Cancer Associated Fibroblasts Breaking Bad - from a Growth Inhibitory to Tumor Promoting Phenotype

Breast tumors are characterized by an extensive desmoplastic stroma, abundantly populated by fibroblasts. Fibroblasts, among other stromal cell types populating the neoplastic microenvironment have an important role in facilitating tumorigenesis. Cancer Associated Fibroblasts (CAFs) are an activated sub-population of stromal fibroblasts, which can have different characteristics in different tumor types. CAFs promote tumor growth by directly stimulating tumor cell proliferation and by enhancing angiogenesis and inflammation. However, not much is known about how normal fibroblasts co-evolve during tumor progression to become CAFs.

To address this question, we have profiled the transcriptome of mammary CAFs isolated from distinct stages of mammary carcinogenesis. We found that fibroblasts express unique gene signature in each tumorigenic stages, supporting the hypothesis that the stroma co-evolves with tumor development. Interestingly, fibroblasts derived from hyperplasic tissues (HAFs) exhibit a growth inhibitory gene expression signature, while fibroblasts isolated from mammary tumors expressed pro-inflammatory and growth promoting genes. Moreover, we show that this growth-inhibitory phenotype is exhibited also by fibroblasts isolated from lactating mammary glands, which is a physiologic, non-tumorigenic, hyperplasic tissue. Furthermore, we show that normal mammary fibroblasts (NMFs) are reprogrammed to CAFs by tumor cell-secreted Osteopontin (OPN). Activation of mammary fibroblasts by secreted OPN depends on two of its known receptors: CD44 and αVβ3 integrin. Strikingly, knockdown of OPN in tumor cells in vivo resulted in attenuated stromal activation and significant inhibition of tumor growth.

Thus, we revealed a crosstalk between fibroblasts residing in the tumor microenvironment and cancer cells which mediate the co-evolution of fibroblasts during tumor progression. Maintaining the HAFs phenotype as well as blocking signaling by tumor-derived OPN may be an effective way to inhibit tumor development.