Abstract
Cancer-associated fibroblasts (CAF) are essential components of the stroma that play a critical role in cancer progression. This study aimed to identify novel CAFs markers that might contribute to the invasion and the prognosis of colorectal cancer. The azoxymethane/dextran sodium sulfate mouse model of sporadic colon cancer represents an adequate source for the isolation of CAFs and normal fibroblasts. By using the explants technique, we purified CAFs and normal fibroblasts from colon tissues. Whole-cell extracts and supernatants were subjected to in-depth quantitative proteomic analysis by tandem mass spectrometry. Further validations of upregulated proteins in CAFs were carried out by chemokine microarray and immunohistochemical analyses of mouse and human tissues. Using a fold-change of 1.4 or more, we found 132 and 125 differentially expressed proteins in whole-cell extracts and supernatants, respectively. We found CAFs-associated proinflammatory and desmoplastic signatures. The proinflammatory signature was composed of several cytokines. Among them, CCL2 and CCL8 caused an increase in migration and invasion of colorectal cancer KM12 cells. The desmoplastic signature was composed of 30 secreted proteins. In mouse and human samples, expression of LTBP2, CDH11, OLFML3, and, particularly, FSTL1 was significantly increased in the tumoral stroma, without significant expression in the cancer epithelial cells. The combination of CALU and CDH11 stromal expression showed a significant association with disease-free survival and poor prognosis. We have identified LTBP2, CDH11, OLFML3, and FSTL1 as selective biomarkers of cancer stroma, and CALU and CDH11 as candidate stromal biomarkers of prognostic significance in colon cancer.
Highlights
The tumor stroma comprises most of the cancer mass and is mainly composed of fibroblasts and endothelial cells, Authors' Affiliations: 1Department of Cellular and Molecular Medicine; 2Proteomics Core Facility, Centro de Investigaciones Biologicas (CIBCSIC); 3Department of Pathology, Fundacion Jimenez Díaz; 4Department of Oncology, Hospital Puerta de Hierro Majadahonda, Madrid; and 5IMIMHospital del Mar, Barcelona, SpainNote: Supplementary data for this article are available at Clinical Cancer Research Online.S
In mouse and human samples, expression of LTBP2, CDH11, OLFML3, and, FSTL1 was significantly increased in the tumoral stroma, without significant expression in the cancer epithelial cells
The combination of CALU and CDH11 stromal expression showed a significant association with disease-free survival and poor prognosis
Summary
The tumor stroma comprises most of the cancer mass and is mainly composed of fibroblasts and endothelial cells, Authors' Affiliations: 1Department of Cellular and Molecular Medicine; 2Proteomics Core Facility, Centro de Investigaciones Biologicas (CIBCSIC); 3Department of Pathology, Fundacion Jimenez Díaz; 4Department of Oncology, Hospital Puerta de Hierro Majadahonda, Madrid; and 5IMIMHospital del Mar, Barcelona, Spain. Note: Supplementary data for this article are available at Clinical Cancer Research Online (http://clincancerres.aacrjournals.org/). S. Torres and R.A. Bartolome contributed to this work. Barderas: Department of Biochemistry and Molecular Biology, I.
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