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The Desmoplastic Reaction Surrounding Hepatic Colorectal Adenocarcinoma Metastases Aids Tumor Growth and Survival via _v Integrin Ligation

Authors' Affiliations: ¹ Liver and Pancreas Research Group, Infection, Inflammation and Repair Division and ² Cancer Sciences Division, University of Southampton; ³ Histopathology Department, Southampton General Hospital, Southampton, United Kingdom; and ⁴ Centre for Inflammation Repair, University of Edinburgh, Queen's Medical Research Institute, Edinburgh, United Kingdom

Requests for reprints: John A. Conti, Infection, Inflammation and Repair Division, Southampton University, E Level, South Block, Southampton General Hospital, Mailpoint 811, Tremona Road, Southampton SO16 6YD, United Kingdom. Phone: 44-2380796144; E-mail: jaconti1{at}soton.ac.uk.

Purpose: The treatment of metastatic colorectal carcinoma represents a major clinical challenge. We investigated the hypothesis that the desmoplastic reaction within the liver elicited by metastatic adenocarcinoma, characterized by collagen I deposition and altered collagen IV distribution, promotes the growth and survival of hepatic colorectal carcinoma metastases.

Experimental Design: Partial hepatectomy specimens for metastatic colorectal adenocarcinoma were examined immunohistochemically for differential integrin expression. Human colorectal adenocarcinoma cell lines HT-29, KM12SM, and KM12c were grown on wild-type collagen I or IV, or cleavage-resistant r/r collagen I, and assessed for their growth, survival, and resistance to 5-fluorouracil. The effect of _vβ₃ and _vβ₅ integrin blockade by neutralizing antibodies was examined.

Results: Collagen I, in contrast to collagen IV, significantly enhanced the growth, survival, and chemoresistance of colorectal carcinoma cells. Blockade of the _vβ₃ and _vβ₅ integrins significantly reduced colorectal carcinoma cell proliferation on collagen, especially in the cell line with the most metastatic potential. These in vitro findings correlated with the pattern of integrin expression identified within resected hepatic colorectal carcinoma metastases. Using matrix metalloproteinase-resistant r/r collagen I as a dominant negative ligand for _v integrins, we showed a key role for this integrin-ligand interaction in mediating the survival and proliferation of colorectal carcinoma cells.

Conclusions: Desmoplasia has an important role in the development of hepatic colorectal carcinoma metastasis. The interaction between integrin and collagen I is identified as a potential therapeutic target.

Commentary

v Integrins Lead the Way for Colorectal Metastases

Joseph H. McCarty
Clin. Cancer Res. 2008 14: 6351-6353. [Abstract] [Full Text] [PDF]

This article has been cited by other articles:

				J. H. McCarty {alpha}v Integrins Lead the Way for Colorectal Metastases Clin. Cancer Res., October 15, 2008; 14(20): 6351 - 6353. [Abstract] [Full Text] [PDF]