Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

At a glance: The STEP trials

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.
ADVANCED SEARCH
Log in
Top
Tumor Biology
Published in: Tumor Biology 2/2016

01-02-2016 | Original Article

Cancer-associated fibroblasts promote angiogenesis in gastric cancer through galectin-1 expression

Authors: Dong Tang, Jun Gao, Sen Wang, Nianyuan Ye, Yang Chong, Yuqin Huang, Jie Wang, Bin Li, Wei Yin, Daorong Wang

Published in: Tumor Biology | Issue 2/2016

Login to get access

Abstract

Background

Galectin-1, an evolutionarily conserved glycan-binding protein with angiogenic potential, was recently identified as being overexpressed in cancer-associated fibroblasts (CAFs) of gastric cancer. The role of endogenous CAF-derived galectin-1 on angiogenesis in gastric cancer and the mechanism involved remain unknown.

Methods

Immunohistochemical staining was used to investigate the correlation between galectin-1 and vascular endothelial growth factor (VEGF) and CD31 expression in gastric cancer tissues and normal gastric tissues. Galectin-1 was knocked down in CAFs isolated from gastric cancer using small interfering ribonucleic acid (RNA), or overexpressed using recombinant lentiviruses, and the CAFs were co-cultured with human umbilical vein endothelial cells (HUVECs) or cancer cells. Subsequently, proliferation, migration, tube formation, and VEGF/VEGF receptor (VEGFR) 2 expression were detected. The role of CAF-derived galectin-1 in tumor angiogenesis in vivo was studied using the chick chorioallantoic membrane (CAM) assay.

Results

Galectin-1 was highly expressed in the CAFs and was positively associated with VEGF and CD31 expression. In the co-culture, high expression of galectin-1 in the CAFs increased HUVEC proliferation, migration, tube formation, and VEGFR2 phosphorylation and enhanced VEGF expression in gastric cancer cells. The CAM assay indicated that high expression of galectin-1 in the CAFs accelerated tumor growth and promoted angiogenesis. In contrast, galectin-1 knockdown in the CAFs significantly inhibited this effect.

