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

Abstract

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: Partialhepatectomy specimens for metastatic colorectaladenocarcinoma 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, andassessed for their growth, survival, and resistanceto 5-fluorouracil. The effect of a v h 3 and a v h 5 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 a v h 3 and a v h 5 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 a 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.

The morphological growth patterns of colorectal liver metastases are prognostic for overall survival

“…[16][17][18][19][20] However, for some cell lines from colorectal hepatic metastases, in vitro interactions with type-I collagen have been reported to promote growth, survival, and chemoresistance via a v integrin ligation. 21 Vermeulen et al 1 described the growth patterns as three fundamentally different types of expansion, yet the mixed-type pattern and the variable growth patterns among multiple and recurrent metastases, documented by Eefsen et al 4 and the present study, suggest interrelations between the growth patterns. Based on a study on autopsied livers, which showed that the replacement pattern was highly predominant among micrometastases o1 mm, Terayama et al 22 hypothesized that the replacement pattern is simply a stage that precedes the pushing and desmoplastic patterns.…”

Connective Tissue Growth Factor Acts as a Therapeutic Agent and Predictor for Peritoneal Carcinomatosis of Colorectal Cancer

“…Several previous studies have suggested that integrins expression and colon cancer invasion are correlated. In one study, Conti and colleagues reported that integrin av inhibition in CRC specimens from hepatic metastases caused a significant reduction in tumor cell proliferation on collagen plates (34). A previous study utilizing animal models showed that the resection of CRC dramatically increased malignant cell adhesion within the liver, and blocking of a2 integrin prevented the increase of colorectal hepatic metastases (35).…”

Detection of desmoplastic reaction in biopsy specimens is useful for predicting the depth of invasion of early colorectal cancer: a Japanese collaborative study

“…Indeed, in the present study, we clearly demonstrated that the presence of DR was significantly correlated with SM depth in nonpedunculated SICRCs. Although it is still unclear whether DR represents a form of host defense against tumor invasion or metastasis [25,26], the initiation of DR may be associated with destruction of the muscularis mucosae [17]. In support of this idea, DR is hardly ever observed in intramucosal carcinoma [14], but is known to be involved in the biological changes in the muscularis mucosae during tumor invasion [27,28].…”