Abstract
Since the authors first reviewed this subject in 2016 significant progress has been documented in the CCN field with advances made in the understanding of how members of the CCN family of proteins, CCN1-6, contribute to the pathogenesis and progression, positive and negative, of a larger variety of cancers. As termed matricellular proteins, and more recently the connective communication network, it has become clearer that members of the CCN family interact complexly with other proteins in the extracellular microenvironment, membrane signaling proteins, and can also operate intracellularly at the transcriptional level. In this review we expand on this earlier information providing new detailed information and insights that appropriate a much greater involvement and importance of their role in multiple aspects of cancer. Despite all the new information many more questions have been raised and intriguing results generated that warrant greater investigation. In order to permit the reader to smoothly integrate the new information we discuss all relevant CCN members in the context of cancer subtypes. We have harmonized the nomenclature with CCN numbering for easier comparisons. Finally, we summarize what new has been learned and provide a perspective on how our knowledge about CCN1-6 is being used to drive new initiatives on cancer therapeutics.
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Abbreviations
- ABCG2:
-
ATP-binding cassette super-family G member 2, drug pump
- ACC-MESO-4:
-
Malignant pleural mesothelioma cell line-4
- AGS:
-
Receptor-independent activators of G-protein signaling
- Akt:
-
Protein kinase B (PKB), also known as Akt
- p-Akt:
-
Phosphorylate form of Akt
- AMPKα:
-
5′-AMP-activated protein kinase catalytic subunit alpha-1
- Annexin V-PE:
-
Annexin V-phycoerythrin conjugate, affinity for phosphotidylserine
- APC:
-
Adenomatous polyposis coli, gene negative regulator of β-catenin
- ATP:
-
Adenosine triphosphate
- B16-F10:
-
Murine melanoma cell line
- BAX:
-
BCL2-associated X protein
- BRAF:
-
B-Raf, Raf kinase family of growth signal transduction protein kinases
- CacyBP/SIP:
-
Calcyclin-binding protein and Siah-1 interacting protein
- CBP:
-
CREB-binding protein
- CAFs:
-
Cancer associated fibroblasts
- CCL18:
-
C–C Motif Chemokine Ligand 18, small cytokine of the small chemokine family
- CDH2:
-
Gene encoding cadherin-2
- ChIP-seq:
-
Chromatin immunoprecipitation (ChIP) with massively parallel DNA sequencing
- CMS4:
-
Mesenchymal (CMS4) colorectal carcinoma, subtype of trefoil factor 3
- COL1A2:
-
Collagen alpha-2(I) chain
- COX-2:
-
Cyclooxygenase-2
- CRISPR/Cas9:
-
Stands for clustered regularly interspaced short palindromic repeats/CRISPR associated protein-9, genetic engineering technology
- CRP:
-
C-reactive protein
- CRPC:
-
Castration resistant prostate cancer
- CRPC:
-
Castration resistant prostate cancer
- CT:
-
C-terminal cysteine-knot
- CTNNB1:
-
Catenin (cadherin-associated protein), beta 1, encodes β-catenin
- CXCL5:
-
C-X-C motif chemokine ligand 5
- CXCR4:
-
C-X-C chemokine receptor type 4
- DG44 CHO:
-
Dihydrofolate reductase-deficient Chinese hamster ovary (CHO) cell line DG44
- DKK1:
-
Dickkopf WNT signaling pathway inhibitor 1, protein
- ECM:
-
Extracellular matrix
- EMT:
-
Epithelial mesenchymal transition
- Eno1:
-
Enolase 1
- FAK/Akt/Hif1α pathway:
-
Focal adhesion kinase/Akt/hypoxia inducible factor 1 alpha
- FC1199:
-
Pancreatic ductal cell line, mouse origin
- FIGO:
-
International Federation of Gynecology and Obstetrics
- FOXA1:
-
Forkhead box protein A1, also known as hepatocyte nuclear factor 3-alpha
- 5-FU:
-
5-Fluorouracil
- GPCR:
-
G-protein coupled receptor
- GSK3β:
-
Glycogen synthase kinase 3 beta
- H1975:
-
Human non-small cell lung carcinoma cell line
- HepG2:
-
Liver hepatocellular carcinoma cell line, well-differentiated
- HGC27:
-
Metastatic in lymph node gastric cancer cell line
- HIF1α:
-
Hypoxia inducible factor 1 alpha
- HIF2α:
-
Hypoxia inducible factor 2 alpha
- HMGA2:
-
High mobility group AT-hook 2, non-histone
- HNF4α:
-
Hepatocyte nuclear factor 4 alpha
