Fibroblast-specific protein 1/S100A4-positive cells prevent carcinoma through collagen production and encapsulation of carcinogens

Stromal restraints to cancer are critical determinants of disease but they remain incompletely understood. Here we report a novel mechanism for host surveillance against cancer contributed by S100A4+ (FSP1+) fibroblasts. Mechanistic studies of fibrosarcoma formation caused by subcutaneous injection of the carcinogen methylcholanthrene (MCA) had suggested that interferon-gamma receptor signaling may restrict MCA diffusion by inducing expression of collagen (foreign body reaction). We tested the hypothesis that this reaction encapsulated MCA and limited carcinogenesis by determining whether its ability to induce fibrosarcomas was impaired in the absence of proliferating fibroblasts. We found that S100A4+ fibroblasts accumulated around the carcinogen where they produced collagens, encapsulating MCA and protecting epithelial cells from DNA damage. Ablation of these cells at the site of MCA injection by local administration of Ganciclovir (GCV) in FSP1-TK transgenic mice altered tumor morphology to an epithelial phenotype, indicating that in the absence of encapsulating fibroblasts, MCA targeted epithelial cells. Notably, we showed that destruction of the fibrous capsule around the MCA by local injection of collagenase induced rapid tumor development in mice that were otherwise durably tumor-free. Our findings demonstrate that the S100A4+ fibroblasts prevent epithelial malignancy and that collagen encapsulation of carcinogens protects against tumor development. Together, this study provides a novel mechanism for host surveillance against cancer.