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Cancer Cell International
Published in: Cancer Cell International 1/2019

Open Access 01-12-2019 | Metastasis | Primary research

Human colorectal cancer-derived carcinoma associated fibroblasts promote CD44-mediated adhesion of colorectal cancer cells to endothelial cells by secretion of HGF

Authors: Rongsheng Zhang, Fan Qi, Shengli Shao, Geng Li, Yongdong Feng

Published in: Cancer Cell International | Issue 1/2019

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Abstract

Background

Carcinoma-associated fibroblasts (CAFs) are dominant components of tumor microenvironment, which has been reported to promote development, progression, and metastasis of cancer. However, the role of CAFs during adhesion process remains unknown. It has been hypothesized that CAFs contribute to adhesion to endothelial cells of colorectal cancer (CRC) via HGF/c-Met pathway.

Methods

Clinical specimen and orthotopic liver metastasis model was used to investigate association between CD44 expression and propensity of metastasis in CRC. Human CRC derived cancer associated fibroblasts was isolated and its effect on migration and adhesion of CRC cells was investigated. We also confirm the conclusion on animal metastasis model.

Results

In this study, clinical specimen and orthotopic liver metastatic model indicated that overexpression of CD44 is associated with CRC metastasis, and we found that colorectal cancer-derived CAFs (CC-CAFs) increased the adhesion and migration of CRC cells in vitro through up-regulation of CD44, we also found that CC-CAFs promoted adhesion and liver or lung metastasis in vivo. Mechanistically, we found that the expression of HGF increased tenfolds compared CC-CAFs with adjacent normal fibroblasts, and HGF promoted adhesion through up-regulation of CD44 via HGF/c-MET signal pathway.

