A functional in vitro model of heterotypic interactions reveals a role for interferon-positive carcinoma associated fibroblasts in breast cancer

Abstract

BackgroundCancer-associated fibroblasts (CAFs) play an important role in breast cancer pathogenesis by paracrine regulation of breast cancer cell biology. Several in vitro and mouse models have characterized the role of cell contact and cytokine molecules mediating this relationship, although few reports have used human CAFs from breast tumors.MethodsPrimary breast CAF cultures were established and gene expression profiles analysed in order to guide subsequent co-culture models. We used a combination of colorimetric proliferation assays and gene expression profiling to determine the effect of CAFs on the MCF-7 breast cancer cell in an indirect co-culture system.ResultsUsing gene expression profiling, we found that a subgroup of breast CAFs are positive for a type one interferon response, confirming previous reports of an activated type one interferon response in whole tumor datasets. Interferon positive breast cancer patients show a poor prognostic outcome in an independent microarray dataset. In addition, CAFs positive for the type one interferon response promoted the growth of the MCF-7 breast cancer cell line in an indirect co-culture model. The addition of a neutralizing antibody against the ligand mediating the type one response in fibroblasts, interferon-β, reverted this co-culture phenotype. CAFs not expressing the interferon response genes also promoted the growth of the MCF-7 breast cancer cell line but this phenotype was independent of the type one fibroblast interferon ligand.ConclusionsPrimary breast CAFs show inter-patient molecular heterogeneity as evidenced by interferon response gene elements activated in a subgroup of CAFs, which result in paracrine pro-proliferative effects in a breast cancer cell line co-culture model.Electronic supplementary materialThe online version of this article (doi:10.1186/s12885-015-1117-0) contains supplementary material, which is available to authorized users.

Cancer-Associated Fibroblasts: Their Characteristics and Their Roles in Tumor Growth

“…CAFs can be isolated from various cancer types such as breast cancer, prostate cancer, pancreatic cancer, cholangiocarcinoma, lung cancer, gastric cancer, and colorectal cancer. However, CAFs are relatively rare in brain, renal, and ovarian cancers [ 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 ].…”

Crosstalk between cancer‐associated fibroblasts and immune cells in cancer

“…However, CAFs are actually defined as an assembly of heterogeneous mesenchymal cells, whose function may be different from resident tissue fibroblasts . Cancer‐associated fibroblasts have been isolated from various tumours, such as prostate cancer, lung cancer, breast cancer, gastric cancer, colorectal cancer and pancreatic cancer, whereas CAFs are relatively rare in brain cancer, ovarian cancer and kidney cancer . Interactions between cancer cells and the tumour microenvironment (TME) are well known to contribute to the outcome of tumours.…”

Reprogramming of stromal fibroblasts by chemotherapy-induced secretion of IFNβ1 drives re-growth of breast cancer cells after treatment

“…In recent years, the secretome of cancer cells and its impact on therapy response has gained attention and numerous studies explore its role in several aspects of tumour including in which compartment of the tumour this pathway is activated. Moreover, high expression of interferon-regulated genes in several tumour entities also strongly correlated with a worse outcome in patients 37,38 . All of these studies highlight the high degree of plasticity of type I IFN and the need for a better understanding of the role of this pathway in the context of cancer.…”

“…identified in breast cancer a subset of fibroblasts characterized by a type I IFN response and showed that high expression of certain interferon stimulated genes in patient samples correlated with patient outcome 37 . In our study we show that cancer cells exposed to chemotherapeutic agents upregulate the expression of type I IFN, namely IFNb1.…”