Abstract
Cancer-associated fibroblasts (CAF) actively participate in reciprocal communication with tumor cells and with other cell types in the microenvironment, contributing to a tumor-permissive neighborhood and promoting tumor progression. The aim of this study is the characterization of how CAFs from primary human colon tumors promote migration of colon cancer cells. Primary CAF cultures from 15 primary human colon tumors were established. Their enrichment in CAFs was evaluated by the expression of various epithelial and myofibroblast specific markers. Coculture assays of primary CAFs with different colon tumor cells were performed to evaluate promigratory CAF-derived effects on cancer cells. Gene expression profiles were developed to further investigate CAF characteristics. Coculture assays showed significant differences in fibroblast-derived paracrine promigratory effects on cancer cells. Moreover, the association between CAFs' promigratory effects on cancer cells and classic fibroblast activation or stemness markers was observed. CAF gene expression profiles were analyzed by microarray to identify deregulated genes in different promigratory CAFs. The gene expression signature, derived from the most protumorogenic CAFs, was identified. Interestingly, this "CAF signature" showed a remarkable prognostic value for the clinical outcome of patients with colon cancer. Moreover, this prognostic value was validated in an independent series of 142 patients with colon cancer, by quantitative real-time PCR (qRT-PCR), with a set of four genes included in the "CAF signature." In summary, these studies show for the first time the heterogeneity of primary CAFs' effect on colon cancer cell migration. A CAF gene expression signature able to classify patients with colon cancer into high- and low-risk groups was identified.
Highlights
Tumor epithelial cells within a tumor coexist with a complex microenvironment
carcinoma-associated fibroblasts (CAF) gene expression profiles were analyzed by microarray to identify deregulated genes in different promigratory CAFs
The gene expression signature, derived from the most protumorogenic CAFs, was identified. This "CAF signature" showed a remarkable prognostic value for the clinical outcome of patients with colon cancer. This prognostic value was validated in an independent series of 142 patients with colon cancer, by quantitative real-time PCR, with a set of four genes included in the "CAF signature."
Summary
Tumor epithelial cells within a tumor coexist with a complex microenvironment. In this microenvironment, extracellular matrix, growth factors, cytokines, and a variety of nonepithelial cell types, including vascular space-related cells (endothelial cells, pericytes, and smooth-muscle cells), inflammatory response cells (lymphocytes, macrophages, Authors' Affiliations: Departments of 1Medical Oncology and 2Pathology, Hospital Universitario Puerta de Hierro Majadahonda, Majadahonda; 3Functional Proteomics Laboratory, Centro de Investigaciones Biologicas (CIB-CSIC), Madrid; 4Programa de Recerca en Cancer, IMIM-Hospital del Mar, Barcelona, Spain; and 5Department of Genetic Engineering and Biotechnology, University of Dhaka, Dhaka, BangladeshA.B.M.M.K. Fibroblasts are one of the most active cell types of the stroma They form the basic cell component of the connective tissue that contributes to structural integrity, as well as the maintenance of the extracellular matrix [4]. Fibroblasts of the tumor stroma have received various names: tumor-associated fibroblasts, carcinoma-associated fibroblasts (CAF), or myofibroblasts [6]. They are similar to those found in the wound-healing process, CAFs are constantly activated [6]. CAFs are involved in various tumor mechanisms, such as extracellular matrix remodeling, release of soluble factors, regulation of tumor cell motility, and the
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