Conclusions

These results indicated that CC-CAFs-derived HGF induced up-regulation of CD44 which mediated adhesion of CRC cells to endothelial cells, and subsequently resulted in enhancement of metastasis of CRC cells, it could provide a novel therapeutic or preventive target.
Literature
1.
Elliott VA, Rychahou P, Zaytseva YY, Evers BM. Activation of c-Met and upregulation of CD44 expression are associated with the metastatic phenotype in the colorectal cancer liver metastasis model. PLoS ONE. 2014;9:e97432.CrossRef
2.
Hunter KW, Crawford NP, Alsarraj J. Mechanisms of metastasis. New York: Springer; 2008.CrossRef
3.
Senbanjo LT, Chellaiah MA. CD44: a multifunctional cell surface adhesion receptor is a regulator of progression and metastasis of cancer cells. Front Cell Dev Biol. 2017;5:18.CrossRef
4.
Lee SY, Kim KA, Kim CH, Kim YJ, Lee JH, Kim HR. CD44-shRNA recombinant adenovirus inhibits cell proliferation, invasion, and migration, and promotes apoptosis in HCT116 colon cancer cells. Int J Oncol. 2017;50:329–36.CrossRef
5.
Mao M, Zheng X, Jin B, Zhang F, Zhu L, Cui L. Effects of CD44 and E-cadherin overexpression on the proliferation, adhesion and invasion of ovarian cancer cells. Exp Ther Med. 2017;14:5557–63.PubMedPubMedCentral
6.
Garouniatis A, Zizi-Sermpetzoglou A, Rizos S, Kostakis A, Nikiteas N, Papavassiliou AG. FAK, CD44v6, c-Met and EGFR in colorectal cancer parameters: tumour progression, metastasis, patient survival and receptor crosstalk. Int J Colorectal Dis. 2012;28:9–18.CrossRef
7.
Orian-Rousseau V. CD44, a therapeutic target for metastasising tumours. Eur J Cancer. 2010;46:1271–7.CrossRef
8.
Yan Y. Role of cancer-associated fibroblasts in invasion and metastasis of gastric cancer. World J Gastroenterol. 2015;21:9717.CrossRef
9.
Shiga K, Hara M, Nagasaki T, Sato T, Takahashi H, Takeyama H. Cancer-associated fibroblasts: their characteristics and their roles in tumor growth. Cancers. 2015;7:2443–58.CrossRef
10.
Gao P, Li C, Chang Z, Wang X, Xuan M. Carcinoma associated fibroblasts derived from oral squamous cell carcinoma promote lymphangiogenesis via c-Met/PI3K/AKT in vitro. Oncol Lett. 2018;15:331–7.PubMed
11.
Zhang X, Hu F, Li G, Li G, Yang X, Liu L, Zhang R, Zhang B, Feng Y. Human colorectal cancer-derived mesenchymal stem cells promote colorectal cancer progression through IL-6/JAK2/STAT3 signaling. Cell Death Dis. 2018;9:25.CrossRef
12.
Zhu Q, Zhang X, Zhang L, Li W, Wu H, Yuan X, Mao F, Wang M, Zhu W, Qian H, Xu W. The IL-6-STAT3 axis mediates a reciprocal crosstalk between cancer-derived mesenchymal stem cells and neutrophils to synergistically prompt gastric cancer progression. Cell Death Dis. 2014;5:e1295.CrossRef
13.
Kwon Y, Godwin AK. Regulation of HGF and c-MET interaction in normal ovary and ovarian cancer: importance of targeting c-MET and HGF interaction. Reprod Sci. 2017;24:494–501.CrossRef
14.
Arlt F, Stein U. Colon cancer metastasis: MACC1 and Met as metastatic pacemakers. Int J Biochem Cell Biol. 2009;41:2356–9.CrossRef
15.
Giordano S, Di RM, Olivero M, Mondino A, Zhen Z, Medico E, Comoglio PM. The c-met/HGF receptor in human tumours. Eur J Cancer Prev. 1992;1(Suppl 3):45.CrossRef
16.
Damm S, Koefinger P, Stefan M, Wels C, Mehes G, Richtig E, Kerl H, Otte M, Schaider H. HGF-promoted motility in primary human melanocytes depends on CD44v6 regulated via NF-kappa B, Egr-1, and C/EBP-beta. J Invest Dermatol. 2010;130:1893–903.CrossRef
17.
Kalluri R. The biology and function of fibroblasts in cancer. Nat Rev Cancer. 2016;16:582–98.CrossRef
18.
Cheng Y, Li H, Deng Y, Tai Y, Zeng K, Zhang Y, Liu W, Zhang Q, Yang Y. Cancer-associated fibroblasts induce PDL1+ neutrophils through the IL6-STAT3 pathway that foster immune suppression in hepatocellular carcinoma. Cell Death Dis. 2018;9:422.CrossRef
19.