- sICAM1:
-
Soluble intercellular adhesion molecule-1
- ICAM-1:
-
Intercellular Adhesion Molecule 1
- Id-1:
-
Inhibitor of differentiation/DNA binding
- IGF-1:
-
Insulin-like growth factor 1
- IGFBP:
-
Insulin like growth factor binding protein
- IGF2BP2:
-
Insulin like growth factor 2 binding protein 2
- IL-8:
-
Interleukin 8
- IL-6:
-
Interleukin 6
- JAK:
-
Janus kinase
- JJ012(S10):
-
Highly migratory primordial cell line, chondrosarcoma
- KE39:
-
Gastric carcinoma cell line
- K562:
-
Human myelogenous leukemia cell line
- K562-ADM:
-
Adriamycin resistant clone of K562
- KrasG12D:
-
Kirsten ras membrane signaling family, mammalian G12D mutant
- LNCaP:
-
Androgen-sensitive human prostate adenocarcinoma cell line
- LRP6:
-
Low-density lipoprotein receptor-related protein 6
- LuM1:
-
Murine colon adenocarcinoma cell line-1
- MAZ:
-
Myc-associated zinc-finger protein, transcription factor
- MCF-7:
-
Luminal A breast cancer cell line
- MDA-MB-231:
-
MD Andersen breast cancer cell line
- MEK/ERK:
-
Mitogen-activated protein kinases (MAPK)/extracellular signal-regulated kinase
- MET:
-
Mesenchymal epithelial transition
- MG-63:
-
Osteosarcoma cell line
- miR:
-
MicroRNA
- MKN45:
-
Gastric carcinoma cell line
- MMTV-Cre;Ccn6fl/fl:
-
Cre recombinase floxed Ccn 6 mouse model, construct on mouse mammary tumor virus background
- MMP7:
-
Metalloproteinase-7
- MMP-9:
-
Matrix metalloproteinase 9
- MST1/2:
-
Serine/threonine protein kinases, homologs of Hippo kinase
- p-mTOR:
-
Phosphorylated mammalian target of rapamycin
- cMyc:
-
Homology with avian virus, myelocytomatosis/cellular transcription factor C protooncogene
- Nalm-6:
-
B cell precursor leukemia cell line
- NCI-N87:
-
National Cancer Institute derived gastric carcinoma cell line
- NF-κB:
-
Nuclear factor kappa light chain enhancer of activated B cells
- NOS2:
-
Nitric oxide synthase-2
- NOS3:
-
Nitric oxide synthase-3
- NOD/SCID:
-
Non-obese diabetic /severe combined immunodeficiency mouse
- NUGC3:
-
Gastric cancer cell line
- NSCLC:
-
Non-small cell lung carcinoma
- PANC-1:
-
Pancreatic cancer cell line, ductal origin
- PanIN:
-
Pancreatic intraepithelial neoplasia, dysplasia
- PC-3AcT:
-
Prostate cancer cell line, acid tolerant
- Pgk1:
-
Phosphoglycerate kinase 1
- Pgam1:
-
Phosphoglycerate mutase 1
- PI3k:
-
Phosphoinositide-3-kinase
- PLG:
-
Plasminogen gene
- PTEN:
-
Phosphatase and tensin homolog
- TSP1:
-
Thrombospondin type 1 repeat
- RKO:
-
Poorly differentiated colon carcinoma cell line
- ROS:
-
Reactive oxygen species
- Runx2:
-
Runt-related transcription factor 2, osteogenesis
- SNAIL:
-
Zinc finger transcriptional repressor, downregulates expression of ectodermal genes within the mesoderm.
- Saos-2:
-
Osteosarcoma cell line
- SDC2:
-
Syndecan 2
- S1P2:
-
Sphingosine-1-Phosphate 2
- α-SMA:
-
Alpha smooth muscle actin
- SNA1:
-
RCI2 homologous gene, EMT marker Snail1
- SUM159:
-
Triple negative breast cancer cell line
- STAT3:
-
Signal transducer and activator of transcription 3
- TCF21:
-
Transcription factor 21 (TCF21), also known as pod-1
- TCF/LEF:
-
T cell factor/lymphoid enhancer factor, transcription factors
- TGFβR1:
-
Transforming growth factor beta receptor 1
- TIMP1:
-
Tissue inhibitor of metalloproteinase 1
- TRAIL:
-
TNF-related apoptosis-inducing ligand, apoptosis
- TSP2:
-
Thrombospondin-2
- U2OS:
-
Human osteosarcoma epithelial cell line
- U373-MG:
-
Glioblastoma cell line
- U87MG:
-
Glioblastoma cell line
- U251:
-
Glioblastoma cell line
- VCAM-1:
-
Vascular cell adhesion molecule 1
- VEGFC:
-
Vascular Endothelial Growth Factor C
- VWC:
-
Von Willebrand factor type C repeat
- Wnt:
-
Signaling pathways-a portmanteau created from the names Wingless and Int-1
- YAP/TEAD:
-
Yes-associated protein 1/TEAD transcription factor, Hippo signaling
- YAP/TAZ:
-
Transcription co-factors, Hippo signaling
- ZEB1:
-
Zinc finger E-box-binding homeobox 1 associated with EMT
- ZR-75–1:
-
Human breast cancer cell line, invasive ductal carcinoma
References
