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

Keynote webinar | Spotlight on medication adherence

LIVE: Thursday 27th June 2024, 18:00-19:30 (CEST)
Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.
ADVANCED SEARCH
Log in
Top
Gastric Cancer
Published in: Gastric Cancer 3/2015

01-07-2015 | Original Article

Connective tissue growth factor inhibits gastric cancer peritoneal metastasis by blocking integrin α3β1-dependent adhesion

Authors: Chiung-Nien Chen, Cheng-Chi Chang, Hong-Shiee Lai, Yung-Ming Jeng, Chia-I Chen, King-Jeng Chang, Po-Huang Lee, Hsinyu Lee

Published in: Gastric Cancer | Issue 3/2015

Login to get access

Abstract

Background

Connective tissue growth factor (CTGF) plays important roles in normal and pathological conditions. The aim of this study was to investigate the role of CTGF in peritoneal metastasis as well as the underlying mechanism in gastric cancer progression.

Methods

CTGF expression levels for wild-type and stable overexpression clones were determined by Western blotting and quantitative polymerase chain reaction (Q-PCR). Univariate and multivariate analyses, immunohistochemistry, and survival probability analyses were performed on gastric cancer patients. The extracellular matrix components involved in CTGF-regulated adhesion were determined. Recombinant CTGF was added to cells or coinoculated with gastric cancer cells into mice to evaluate its therapeutic potential.

Results

CTGF overexpression and treatment with the recombinant protein significantly inhibited cell adhesion. In vivo peritoneal metastasis demonstrated that CTGF-stable transfectants markedly decreased the number and size of tumor nodules in the mesentery. Statistical analysis of gastric cancer patient data showed that patients expressing higher CTGF levels had earlier TNM staging and a higher survival probability after the surgery. Integrin α3β1 was the cell adhesion molecule mediating gastric cancer cell adhesion to laminin, and blocking of integrin α3β1 prevented gastric cancer cell adhesion to recombinant CTGF. Coimmunoprecipitation results indicated that CTGF binds to integrin α3. Coinoculation of recombinant CTGF and gastric cancer cell lines in mice showed effective inhibition of peritoneal dissemination.