Deying W, Feng G, Shumei L, Hui Z, Ming L, Hongqing W. CAF-derived HGF promotes cell proliferation and drug resistance by up-regulating the c-Met/PI3K/Akt and GRP78 signalling in ovarian cancer cells. Biosci Rep. 2017;37:BSR20160470.CrossRef
20.
Karakasheva TA, Lin EW, Tang Q, Qiao E, Waldron TJ, Soni M, Klein-Szanto AJ, Sahu V, Basu D, Ohashi S, Baba K, Giaccone ZT, Walker SR, Frank DA, Wileyto EP, Long Q, Dunagin M, Raj A, Diehl JA, Wong KK, Bass AJ, Rustgi AK. IL-6 mediates cross-talk between activated fibroblasts and tumor cells in the tumor microenvironment. Cancer Res. 2018;78(17):4957–70.CrossRef
21.
Ying L, Zhu Z, Xu Z, He T, Li E, Guo Z, Liu F, Jiang C, Wang Q. Cancer associated fibroblast-derived hepatocyte growth factor inhibits the paclitaxel-induced apoptosis of lung cancer A549 cells by up-regulating the PI3K/Akt and GRP78 signaling on a microfluidic platform. PLoS ONE. 2015;10:e0129593.CrossRef
22.
Owusu BY, Galemmo R, Janetka J, Klampfer L. Hepatocyte growth factor, a key tumor-promoting factor in the tumor microenvironment. Cancers (Basel). 2017;9:35.CrossRef
23.
Konstorum A, Lowengrub JS. Activation of the HGF/c-Met axis in the tumor microenvironment: a multispecies model. J Theor Biol. 2018;439:86–99.CrossRef
24.
Yi Y, Zeng S, Wang Z, Wu M, Ma Y, Ye X, Zhang B, Liu H. Cancer-associated fibroblasts promote epithelial-mesenchymal transition and EGFR-TKI resistance of non-small cell lung cancers via HGF/IGF-1/ANXA2 signaling. Biochim Biophys Acta. 2018;1864:793–803.CrossRef
25.
Li H, Fan X, Houghton J. Tumor microenvironment: the role of the tumor stroma in cancer. J Cell Biochem. 2010;101:805–15.CrossRef
26.
Mine S. Hepatocyte growth factor enhances adhesion of breast cancer cells to endothelial cells in vitro through up-regulation of CD44. Exp Cell Res. 2003;288:189–97.CrossRef
27.
Naldini L, Weidner KM, Vigna E, Gaudino G, Bardelli A, Ponzetto C, Narsimhan RP, Hartmann G, Zarnegar R, Michalopoulos GK. Scatter factor and hepatocyte growth factor are indistinguishable ligands for the MET receptor. EMBO J. 1991;10:2867–78.CrossRef
28.
Nakamura T, Nishizawa T, Hagiya M, Seki T, Shimonishi M, Sugimura A, Tashiro K, Shimizu S. Molecular cloning and expression of human hepatocyte growth factor. Nature. 1989;342:440–3.CrossRef
29.
Liska D, Chen CT, Bachleitner-Hofmann T, Christensen JG, Weiser MR. HGF rescues colorectal cancer cells from EGFR inhibition via MET activation. Clin Cancer Res. 2011;17:472–82.CrossRef
30.
Straussman R, Morikawa T, Shee K, Barzily-Rokni M, Qian ZR, Du J, Davis A, Mongare MM, Gould J, Frederick DT, Cooper ZA, Chapman PB, Solit DB, Ribas A, Lo RS, Flaherty KT, Ogino S, Wargo JA, Golub TR. Tumour micro-environment elicits innate resistance to RAF inhibitors through HGF secretion. Nature. 2012;487:500–4.CrossRef
31.
Lesko E, Majka M. The biological role of HGF-MET axis in tumor growth and development of metastasis. Front Biosci. 2008;13:1271–80.CrossRef
32.
Pennacchietti S, Cazzanti M, Bertotti A, Han M, Gyuris J, Perera T, Comoglio PM, Trusolino L, Michieli P. Microenvironment-derived HGF overcomes genetically determined sensitivity to anti-MET drugs. Can Res. 2014;74:6598–609.CrossRef
33.
Junttila MR, Sauvage FJD. Influence of tumour micro-environment heterogeneity on therapeutic response. Nature. 2013;501:346–54.CrossRef
34.
Tomita T, Sakurai Y, Ishibashi S, Maru Y. Imbalance of Clara cell-mediated homeostatic inflammation is involved in lung metastasis. Oncogene. 2011;30:3429.CrossRef
Metadata
Title
Human colorectal cancer-derived carcinoma associated fibroblasts promote CD44-mediated adhesion of colorectal cancer cells to endothelial cells by secretion of HGF
Authors
Rongsheng Zhang
Fan Qi
Shengli Shao
Geng Li
Yongdong Feng
Publication date
01-12-2019
Publisher
BioMed Central
Published in
Cancer Cell International / Issue 1/2019
Electronic ISSN: 1475-2867
DOI
https://doi.org/10.1186/s12935-019-0914-y

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