Abou-Kheir W, Mukherji D, Hadadeh O, Saleh E, Bahmad HF, Kanso M, Khalifeh M, Shamseddine A, Tamraz S, Jaafar R, Dagher C, Khalifeh I, Faraj W (2020) CYR61/CCN1 expression in resected pancreatic ductal adenocarcinoma: a retrospective pilot study of the interaction between the tumors and their surrounding microenvironment. Heliyon 6:e03842. https://doi.org/10.1016/j.heliyon.2020.e03842
Akashi S, Nishida T, Mizukawa T, Kawata K, Takigawa M, Iida S, Kubota S (2020) Regulation of cellular communication network factor 2 (CCN2) in breast cancer cells via the cell-type dependent interplay between CCN2 and glycolysis. J Oral Biosci 62:280–288. https://doi.org/10.1016/j.job.2020.07.001
Alsaqer SF, Tashkandi MM, Kartha VK, Yang Y-T, Alkherij Y, Salama A, Varelas X, Kukuruzinska M, Monti S, Bais MV (2017) Inhibition of LSD1 epigenetically attenuates oral cancer growth and metastasis. Oncotarget 43:73372–73386. https://doi.org/10.18632/oncotarget.19637
Appunni S, Anand V, Khandelwal M, Gupta N, Rubens M, Sharma A (2019) Small leucine rich proteoglycans (decorin, biglycan and lumican) in cancer. Clin Chim Acta 491:1–7. https://doi.org/10.1016/j.cca.2019.01.003
Armstrong CM, Gao AC (2017) CCN3-EZH2-AR feedback loop: new targets for enzalutamide and castration resistant prostate cancer. J Cell Commun Signal 11:89–91. https://doi.org/10.1007/s12079-017-0378-6
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
Chai D-M, Qin Y-Z, Wu S-W, Ma L, Tan Y-Y, Yong X, Wang X-L, Wang ZP, Tao Y-S (2019) WISP2 exhibits its potential antitumor activity via targeting ERK and E-cadherin pathways in esophageal cancer cells. J Exp Clin Cancer Res 38:102. https://doi.org/10.1186/s13046-019-1108-0
Chen P-C, Tai H-C, Lin T-H, Wang S-W, Lin C-Y, Chao C-C, Yu H-J, Tsai Y-C, Lai Y-W, Lin C-W, Tang C-H (2017) CCN3 promotes epithelial-mesenchymal transition in prostate cancer via FAK/Akt/HIF1α induced twist expression. Oncotarget 8:74506–74518. https://doi.org/10.18632/oncotarget.20171
Chen C-T, Lee H-L, Chiou H-L, Chou C-H, Wang P-H, Yang S-F, Chou Y-E (2018) Impacts of WNT1-inducible signaling pathway protein 1 polymorphism on hepatocellular carcinoma development. PLoS ONE 13:e0198967. https://doi.org/10.1371/journal.pone.0198967
Chen Z, Zhang N, Chu HY, Yu Y, Zhang Z-K, Zhang G, Zhang B-T (2020) Connective tissue growth factor: From molecular understandings to drug discovery. Front Cell Dev Biol 8: https://doi.org/10.3389/fcell.2020.593269
Chen P-C, Liu S-C, Lin T-H, Lin L-W, Wu H-C, Tai H-C, Wang S-W, Tang C-H (2021a) Prostate cancer-secreted CCN3 uses the GSK3β and β-catenin pathways to enhance osteogenic factor levels in osteoblasts mental. Toxicol 36:425–432. https://doi.org/10.1002/tox.23048
Chen R, Masuo K, Yogo A, Yokoyama S, Sugiyama A, Seno H, Yoshizawa A, Takaishi S (2021b) SNAIL regulates gastric carcinogenesis through CCN3 and NEFL. Carcinogenesis 42:190–201. https://doi.org/10.1093/carcin/bgaa133
Cheng J-C, Wang EY, Yi Y, Thakur A, Tsai S-H, Hoodless PA (2018) S1P stimulates proliferation by upregulating CTGF expression through S1PR2-mediated YAP activation. Mol Cancer Res 16:1543–1555. https://doi.org/10.1158/1541-7786.MCR-17-0681
Chevalier G, Yeger H, Martinerie C, Laurent M, Alami J, Schofield PN, Perbal B (1998) novH: differential expression in developing kidney and Wilm’s tumors. Am J Pathol 152:1563–1575
Crawford LJ, Irvine AE (2016) The role of the CCN family of proteins in blood cancers. J Cell Commun Signal 10:197–205. https://doi.org/10.1007/s12079-016-0342-x
Dang T, Modak C, Meng X, Wu J, Narvaez R, Chai J (2017) CCN1 sensitizes esophageal cancer cells to TRAIL-mediated apoptosis. Exp Cell Res 361:163–169. https://doi.org/10.1016/j.yexcr.2017.10.015
Dankner M, Ouellet V, Communal L, Schmitt E, Perkins D, Annis MG, Barrès V, Caron C, Mes-Masson A-M, Saad F, Siegel PM, the Canadian Prostate Cancer Biomarker Network (2019) CCN3/nephroblastoma overexpressed is a functional mediator of prostate cancer bone metastasis that is associated with poor patient prognosis. Am J Pathol 189:1451–1461. https://doi.org/10.1016/j.ajpath.2019.04.006)
Deng W, Fernandez A, McLaughlin SL, Klinke DJ (2019) WNT1-inducible signaling pathway protein 1 (WISP1/CCN4) stimulates melanoma invasion and metastasis by promoting the epithelial–mesenchymal transition. J Biol Chem 294:5261–5280. https://doi.org/10.1074/jbc.RA118.006122