Conclusions

Our results suggested that gastric cancer peritoneal metastasis is mediated through integrin α3β1 binding to laminin, and CTGF effectively blocks the interaction by binding to integrin α3β1, thus demonstrating the therapeutic potential of recombinant CTGF in gastric cancer patients.
Literature
1.
Wagner AD, Grothe W, Haerting J, Kleber G, Grothey A, Fleig WE. Chemotherapy in advanced gastric cancer: a systematic review and meta-analysis based on aggregate data. J Clin Oncol. 2006;24:2903–9.PubMedCrossRef
2.
3.
Maehara Y, Kakeji Y, Takahashi I, Okuyama T, Baba H, Anai H, et al. Noncurative resection for advanced gastric cancer. J Surg Oncol. 1992;51:221–5.PubMedCrossRef
4.
Baba H, Okuyama T, Hiroyuki O, Anai H, Korenaga D, Maehara Y, et al. Prognostic factors for noncurative gastric cancer: univariate and multivariate analyses. J Surg Oncol. 1992;51:104–8.PubMedCrossRef
5.
Yonemura Y. Endou Y [Molecular mechanisms of peritoneal dissemination]. Nippon Shokakibyo Gakkai Zasshi. 2000;97:680–90.PubMed
6.
Michalak M, Groenendyk J, Szabo E, Gold LI, Opas M. Calreticulin, a multi-process calcium-buffering chaperone of the endoplasmic reticulum. Biochem J. 2009;417:651–66.PubMedCrossRef
7.
Chen CN, Chang CC, Su TE, Hsu WM, Jeng YM, Ho MC, et al. Identification of calreticulin as a prognosis marker and angiogenic regulator in human gastric cancer. Ann Surg Oncol. 2009;16:524–33.PubMedCrossRef
8.
Bradham DM, Igarashi A, Potter RL, Grotendorst GR. Connective tissue growth factor: a cysteine-rich mitogen secreted by human vascular endothelial cells is related to the SRC-induced immediate early gene product CEF-10. J Cell Biol. 1991;114:1285–94.PubMedCrossRef
9.
Brigstock DR. Regulation of angiogenesis and endothelial cell function by connective tissue growth factor (CTGF) and cysteine-rich 61 (CYR61). Angiogenesis. 2002;5:153–65.PubMedCrossRef
10.
Wenger C, Ellenrieder V, Alber B, Lacher U, Menke A, Hameister H, et al. Expression and differential regulation of connective tissue growth factor in pancreatic cancer cells. Oncogene. 1999;18:1073–80.PubMedCrossRef
11.
Shakunaga T, Ozaki T, Ohara N, Asaumi K, Doi T, Nishida K, et al. Expression of connective tissue growth factor in cartilaginous tumors. Cancer. 2000;89:1466–73.PubMedCrossRef
12.
Pan LH, Beppu T, Kurose A, Yamauchi K, Sugawara A, Suzuki M, et al. Neoplastic cells and proliferating endothelial cells express connective tissue growth factor (CTGF) in glioblastoma. Neurol Res. 2002;24:677–83.PubMedCrossRef
13.
Chen PS, Wang MY, Wu SN, Su JL, Hong CC, Chuang SE, et al. CTGF enhances the motility of breast cancer cells via an integrin-alphavbeta3-ERK1/2-dependent S100A4-upregulated pathway. J Cell Sci. 2007;120:2053–65.PubMedCrossRef
14.
Brigstock DR. The connective tissue growth factor/cysteine-rich 61/nephroblastoma overexpressed (CCN) family. Endocr Rev. 1999;20:189–206.PubMed
15.
16.
Moritani NH, Kubota S, Nishida T, Kawaki H, Kondo S, Sugahara T, et al. Suppressive effect of overexpressed connective tissue growth factor on tumor cell growth in a human oral squamous cell carcinoma-derived cell line. Cancer Lett. 2003;192:205–14.PubMedCrossRef
17.
Yang MH, Lin BR, Chang CH, Chen ST, Lin SK, Kuo MY, et al. Connective tissue growth factor modulates oral squamous cell carcinoma invasion by activating a miR-504/FOXP1 signalling. Oncogene. 2011;31(19):2401–11.
18.
Lin BR, Chang CC, Che TF, Chen ST, Chen RJ, Yang CY, et al. Connective tissue growth factor inhibits metastasis and acts as an independent prognostic marker in colorectal cancer. Gastroenterology. 2005;128:9–23.PubMedCrossRef
19.
Lin BR, Chang CC, Chen RJ, Jeng YM, Liang JT, Lee PH, et al. Connective tissue growth factor acts as a therapeutic agent and predictor for peritoneal carcinomatosis of colorectal cancer. Clin Cancer Res. 2011;17:3077–88.PubMedCrossRef
20.
Chang CC, Shih JY, Jeng YM, Su JL, Lin BZ, Chen ST, et al. Connective tissue growth factor and its role in lung adenocarcinoma invasion and metastasis. J Natl Cancer Inst. 2004;96:364–75.PubMedCrossRef
21.
Takatsuki H, Komatsu S, Sano R, Takada Y, Tsuji T. Adhesion of gastric carcinoma cells to peritoneum mediated by alpha3beta1 integrin (VLA-3). Cancer Res. 2004;64:6065–70.PubMedCrossRef
22.
Saito Y, Sekine W, Sano R, Komatsu S, Mizuno H, Katabami K, et al. Potentiation of cell invasion and matrix metalloproteinase production by alpha3beta1 integrin-mediated adhesion of gastric carcinoma cells to laminin-5. Clin Exp Metastasis. 2010;27:197–205.PubMedCrossRef
23.
Zhang XP, Puzon-McLaughlin W, Irie A, Kovach N, Prokopishyn NL, Laferte S, et al. Alpha 3 beta 1 adhesion to laminin-5 and invasin: critical and differential role of integrin residues clustered at the boundary between alpha 3 N-terminal repeats 2 and 3. Biochemistry. 1999;38:14424–31.PubMedCrossRef
24.
Shi Y, Wang W, Tu Z, Zhang L, Qiu J, Li Q, et al. The C-terminal peptide of connective tissue growth factor blocks the full molecule binding to tubular epithelial cell. Transplant Proc. 2006;38:2187–9.PubMedCrossRef
25.
Hoshijima M, Hattori T, Inoue M, Araki D, Hanagata H, Miyauchi A, et al. CT domain of CCN2/CTGF directly interacts with fibronectin and enhances cell adhesion of chondrocytes through integrin alpha5beta1. FEBS Lett. 2006;580:1376–82.PubMedCrossRef
26.
Gao R, Brigstock DR. Connective tissue growth factor (CCN2) induces adhesion of rat activated hepatic stellate cells by binding of its C-terminal domain to integrin alpha(v)beta(3) and heparan sulfate proteoglycan. J Biol Chem. 2004;279:8848–55.PubMedCrossRef
27.
Gao R, Brigstock DR. A novel integrin alpha5beta1 binding domain in module 4 of connective tissue growth factor (CCN2/CTGF) promotes adhesion and migration of activated pancreatic stellate cells. Gut. 2006;55:856–62.PubMedCentralPubMedCrossRef
28.
Dornhofer N, Spong S, Bennewith K, Salim A, Klaus S, Kambham N, et al. Connective tissue growth factor-specific monoclonal antibody therapy inhibits pancreatic tumor growth and metastasis. Cancer Res. 2006;66:5816–27.PubMedCrossRef
29.
Jiang CG, Lv L, Liu FR, Wang ZN, Liu FN, Li YS, et al. Downregulation of connective tissue growth factor inhibits the growth and invasion of gastric cancer cells and attenuates peritoneal dissemination. Mol Cancer. 2011;10:122.PubMedCentralPubMedCrossRef
30.
Jiang CG, Lv L, Liu FR, Wang ZN, Na D, Li F, et al. Connective tissue growth factor is a positive regulator of epithelial-mesenchymal transition and promotes the adhesion with gastric cancer cells in human peritoneal mesothelial cells. Cytokine. 2013;61:173–80.PubMedCrossRef
31.
32.
Zigler M, Dobroff AS, Bar-Eli M. Cell adhesion: implication in tumor progression. Minerva Med. 2010;101:149–62.PubMed
33.
Makrilia N, Kollias A, Manolopoulos L, Syrigos K. Cell adhesion molecules: role and clinical significance in cancer. Cancer Invest. 2009;27:1023–37.PubMedCrossRef
34.
35.
Cox D, Brennan M, Moran N. Integrins as therapeutic targets: lessons and opportunities. Nat Rev Drug Discov. 2010;9:804–20.PubMedCrossRef
36.
Jang BS, Lim E, Hee Park S, Shin IS, Danthi SN, Hwang IS, et al. Radiolabeled high affinity peptidomimetic antagonist selectively targets alpha(v)beta(3) receptor-positive tumor in mice. Nucl Med Biol. 2007;34:363–70.PubMedCrossRef
Metadata
Title
Connective tissue growth factor inhibits gastric cancer peritoneal metastasis by blocking integrin α3β1-dependent adhesion
Authors
Chiung-Nien Chen
Cheng-Chi Chang
Hong-Shiee Lai
Yung-Ming Jeng
Chia-I Chen
King-Jeng Chang
Po-Huang Lee
Hsinyu Lee
Publication date
01-07-2015
Publisher
Springer Japan
Published in
Gastric Cancer / Issue 3/2015
Print ISSN: 1436-3291
Electronic ISSN: 1436-3305
DOI
https://doi.org/10.1007/s10120-014-0400-0

