Basic Research
Copyright ©2007 Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Oct 21, 2007; 13(39): 5208-5216
Published online Oct 21, 2007. doi: 10.3748/wjg.v13.i39.5208
CTGF, intestinal stellate cells and carcinoid fibrogenesis
M Kidd, IM Modlin, MD Shapiro, RL Camp, SM Mane, W Usinger, JR Murren
M Kidd, IM Modlin, MD Shapiro, Departments of Surgery, Yale University School of Medicine, New Haven, Connecticut 06520-8062, United States
RL Camp, Departments of Pathology, Yale University School of Medicine, New Haven, Connecticut 06520-8062, United States
SM Mane, Departments of Affymetrix Resource, Keck Biotechnology Resource Laboratory, Yale University School of Medicine, New Haven, Connecticut 06520-8062, United States
W Usinger, Fibrogen Inc, San Francisco, CA, United States
JR Murren, Departments of Medical Oncology, Yale University School of Medicine, New Haven, Connecticut 06520-8062, United States
Author contributions: All authors contributed equally to the work.
Correspondence to: Irvin Modlin MD, PhD, Yale University School of Medicine, 333 Cedar Street, PO Box 208062, New Haven, Connecticut 06520-8062, United States. imodlin@optonline.net
Telephone: +1-203-7855429 Fax: +1-203-7374067
Received: March 6, 2007
Revised: July 26, 2007
Accepted: August 10, 2007
Published online: October 21, 2007
Abstract

AIM: To investigate the role of small intestinal carcinoid tumor-derived fibrotic mediators, TGFβ1 and CTGF, in the mediation of fibrosis via activation of an “intestinal” stellate cell.

METHODS: GI carcinoid tumors were collected for Q RT-PCR analysis of CTGF and TGFβ1. Markers of stellate cell desmoplasia were identified in peritoneal fibrosis by immunohistochemistry and stellate cells cultured from fresh resected fibrotic tissue. CTGF and TGFβ1 were evaluated using quantitative tissue array profiling (AQUA analysis) in a GI carcinoid tissue microarray (TMA) with immunostaining and correlated with clinical and histologically documented fibrosis. Serum CTGF was analyzed using a sandwich ELISA assay.

RESULTS: Message levels of both CTGF and TGFβ1 in SI carcinoid tumors were significantly increased (> 2-fold, P < 0.05) versus normal mucosa and gastric (non-fibrotic) carcinoids. Activated stellate cells and markers of stellate cell-mediated fibrosis (vimentin, desmin) were identified in histological fibrosis. An intestinal stellate cell was immunocytochemically and biochemically characterized and its TGFβ1 (10-7M) initiated CTGF transcription response (> 3-fold, P < 0.05) demonstrated. In SI carcinoid tumor patients with documented fibrosis, TMA analysis demonstrated higher CTGF immunostaining (AQUA Score: 92 ± 8; P <0.05), as well as elevated TGFβ1 (90.6 ± 4.4, P < 0.05). Plasma CTGF (normal 12.5 ± 2.6 ng/mL) was increased in SI carcinoid tumor patients (31 ± 10 ng/mL, P < 0.05) compared to non-fibrotic GI carcinoids (< 15 ng/mL).

CONCLUSION: SI carcinoid tumor fibrosis is a CTGF/TGFβ1-mediated stellate cell-driven fibrotic response. The delineation of the biology of fibrosis will facilitate diagnosis and enable development of agents to obviate its local and systemic complications.

Keywords: Carcinoid; Connective tissue growth factor; fibrosis; Small intestine; Stellate cell; TGFβ