Conclusion

CAF-derived galectin-1 significantly promotes angiogenesis in gastric cancer and may be a target for angiostatic therapy.
Literature
1.
Kalluri R, Zeisberg M. Fibroblasts in cancer, nature reviews. Cancer. 2006;6:392–401.PubMed
2.
Fuyuhiro Y, Yashiro M, Noda S, Matsuoka J, Hasegawa T, Kato Y, et al. Cancer-associated orthotopic myofibroblasts stimulates the motility of gastric carcinoma cells. Cancer Sci. 2012;103:797–805.CrossRefPubMed
3.
Sung CO, Lee KW, Han S, Kim SH. Twist1 is up-regulated in gastric cancer-associated fibroblasts with poor clinical outcomes. Am J Pathol. 2011;179:1827–38.CrossRefPubMedPubMedCentral
4.
Worthley DL, Giraud AS, Wang TC. Stromal fibroblasts in digestive cancer. Cancer Microenviron: Off J Int Cancer Microenviron Soc. 2010;3:117–25.CrossRef
5.
Bhowmick NA, Chytil A, Plieth D, Gorska AE, Dumont N, Shappell S, et al. TGF-beta signaling in fibroblasts modulates the oncogenic potential of adjacent epithelia. Science. 2004;303:848–51.CrossRefPubMed
6.
Kitadai Y (2009) Cancer-stromal cell interaction and tumor angiogenesis in gastric cancer. Cancer Microenviron: Off J Int Cancer Microenviron Soc
7.
Guo X, Oshima H, Kitmura T, Taketo MM, Oshima M. Stromal fibroblasts activated by tumor cells promote angiogenesis in mouse gastric cancer. J Biol Chem. 2008;283:19864–71.CrossRefPubMed
8.
Tang D, Wang D, Yuan Z, Xue X, Zhang Y, An Y, et al. Persistent activation of pancreatic stellate cells creates a microenvironment favorable for the malignant behavior of pancreatic ductal adenocarcinoma. Int J Cancer. 2013;132:993–1003.CrossRefPubMed
9.
Watanabe M, Hirano T, Asano G. Roles of myofibroblasts in the stroma of human gastric carcinoma. Nihon Geka Gakkai Zasshi. 1995;96:10–8.PubMed
10.
Semba S, Kodama Y, Ohnuma K, Mizuuchi E, Masuda R, Yashiro M, et al. Direct cancer-stromal interaction increases fibroblast proliferation and enhances invasive properties of scirrhous-type gastric carcinoma cells. Br J Cancer. 2009;101:1365–73.CrossRefPubMedPubMedCentral
11.
Shimoda M, Mellody KT, Orimo A. Carcinoma-associated fibroblasts are a rate-limiting determinant for tumour progression. Semin Cell Dev Biol. 2010;21:19–25.CrossRefPubMedPubMedCentral
12.
Yashiro M, Hirakawa K. Cancer-stromal interactions in scirrhous gastric carcinoma. Cancer microenvironment : official journal of the International Cancer Microenvironment Society. 2010;3:127–35.CrossRef
13.
Mueller MM, Fusenig NE. Friends or foes - bipolar effects of the tumour stroma in cancer. Nat Rev Cancer. 2004;4:839–49.CrossRefPubMed
14.
Holmberg C, Quante M, Steele I, Kumar JD, Balabanova S, Duval C, et al. Release of TGFbetaig-h3 by gastric myofibroblasts slows tumor growth and is decreased with cancer progression. Carcinogenesis. 2012;33:1553–62.CrossRefPubMedPubMedCentral
15.
Zhi K, Shen X, Zhang H, Bi J. Cancer-associated fibroblasts are positively correlated with metastatic potential of human gastric cancers. J Exp Clin Cancer Res: CR. 2010;29:66.CrossRefPubMedPubMedCentral
16.
Tlsty TD, Coussens LM. Tumor stroma and regulation of cancer development. Annu Rev Pathol. 2006;1:119–50.CrossRefPubMed
17.
18.
19.
Fan F, Schimming A, Jaeger D, Podar K. Targeting the tumor microenvironment: focus on angiogenesis. J Oncol. 2012;2012:281261.CrossRefPubMed
20.
Vonlaufen A, Joshi S, Qu C, Phillips PA, Xu Z, Parker NR, et al. Pancreatic stellate cells: partners in crime with pancreatic cancer cells. Cancer Res. 2008;68:2085–93.CrossRefPubMed
21.
Orimo A, Gupta PB, Sgroi DC, Arenzana-Seisdedos F, Delaunay T, Naeem R, et al. Stromal fibroblasts present in invasive human breast carcinomas promote tumor growth and angiogenesis through elevated SDF-1/CXCL12 secretion. Cell. 2005;121:335–48.CrossRefPubMed
22.
Seno H, Oshima M, Ishikawa TO, Oshima H, Takaku K, Chiba T, et al. Cyclooxygenase 2- and prostaglandin E(2) receptor EP(2)-dependent angiogenesis in Apc(Delta716) mouse intestinal polyps. Cancer Res. 2002;62:506–11.PubMed
23.
Shao J, Sheng GG, Mifflin RC, Powell DW, Sheng H. Roles of myofibroblasts in prostaglandin E2-stimulated intestinal epithelial proliferation and angiogenesis. Cancer Res. 2006;66:846–55.CrossRefPubMed