Desnoyers L, Arnott D, Pennica D (2001) WISP-1 binds to decorin and biglycan. J Biol Chem 276:47599–47607. https://doi.org/10.1074/jbc.M108339200
Fong K-W, Zhao JC, Kim J, Li S, Yang YA, Song B, Rittie L, Hu M, Yang X, Perbal YuJ (2017) Polycomb-mediated disruption of an androgen receptor feedback loop drives castration-resistant prostate cancer. Cancer Res 77:412–422. https://doi.org/10.1158/0008
Gao H, Yin F-F, Guan D-X, Feng Y-X, Zheng Q-W, Wang X, Zhu M, Zhang X-L, Cheng S-O, Chen T-W, Jiang H, Zhang E-B, Wang J-J, Ni Q-Z, Yuan Y-M, Zhang F-K, Ma N, Cao H-J, Wang Y-K, Li J-J, Xie D (2019) Liver cancer: WISP3 suppresses hepatocellular carcinoma progression by negative regulation of β-catenin/TCF/LEF signaling. Cell Prolif 52:e12583. https://doi.org/10.1111/cpr.12583
Hao F, Xu Q, Zhao Y, Stevens JV, Young SH, Sinnett-Smith J, Rozengurt E (2017) Insulin receptor and GPCR crosstalk stimulates YAP via PI3K and PKD in pancreatic cancer cells. Mol Cancer Res 15:929–941. https://doi.org/10.1158/1541-7786.MCR-17-0023
Haque I, Ghosh A, Acup S, Banerjee S, Dhar K, Ray A, Sarkar S, Kambhampati S, Banerjee SK (2018) Leptin-induced ER-α-positive breast cancer cell viability and migration is mediated by suppressing CCN5-signaling via activating JAK/AKT/STAT-pathway. BMC Cancer 18:99. https://doi.org/10.1186/s12885-018-3993-6
Holbourn KP, Perbal B, Acharya KR (2009) Proteins on the catwalk: modelling the structural domains of the CCN family of proteins. J Cell Commun Signal 3:25–41. https://doi.org/10.1007/s12079-009-0048-4
Huang YT, Lan Q, Lorusso G, Duffey N, Ruegg C (2017) The matricellular protein CYR61 promotes breast cancer lung metastasis by facilitating tumor cell extravasation and suppressing anoikis. Oncotarget 8:9200–9215. https://doi.org/10.18632/oncotarget.13677
Huang X, Xiang L, Li Y, Zhao Y, Zhu H, Xiao Y, Liu M, Wu X, Wang Z, Jiang P, Qing H, Zhang Q, Liu G, Zhang W, Li A, Chen Y, Liu S, Wang J (2018) Snail/FOXK1/Cyr61 signaling axis regulates the epithelial–mesenchymal transition and metastasis in colorectal cancer. Cell Physiol Biochem 47:590–603. https://doi.org/10.1159/000490015
Hussain SR, Ali S, Singh A, Kumar V, Rizivi N (2017) Identification of the cysteine-rich 61 (CYR61) gene variations in osteosarcoma patients. Turk J Med Sci 47:287–294. https://doi.org/10.3906/sag-1509-4
Hutchenreuther J, Vincent K, Norley C, Racanelli M, Gruber SB, Johnson TM, Fullen DR, Raskin L, Perbal B, Holdsworth DW, Postovit L-M, Leask A (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
Ilhan M, Kucukkose C, Efe E, Gunyuz ZE, Firatligil B, Dogan H, Ozuysal M, Yalcin-Ozuysal O (2020) Pro-metastatic functions of Notch signaling is mediated by CYR61 in breast cells. Eur J Cell Biol 99:151070. https://doi.org/10.1016/j.ejcb.2020.151070
Jia Q, Bu Y, Wang Z, Chen B, Zhang Q, Yu S, Liu Q (2017) Maintenance of stemness is associated with the interaction of LRP6 and heparin-binding protein CCN2 autocrined by hepatocellular carcinoma. J Exp Clin Cancer Res 36:117. https://doi.org/10.1186/s13046-017-0576-3
Jia Q, Xue T, Zhang Q, Cheng W, Zhang C, Ma J, Bu Y, Yu S, Liu Q (2019) CCN3 is a therapeutic target relating enhanced stemness and coagulation in hepatocellular carcinoma. Sci Rep 7:13846. https://doi.org/10.1038/s41598-017-14087-4
Jing D, Zhang Q, Yu H, Zhao Y, Shen L (2017) Identification of WISP1 as a novel oncogene in glioblastoma. Int J Oncol 51:1261–1270. https://doi.org/10.3892/ijo.2017.4119
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
Kaasbøll OJ, Gadicherla AK, Wang J-H, Monsen VT, Hagelin EMV, Dong M-Q, Attramadal H (2018) Connective tissue growth factor (CCN2) is a matricellular preproprotein controlled by proteolytic activation. J Biol Chem 293:17953–17970. https://doi.org/10.1074/jbc.RA118.004559
Lau H-K, Wu E-R, Chen M-K, Hsieh M-J, Yang S-F, Wang L-Y, Chou Y-E (2017) Effect of genetic variation in microRNA binding site in WNT1-inducible signaling pathway protein 1 gene on oral squamous cell carcinoma susceptibility. PLoS ONE 12:e0176246. https://doi.org/10.1371/journal.pone.0176246