Other articles of this Issue 3/2015

Gastric Cancer 3/2015 Go to the issue

Original Article

A novel gene–protein assay for evaluating HER2 status in gastric cancer: simultaneous analyses of HER2 protein overexpression and gene amplification reveal intratumoral heterogeneity

Original Article

Health utility of patients with advanced gastrointestinal stromal tumors (GIST) after failure of imatinib and sunitinib: findings from GRID, a randomized, double-blind, placebo-controlled phase III study of regorafenib versus placebo

Original Article

Predictors of postoperative complications in elderly and oldest old patients with gastric cancer

Original Article

Evaluation of postgastrectomy symptoms after distal gastrectomy with Billroth-I reconstruction using the Postgastrectomy Syndrome Assessment Scale-45 (PGSAS-45)

Original Article

Clinical outcome of lower esophageal sphincter- and vagus-nerve-preserving partial cardiectomy for early gastric cancer of the subcardia

Original Article

Influence of TGFB1 C-509T polymorphism on gastric cancer risk associated with TGF-β1 expression in the gastric mucosa
Live Webinar | 27-06-2024 | 18:00 (CEST)

Keynote webinar | Spotlight on medication adherence

Reserve your place

Live: Thursday 27th June 2024, 18:00-19:30 (CEST)

WHO estimates that half of all patients worldwide are non-adherent to their prescribed medication. The consequences of poor adherence can be catastrophic, on both the individual and population level.

Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.

Prof. Kevin Dolgin
Prof. Florian Limbourg
Prof. Anoop Chauhan
Developed by: Springer Medicine
Obesity Clinical Trial Summary

At a glance: The STEP trials

Read more

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.

Developed by: Springer Medicine

Highlights from the ACC 2024 Congress

Year in Review: Pediatric cardiology

Pediatric Cardiology Video

Watch Dr. Anne Marie Valente present the last year's highlights in pediatric and congenital heart disease in the official ACC.24 Year in Review session.

Year in Review: Pulmonary vascular disease

Cardiopulmonary Comorbidity Video

The last year's highlights in pulmonary vascular disease are presented by Dr. Jane Leopold in this official video from ACC.24.

Year in Review: Valvular heart disease

Valvular Heart Disease Video

Watch Prof. William Zoghbi present the last year's highlights in valvular heart disease from the official ACC.24 Year in Review session.

Year in Review: Heart failure and cardiomyopathies

Heart Failure Video

Watch this official video from ACC.24. Dr. Biykem Bozkurt discusses last year's major advances in heart failure and cardiomyopathies.

ACC 2024 Congress Coverage

Year in Review: Heart failure and cardiomyopathies

Heart Failure Video

Watch this official video from ACC.24. Dr. Biykem Bozkurt discusses last year's major advances in heart failure and cardiomyopathies.

Watch now

Semaglutide benefits people with type 2 diabetes and obesity-related heart failure

16-04-2024 Type 2 Diabetes News

Incentivised to exercise

11-04-2024 Lifestyle Modifications News

New intervention for STEMI-related cardiogenic shock

10-04-2024 Myocardial Infarction News

» View more highlights on the ACC 2024 congress hub page

Image Credits