24.
Sonoshita M, Takaku K, Sasaki N, Sugimoto Y, Ushikubi F, Narumiya S, et al. Acceleration of intestinal polyposis through prostaglandin receptor EP2 in Apc(Delta 716) knockout mice. Nat Med. 2001;7:1048–51.CrossRefPubMed
25.
Tang D, Yuan Z, Xue X, Lu Z, Zhang Y, Wang H, et al. High expression of Galectin-1 in pancreatic stellate cells plays a role in the development and maintenance of an immunosuppressive microenvironment in pancreatic cancer. Int J Cancer. 2012;130:2337–48.CrossRefPubMed
26.
Wu MH, Hong TM, Cheng HW, Pan SH, Liang YR, Hong HC, et al. Galectin-1-mediated tumor invasion and metastasis, up-regulated matrix metalloproteinase expression, and reorganized actin cytoskeletons. Mol Cancer Res: MCR. 2009;7:311–8.CrossRefPubMed
27.
Thijssen VL, Postel R, Brandwijk RJ, Dings RP, Nesmelova I, Satijn S, et al. Galectin-1 is essential in tumor angiogenesis and is a target for antiangiogenesis therapy. Proc Natl Acad Sci U S A. 2006;103:15975–80.CrossRefPubMedPubMedCentral
28.
Kovacs-Solyom F, Blasko A, Fajka-Boja R, Katona RL, Vegh L, Novak J, et al. Mechanism of tumor cell-induced T-cell apoptosis mediated by galectin-1. Immunol Lett. 2010;127:108–18.CrossRefPubMed
29.
Bektas S, Bahadir B, Ucan BH, Ozdamar SO. CD24 and galectin-1 expressions in gastric adenocarcinoma and clinicopathologic significance. Pathol Oncol Res: POR. 2010;16:569–77.CrossRefPubMed
30.
Fuyuhiro Y, Yashiro M, Noda S, Kashiwagi S, Matsuoka J, Doi Y, et al. Upregulation of cancer-associated myofibroblasts by TGF-beta from scirrhous gastric carcinoma cells. Br J Cancer. 2011;105:996–1001.CrossRefPubMedPubMedCentral
31.
Xu X, Zhang X, Wang S, Qian H, Zhu W, Cao H, et al. Isolation and comparison of mesenchymal stem-like cells from human gastric cancer and adjacent non-cancerous tissues. J Cancer Res Clin Oncol. 2011;137:495–504.CrossRefPubMed
32.
Juszczynski P, Ouyang J, Monti S, Rodig SJ, Takeyama K, Abramson J, et al. The AP1-dependent secretion of galectin-1 by Reed Sternberg cells fosters immune privilege in classical Hodgkin lymphoma. Proc Natl Acad Sci U S A. 2007;104:13134–9.CrossRefPubMedPubMedCentral
33.
Cooper D, Norling LV, Perretti M. Novel insights into the inhibitory effects of Galectin-1 on neutrophil recruitment under flow. J Leukoc Biol. 2008;83:1459–66.CrossRefPubMed
34.
Yu LX, Yan HX, Liu Q, Yang W, Wu HP, Dong W, et al. Endotoxin accumulation prevents carcinogen-induced apoptosis and promotes liver tumorigenesis in rodents. Hepatology. 2010;52:1322–33.CrossRefPubMed
35.
Brown AC, Shah C, Liu J, Pham JT, Zhang JG, Jadus MR. Ginger’s (Zingiber officinale Roscoe) inhibition of rat colonic adenocarcinoma cells proliferation and angiogenesis in vitro. Phytother Res: PTR. 2009;23:640–5.CrossRefPubMed
36.
Masamune A, Kikuta K, Watanabe T, Satoh K, Satoh A, Shimosegawa T. Pancreatic stellate cells express Toll-like receptors. J Gastroenterol. 2008;43:352–62.CrossRefPubMed
37.
Bellou S, Pentheroudakis G, Murphy C, Fotsis T. Anti-angiogenesis in cancer therapy: Hercules and hydra. Cancer Lett. 2013;338:219–28.CrossRefPubMed
38.
Chang HL, Wu YC, Su JH, Yeh YT, Yuan SS. Protoapigenone, a novel flavonoid, induces apoptosis in human prostate cancer cells through activation of p38 mitogen-activated protein kinase and c-Jun NH2-terminal kinase 1/2. J Pharmacol Exp Ther. 2008;325:841–9.CrossRefPubMed
39.
D’Haene N, Sauvage S, Maris C, Adanja I, Le Mercier M, Decaestecker C, et al. VEGFR1 and VEGFR2 involvement in extracellular galectin-1- and galectin-3-induced angiogenesis. PLoS One. 2013;8, e67029.
40.
Hsieh SH, Ying NW, Wu MH, Chiang WF, Hsu CL, Wong TY, et al. Galectin-1, a novel ligand of neuropilin-1, activates VEGFR-2 signaling and modulates the migration of vascular endothelial cells. Oncogene. 2008;27:3746–53.CrossRefPubMed
41.
Lazar D, Raica M, Sporea I, Taban S, Goldis A, Cornianu M. Tumor angiogenesis in gastric cancer. Rom J Morphol Embryol Rev Roum Morphol Embryol. 2006;47:5–13.
42.