Lazar N, Manara C, Navarro S, Bleau AM, Llombart-Bosch A, Scotlandi K, Planque N, Perbal B (2007) Domain-specific CCN3 antibodies as unique tools for structural and functional studies. J Cell Commun Signal 1:91–102. https://doi.org/10.1007/s12079-007-0009-8
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. Sem 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–C1054. https://doi.org/10.1152/ajpcell.00028.2020
Lee Y-J, Nam H-S, Cho M-K, Lee S-H (2020) Arctigenin induces necroptosis through mitochondrial dysfunction with CCN1 upregulation in prostate cancer cells under lactic acidosis. Mol Cell Biochem 467:45–56. https://doi.org/10.1007/s11010-020-03699-6
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 11:1–32. https://doi.org/10.1007/s12079-020-00602-2
Li X, Ling W, Khan S, Yaccoby S (2012) Therapeutic effects of intrabone and systemic mesenchymal stem cell cytotherapy on myeloma bone disease and tumor growth. J Bone Miner Res 27:1635–1648. https://doi.org/10.1002/jbmr.1620
Li J, Ye L, Sun P-H, Zheng F, Ruge F, Satherley LK, Feng Y, Zhao H, Du G, Wang T, Yang Y, Ma X, Cheng S, Yang X, Yu H, Teng X, Si Y, Zhang Z, Jiang WG (2017) Reduced NOV expression correlates with disease progression in colorectal cancer and is associated with survival, invasion and chemoresistance of cancer cells. Oncotarget 8:26231–26244. https://doi.org/10.18632/oncotarget.15439
Li W, Liao X, Ning P, Cao Y, Zhang M, Bu Y, Lv J, Jia Q (2019a) Paracrine effects of CCN3 from noncancerous hepatic cells increase signaling and progression of hepatocellular carcinoma. BMC Cancer 19:395. https://doi.org/10.1186/s12885-019-5603-7
Li H, Li J, Cheng J, Chen X, Zhou L, Li Z (2019b) AML-derived mesenchymal stem cells upregulate CTGF expression through the BMP pathway and induce K562-ADM fusiform transformation and chemoresistance. Oncol Rep 42:1035–1046. https://doi.org/10.3892/or.2019.7237
Liao X, Bu Y, Jiang S, Chang F, Jia F, Xiao X, Song G, Zhang M, Ning P, Jia Q (2019a) 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/s12072-019-099960-5
Liao X, Bu Y, Chang F, Jia F, Song G, Xiao X, Zhang M, Ning P, Jia Q (2019b) Remodeling of hepatic stellate cells orchestrated the stroma-derived oxaliplatin-resistance through CCN3 paracrine in hepatocellular carcinoma. BMC Cancer 19:1192
Lin C-C, Chen P-C, Lein M-Y, Tsao C-W, Huang C-C, Wang S-W, Tang C-H, Tung K-C (2016) WISP-1 promotes VEGF-C-dependent lymphangiogenesis by inhibiting miR-300 in human oral squamous cell carcinoma cells. Oncotarget 7:9993–10005. https://doi.org/10.18632/oncotarget.7014
Liu S, Liu Z, Bi DB, Yuan XD, Liu XW, Ding ST, Lu JJ, Niu ZH (2012) CCN3 (NOV) regulates proliferation, adhesion, migration and invasion in clear cell renal cell carcinoma. Oncol Lett 35:1099–1104. https://doi.org/10.3892/ol.2012.607
Liu S, Han L, Wang X, Liu Z, Ding S, Lu J, Bi D, Mei Y, Niu Z (2015) 1 Nephroblastoma overexpressed gene (NOV) enhances RCC cell motility through upregulation of ICAM-1 and COX-2 expression via Akt pathway. Int J Clin Exp Pathol 8:1302–1311
Liu Y, Song Y, Ye M, Hu X, Wang ZP, Zhu X (2019) The emerging role of WISP proteins in tumorigenesis and cancer therapy. J Transl Med 17:28. https://doi.org/10.1186/s12967-019-1769-7
Maity G, Haque I, Ghosh A, Dhar G, Gupta V, Sarkar S, Azeem I, McGregor D, Choudhary A, Campbell DR, Kambhampati S, Banerjee SK, Banerjee S (2018) The MAZ transcription factor is a downstream target of the oncoprotein Cyr61/CCN1 and promotes pancreatic cancer cell invasion via CRAF–ERK signaling. J Biol Chem 293:4334–4349. https://doi.org/10.1074/jbc.RA117.000333
Maity G, Ghosh A, Gupta V, Haque I, Sarkar S, Das A, Dhar K, Bhavanasi S, Gunewardena SS, Von Hoff DD, Mallik S, Kambhampati S, Banerjee SK, Banerjee S (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
Makino Y, Hikita H, Kodama T, Shigekawa M, Yamada R, Sakamori R, Eguchi H, Morii E, Yokoi H, Mukoyama M, Hiroshi S, Tatsumi T, Takehara T (2018) CTGF mediates tumor–stroma interactions between hepatoma cells and hepatic stellate cells to accelerate HCC progression. Cancer Res 78:4902–4914. https://doi.org/10.1158/0008-5472.CAN-17-3844
