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By Trimmer et al. [49] identified loss of caveolin-1 (CAV-1) in CAFs as a predictor of clinical outcome, probably resulting from autophagy of CAFs with CAV-1. A proteomic analysis of CAV-1-deficient fibroblasts supported this hypothesis by showing upregulation of proteins related to oxidative stress. Superoxide dismutase 2 (SOD2) was identified as a suppressor of this effect by reducing oxidative stress [49]. A proteomic analysis comparing MMP7-treated and untreated colonic fibroblasts identified Insulin growth factor binding protein-5 (IGFBP-5) as a substrate of MMP7 activity [50]. MMP-7 acts as a stimulating factor in the proliferation and migration of colonic myofibroblasts through blockade of IGFBP-5 inhibition of IGF-II [50]. An MS analysis of PTEN (phosphatase and tensin homolog)-null stromal cells expressing the microRNA miR-320 revealed altered secretome expression of proteins such as MMP9, MMP2, bone morphogenic protein 1 (BMP1), lysyl oxidase-like 2 (LOXL2) and EMILIN2 when compared to a control [51]. Confirmatory studies demonstrated that blocking of MMP9 and EMILIN2 reduced the ability of conditioned media to promote the migration of epithelial cancer cells or to recruit endothelial cells, respectively. Furthermore, the secretome signature also correlated with patient outcome [51]. Newman et al. [52] identified factors secreted from fibroblasts that support endothelial cell lumen formation. PCOLCE, Col1A1, transforming growth factor -inducible gene H3 (IG-H3), SPARC, or IGFBP7 were identified in fibroblast-conditioned media fractions that were necessary for endothelial cell lumen formation [52]. Knockdown of combinations of these factors in fibroblasts inhibited endothelial cell lumen formation [52]. While stromal cells affect tumor cell behavior, there are reciprocal interactions. CAFs and tumor-adjacent fibroblasts (TAFs) in the microenvironment of breast cancer cells display features similar to those of tumor cells. CAFs and TAFs can Capecitabine be distinguished from normal breast fibroblasts on the basis of their proteome [53]. The co-culture of fibroblasts and cancer cells enables direct interactions to be studied. Co-culture of a murine K-ras mutant lung adenocarcinoma cell line (LKR-13) with murine lung stromal cells enhanced the migration and increased the proliferation of LKR-13 cells; coculture also induced these cells to form epithelial tubes [54]. An LC-MS/MS analysis revealed loss of cell adhesion proteins such as E-cadherin and provided evidence of EMT in the cancer cell line when grown withHanash and Schliekelman Genome Medicine 2014, 6:12 http://genomemedicine.com/content/6/2/Page 7 offibroblasts. This LC-MS/MS analysis was supplemented by a multiplexed cytokine assay to identify signaling molecules at concentrations below the limit of detection of MS. Chemokine CXCL1 and IL-18 were found to be necessary for increased proliferation and migration [54]. Conditioned media from gastric cancer-associated myofibroblasts increased cancer cell proliferation, migration and invasion in a cancer cell line [55]. An LC-MS/MS analysis of isobaric tagged cells identified downregulation of IG-H3 in CAFs compared to normal or adjacent myofibroblasts. IG-H3 inhibited IGF-II-stimulated migration and proliferation of cancer cells [55]. Co-culture with stromal cells has also been shown to increase resistance to anti-cancer therapies in many cancer cell PubMed ID:https://www.ncbi.nlm.nih.gov/pubmed/7500280 lines [56-59]. Conditioned media from some stromal lines were found to be capable of resc.