Terai S, Fushida S, Tsukada T, Kinoshita J, Oyama K, Okamoto K, Makino I, Tajima H, Ninomiya I, Fujimura T, Harada S, Ohta T (2014) Bone marrow derived “fibrocytes” contribute to tumor proliferation and fibrosis in gastric cancer. Gastric Cancer: Off J Int Gastric Cancer Assoc Jpn Gastric Cancer Assoc
43.
Balabanova S, Holmberg C, Steele I, Ebrahimi B, Rainbow L, Burdyga T, et al. The neuroendocrine phenotype of gastric myofibroblasts and its loss with cancer progression. Carcinogenesis. 2014;35:1798–806.CrossRefPubMedPubMedCentral
44.
45.
46.
Granot D, Addadi Y, Kalchenko V, Harmelin A, Kunz-Schughart LA, Neeman M. In vivo imaging of the systemic recruitment of fibroblasts to the angiogenic rim of ovarian carcinoma tumors. Cancer Res. 2007;67:9180–9.CrossRefPubMedPubMedCentral
47.
Fang J, Yan L, Shing Y, Moses MA. HIF-1alpha-mediated up-regulation of vascular endothelial growth factor, independent of basic fibroblast growth factor, is important in the switch to the angiogenic phenotype during early tumorigenesis. Cancer Res. 2001;61:5731–5.PubMed
48.
Crawford Y, Kasman I, Yu L, Zhong C, Wu X, Modrusan Z, et al. PDGF-C mediates the angiogenic and tumorigenic properties of fibroblasts associated with tumors refractory to anti-VEGF treatment. Cancer Cell. 2009;15:21–34.CrossRefPubMed
49.
Orimo A, Weinberg RA. Stromal fibroblasts in cancer: a novel tumor-promoting cell type. Cell Cycle. 2006;5:1597–601.CrossRefPubMed
50.
Astorgues-Xerri L, Riveiro ME, Tijeras-Raballand A, Serova M, Neuzillet C, Albert S, et al. Unraveling galectin-1 as a novel therapeutic target for cancer. Cancer Treat Rev. 2014;40:307–19.CrossRefPubMed
51.
Thijssen VL, Griffioen AW. Galectin-1 and −9 in angiogenesis: a sweet couple. Glycobiology. 2014;24:915–20.CrossRefPubMed
52.
Thijssen VL, Barkan B, Shoji H, Aries IM, Mathieu V, Deltour L, et al. Tumor cells secrete galectin-1 to enhance endothelial cell activity. Cancer Res. 2010;70:6216–24.CrossRefPubMed
53.
Le Mercier M, Mathieu V, Haibe-Kains B, Bontempi G, Mijatovic T, Decaestecker C, et al. Knocking down galectin 1 in human hs683 glioblastoma cells impairs both angiogenesis and endoplasmic reticulum stress responses. J Neuropathol Exp Neurol. 2008;67:456–69.CrossRefPubMed
54.
Freitag N, Tirado-Gonzalez I, Barrientos G, Herse F, Thijssen VL, Weedon-Fekjaer SM, et al. Interfering with Gal-1-mediated angiogenesis contributes to the pathogenesis of preeclampsia. Proc Natl Acad Sci U S A. 2013;110:11451–6.CrossRefPubMedPubMedCentral
55.
56.
Ito K, Stannard K, Gabutero E, Clark AM, Neo SY, Onturk S, et al. Galectin-1 as a potent target for cancer therapy: role in the tumor microenvironment. Cancer Metastasis Rev. 2012;31:763–78.CrossRefPubMed
57.
Tang D, Zhang J, Yuan Z, Gao J, Wang S, Ye N, et al. Pancreatic satellite cells derived galectin-1 increase the progression and less survival of pancreatic ductal adenocarcinoma. PLoS One. 2014;9, e90476.
Metadata
Title
Cancer-associated fibroblasts promote angiogenesis in gastric cancer through galectin-1 expression
Authors
Dong Tang
Jun Gao
Sen Wang
Nianyuan Ye
Yang Chong
Yuqin Huang
Jie Wang
Bin Li
Wei Yin
Daorong Wang
Publication date
01-02-2016
Publisher
Springer Netherlands
Published in
Tumor Biology / Issue 2/2016
Print ISSN: 1010-4283
Electronic ISSN: 1423-0380
DOI
https://doi.org/10.1007/s13277-015-3942-9

Other articles of this Issue 2/2016

Tumor Biology 2/2016 Go to the issue

Original Article

Altered expression of LINC-ROR in cancer cell lines and tissues

Original Article

PEBP4 promoted the growth and migration of cancer cells in pancreatic ductal adenocarcinoma

Original Article

∆Np73beta induces caveolin-1 in human non-small cell lung cancer cell line H1299

Original Article

MiR-378 suppresses prostate cancer cell growth through downregulation of MAPK1 in vitro and in vivo

Original Article

Influences of ERCC1, ERCC2, XRCC1, GSTP1, GSTT1, and MTHFR polymorphisms on clinical outcomes in gastric cancer patients treated with EOF chemotherapy

Original Article

Apoptotic effects of non-edible parts of Punica granatum on human multiple myeloma cells
Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras
Prof. Fabrice Barlesi
Developed by: Springer Medicine
Image Credits