McMullen ER, Zoumberos NA, Kleer CG (2019) Metaplastic breast carcinoma update on histopathology and molecular alterations. Arch Pathol Lab Med 143:1492–1496. https://doi.org/10.5858/arpa.2019-0396-RA
Neely BA, Wilkins CE, Marlow LA, Malyarenko D, Kim Y, Ignatchenko A, Sasinowska H, Sasinowski M, Nyalwidhe JO, Kislinger T, Copland JA, Drake RR (2016) Proteotranscriptomic analysis reveals stage specific changes in the molecular landscape of clear-cell renal cell carcinoma. PLoS ONE 11:e0154074. https://doi.org/10.1371/journal.pone.0154074
Nikitovic D, Berdiaki K, Chalkiadaki G, Karamanos N, Tzanakakis G (2008) The role of SLRP-proteoglycans in osteosarcoma pathogenesis. Connect Tissue Res 49:235–238. https://doi.org/10.1080/03008200802147589
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
Ohara Y, Chew SH, Misawa N, Wang S, Somiya D, Nakamura K, Kajiyama H, Kikkawa F, Tsuyuki Y, Jiang L, Yamashita K, Sekido Y, Lipson KE, Toyokuni S (2018) Connective tissue growth factor-specific monoclonal antibody inhibits growth of malignant mesothelioma in an orthotopic mouse model. Oncotarget 9:18494–18509. https://doi.org/10.18632/oncotarget.24892
Ohta K, Aoyama E, Ahmad SAI, Ito N, Anam MB, Kubota S, Takigawa M (2019) CCN2/CTGF binds the small leucine rich proteoglycan protein Tsukushi. J Cell Commun Signal 13:113–118. https://doi.org/10.1007/s12079-018-0487-x
Okusha Y, Eguchi T, Tran MT, Sogawa C, Yoshida K, Itagaki M, Taha EA, Ono K, Aoyama E, Okamura H, Kozaki K-I, Calderwood SK, Takigawa M, Okamoto K (2020) Extracellular Vesicles enriched with moonlighting metalloproteinase are highly transmissive, pro-tumorigenic, and trans-activates cellular communication network factor (CCN2/CTGF): CRISPR against cancer. Cancers 12:881. https://doi.org/10.3390/cancers12040881
Otani Y, Ishida J, Kurozumi K, Oka T, Shimizu T, Tomita Y, Hattori Y, Uneda A, Matsumoto Y, Michiue H, Tomida S, Matsubara T, Ichikawa T, Date I (2017) PIK3R1Met326Ile germline mutation correlates with cysteine rich protein 61 expression and poor prognosis in glioblastoma. Sci Rep 7:7391. https://doi.org/10.1038/s41598-017-07745-0
Perbal B (2004) CCN proteins: multifunctional signalling regulators. Lancet 363:62–64. https://doi.org/10.1016/S0140-6736(03)15172-0
Perbal B (2012) Flaws in the peer-reviewing process: a critical look at a recent paper studying the role of CCN3 in renal cell carcinoma. J Cell Commun Signal 6:181–184. https://doi.org/10.1007/s12079-012-0174-2
Perbal B (2013) CCN proteins: a centralized communication network. J Cell Commun Signal 7:169–177. https://doi.org/10.1007/s12079-013-0193-7
Perbal B (2018) The concept of the CCN protein family revisited: a centralized coordination network. J Cell Commun Signal 12:3–12. https://doi.org/10.1007/s12079-018-0455-5
Perbal A, Perbal B (2016) The CCN family of proteins: a 25th anniversary picture. J Cell Commun Signal 10:177–190. https://doi.org/10.1007/s12079-016-0340-z
Perbal B, Tweedie S, Bruford E (2018) The official unified nomenclature adopted by the HGNC calls for the use of the acronyms, CCN1–6, and discontinuation in the use of CYR61, CTGF, NOV and WISP 1–3 respectively. J Cell Commun Signal 12:625–629. https://doi.org/10.1007/s12079-018-0491-1
Proposal for a unified CCN nomenclature (2001) J Clin Pathol Mol Pathol 54: 108. https://doi.org/10.1136/mp.54.2.108
Ramazani Y, Knops N, Elmonem MA, Nguyen TQ, Arcolino FO, van den Heuvel L, Leytchenko E, Kuypers D, Gpldschmeding R (2018) Connective tissue growth factor (CTGF) from basics to clinics. Matrix Biol 68–69:44–66. https://doi.org/10.1016/j.matbio.2018.03.007
Resovi A, Bani M-R, Porcu L, Anastasia A, Minoli L, Allavena P, Cappello P, Novelli F, Scarpa A, Morandi E, Falanga A, Torri V, Taraboletti G, Belotti D, Giavazzi R (2018) Soluble stroma-related biomarkers of pancreatic cancer. EMBO Mol Med 10:e874. https://doi.org/10.15252/emmm.201708741
