preparation, LB; review and editing, SKB, SB, and MQ; design of figures, LB and SKB; funding acquisition, SKB, and SB. All authors have read and agreed to the published version of the manuscript.
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Birkeness, L.B., Banerjee, S., Quadir, M. et al. The role of CCNs in controlling cellular communication in the tumor microenvironment. J. Cell Commun. Signal. 17, 35–45 (2023). https://doi.org/10.1007/s12079-022-00682-2
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DOI: https://doi.org/10.1007/s12079-022-00682-2