Resovi A, Borsotti P, Ceruti T, Passoni A, Zucchetti M, Berndt A, Riser BL, Taraboletti G, Belotti D (2020) CCN-based therapeutic peptides modify pancreatic ductal adenocarcinoma microenvironment and decrease tumor growth in combination with chemotherapy. Cells 9:952. https://doi.org/10.3390/cells9040952
Shao H, Cai L, Moller M, Issac B, Zhang L, Owyong M, Moscowitz AE, Vazquez-Padron R, Radtke F, Liu Z-J (2016) Notch1—WISP-1 axis determines the regulatory role of mesenchymal stem cell-derived stromal fibroblasts in melanoma metastasis. Oncotarget 48:79262–79273. https://doi.org/10.18632/oncotarget.13021
Shi W, Zhang C, Chen Z, Chen H, Liu L, Meng Z (2016) Cyr61-positive cancer stem-like cells enhances distal metastases of pancreatic cancer. Oncotarget 7:73160–73170. https://doi.org/10.18632/oncotarget.12248
Shi J, Huo R, Li N, Li H, Zhai T, Li H, Shen B, Ye J, Fu R, Di W (2019) BMC CYR61, a potential biomarker of tumor inflammatory response in epithelial ovarian cancer microenvironment of tumor progress. Cancer 19:1140. https://doi.org/10.1186/s12885-019-6321-x
Shimbo A, Kajiyama H, Tamauchi S, Yoshikawa N, Ikeda Y, Nishino K, Suzuki S, Niimi K, Sakata J, Kikkawa F (2019) Expression of connective tissue growth factor as a prognostic indicator and its possible involvement in the aggressive properties of epithelial ovarian carcinoma. Oncol Rep 42:2323–2332. https://doi.org/10.3892/or.2019.7352
Song Y, Lin Q, Cai Z, Hao T, Zhang Y, Zhu X (2019) Cysteine-rich protein 61 regulates the chemosensitivity of chronic myeloid leukemia to imatinib mesylate through the nuclear factor kappa B/Bcl-2 pathway. Cancer Sci 110:2421–30. https://doi.org/10.1111/cas.14083
Su R-L, Qiao Y, Guo R-F, Lv Y-Y (2019) Cyr61 overexpression induced by interleukin 8 via NF-kB signaling pathway and its role in tumorigenesis of gastric carcinoma in vitro. Int J Clin Exp Pathol 12:3197–3207
Subramaniam MM, Lazar N, Navarro S, Perbal B, Llombart-Bosch A (2008) Expression of CCN3 protein in human Wilms’ tumors: immunohistochemical detection of CCN3 variants using domain-specific antibodies. Virchows Arch 452:33–39. https://doi.org/10.1007/s00428-007-0523-3
Tao W, Chu C, Zhou W, Huang Z, Zhai K, Fang X, Huang Q, Zhang A, Wang X, Yu X, Huang H, Wu Q, Sloan AE, Yu JS, Li X, Stark GR, Rich JN, Bao S (2020) Dual role of WISP1 in maintaining glioma stem cells and tumor-supportive macrophages in glioblastoma. Nat Commun 11:3015. https://doi.org/10.1038/s41467-020-16827-z
Tran MN, Kleer CG (2018) Matricellular CCN6 (WISP3) protein: a tumor suppressor for mammary metaplastic carcinomas. J Cell Commun Signal 12:13–19. https://doi.org/10.1007/s12079-018-0451-9
Tsai H-C, Chang A-C, Tsai C-H, Huang Y-L, Gan L, Chen C-K, Liu S-C, Huang T-Y, Fong Y-C, Tang C-H (2019) CCN2 promotes drug resistance in osteosarcoma by enhancing ABCG2 expression. J Cell Physiol 234:9297–9307. https://doi.org/10.1002/jcp.27611
Tsang M, Quesnel K, Vincent K, Hutchenreuther J, Postovit L-M, Leask A (2020) Cellular communication network 2 is required for activation of cancer-associated fibroblasts in a murine model of melanoma. Am J Pathol 190:206–221. https://doi.org/10.1016/j.apath.2019.09.006
Tzeng H-E, Tang C-H, Wu S-H, Chen H-T, Fong Y-C, Lu Y-C, Chen W-C, Huang H-D, Lin C-Y, Wang S-W (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
Ubink I, Verhaar ER, Kranenburg O, Goldschmeding R (2016) A potential role for CCN2/CTGF in aggressive colorectal cancer. J Cell Commun Signal 10:223–227. https://doi.org/10.1007/s12079-016-0347-5
Vatanmakanian M, Tavallaie M, Ghadami S (2019) Imatinib independent aberrant methylation of NOV/CCN3 in chronic myelogenous leukemia patients: a mechanism upstream of BCR-ABL1 function? Cell Commun Signal 17:38. https://doi.org/10.1186/s12964-019-0350-6
Vial C, Gutierrez J, Santander C, Cabrera D, Brandan E (2011) Decorin Interacts with connective tissue growth factor (CTGF)/CCN2 by LRR12 inhibiting its biological activity. J Biol Chem 286:24242–24252. https://doi.org/10.1074/jbc.M110.189365
Videira A, Beckedorff FC, daSilva LF, Verjovski-Almeida S (2021) PVT1 signals an androgen-dependent transcriptional repression program in prostate cancer cells and a set of the repressed genes predicts high-risk tumors. Cell Commun Signal 19:5. https://doi.org/10.1186/s12964-020-00691-x
Vyskocil E, Pammer J, Altorjai G, Ch GM, Parzefall T, Haymerle G, Janik S, Perisanidis C, Erovic BM (2019) Dysregulation of ß-catenin, WISP1 and TCF21 predicts disease-specific survival and primary response against radio (chemo)therapy in patients with locally advanced squamous cell carcinomas of the head and neck. Clin Otolaryngol 44:263–272. https://doi.org/10.1111/coa.13281
Wang Y, Wang M (2016) Prognostic significance of expression of cysteine-rich 61 and cyclooxygenase-2 in gastric cancer. BMC Gastroenterol 16:74. https://doi.org/10.1186/s12876-016-0478-4
Wang X, Xu T, Gao F, He H, Zhu Y, Shen Z (2017) Targeting of CCN2 suppresses tumor progression and improves chemo-sensitivity in urothelial bladder cancer. Oncotarget 39:66316–66327. https://doi.org/10.18632/oncotarget.19987
Wu J, Long X, Cai H, Du C, Liu X, Yu S, Wang Y (2016) High expression of WISP1 in colon cancer is associated with apoptosis, invasion and poor prognosis. Oncotarget 31:49834–49847. https://doi.org/10.18632/oncotarget.10486
Wu Y-L, Li H-Y, Zhao X-P, Jiao J-Y, Tang D-X, Yan L-J, Wan Q, Chao-Bin Pan C-B (2017) Mesenchymal stem cell-derived CCN2 promotes the proliferation, migration and invasion of human tongue squamous cell carcinoma cells. Cancer Sci 108:897–909. https://doi.org/10.1111/cas.13202
Xie L, Song X, Lin H, Chen Z, Li Q, Guo T, Xu T, Su T, Xu M, Chang X, Wang L-K, Liang B, Huang D (2019) Aberrant activation of CYR61 enhancers in colorectal cancer development. J Exp Clin Cancer Res 38:213. https://doi.org/10.1186/s13046-019-1217-9
Xu Y, Chu H, Zhou Y, Wang J, Dong C, Yin R (2018) miR-365 functions as a tumor suppressor by directly targeting CYR61 in osteosarcoma. Biomed Pharmacother 90:531–537. https://doi.org/10.1016/j.biopha.2017.12.086
Yamada T, Ohta K, Motook Y, Fujino K, Kudoh SY, Sato Y, Matsuo A, Ikeda K, Suzuki M, Ito T (2019) Significance of Tsukushi in lung cancer. Lung Cancer 131(104):111. https://doi.org/10.1016/j.lungcan.2019.03.024
Yan J, Yang B, Lin S, Xing R, Lu Y (2019) Downregulation of miR-142-5p promotes tumor metastasis through directly regulating CYR61 expression in gastric cancer. Gastric Cancer 22:302–313. https://doi.org/10.1007/s10120-018-0872-4
Yan S, Liu H, Liu Z, Peng F, Jiang F, Li L, Fu R (2020) CCN1 stimulated the osteoblasts via PTEN/AKT/GSK3β/cyclinD1 signal pathway in myeloma bone disease. Cancer Med 9:737–744. https://doi.org/10.1002/cam4.2608
Yeger H, Perbal B (2016) CCN family of proteins: critical modulators of the tumor cell microenvironment. J Cell Commun Signal 10:229–240. https://doi.org/10.1007/s12079-016-0346-6
Zaidi ARS, Dresman S, Burt C, Rule S, McCallum L (2019) Molecular signatures for CCN1, p21 and p27 in progressive mantle cell lymphoma. J Cell Commun Signal 13:421–434. https://doi.org/10.1007/s12079-018-0494-y
Zhang F, Chen H, Du J, Wang B, Yang L (2018) Anticancer activity of metformin, an antidiabetic drug, against ovarian cancer cells involves inhibition of cysteine-rich 61 (Cyr61)/Akt/mammalian target of rapamycin (mTOR) signaling pathway. Med Sci Monit 24:6093–6101. https://doi.org/10.12659/MSM.909745
Zhang L-H, Qian Y-W, Fan Q, Yan Q-F, Kui F-Y, Long L, Li H, Xiao H-L, Qi W, Mao Y, Hua D (2019) Up-regulated Wnt1-inducible signaling pathway protein 1 correlates with poor prognosis and drug resistance by reducing DNA repair in gastric cancer. World J Gastroenterol 25:5814–5825. https://doi.org/10.3748/wjg.v25.i38.5814
Zhu X, Song Y, Wu C, Pan C, Lu P, Wang M, Zheng P, Huo R, Zhang C, Li W, Lin Y, Cao Y, Li N (2016) Cyr61 participates in the pathogenesis of acute lymphoblastic leukemia by enhancing cellular survival via the AKT/NF-κB signaling pathway. Sci Rep 6:34018. https://doi.org/10.1038/srep34018
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Yeger, H., Perbal, B. The CCN axis in cancer development and progression. J. Cell Commun. Signal. 15, 491–517 (2021). https://doi.org/10.1007/s12079-021-00618-2
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DOI: https://doi.org/10.1007/s12079-021-00618-2