Fibroblast-Specific Protein 1/S100A4–Positive Cells Prevent Carcinoma through Collagen Production and Encapsulation of Carcinogens

Abstract

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 fibroblast-specific protein 1 (FSP1) þ / S100A4 þ fibroblasts. Mechanistic studies of fibrosarcoma formation caused by subcutaneous injection of the carcinogen methylcholanthrene (MCA) had suggested that IFN-g 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 FSP1 þ /S100A4 þ 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 in FSP-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 FSP1 þ /S100A4 þ 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. Cancer Res; 73(9); 2770-81. Ó2013 AACR.

Expression of cancer-associated fibroblast-related proteins in adipose stroma of breast cancer

“…Those of PDGFRβ type are thought to be associated with metastatic spread [25] and high interstitial fluid pressure [26]. S100A4 (FSP-1)-type CAFs, which were highly expressed in breast cancer with fibrous stroma in our study, have been suggested to associate with metastatic colonization [27], macrophage infiltration [28], and protection from carcinogens [29]. There are several possible explanations for the differential expression of CAFrelated proteins between breast cancer with fibrous and adipose stroma.…”

S100A4 protects mice from high-fat diet-induced obesity and inflammation

“…S100A4, also known as fibroblast-specific protein 1, is a member of the S100 calcium-binding protein family and was first cloned in metastatic cells and fibroblasts [13,14]. It is expressed in various cell types, including fibroblasts, macrophages and tumor cells [15][16][17][18][19][20]. S100A4 was reported to be intracellular, or secreted as a normal cytokine, and it plays important roles in tumor cell survival and metastasis [19,21,22].…”

S100A4 promotes colon inflammation and colitis-associated colon tumorigenesis

“…17 , 18 Previous studies have reported that S100A4 is expressed in a variety of cells, such as fibroblasts, macrophages, and malignant cells, and plays a crucial role in mediating tumor-stromal interplay. 19-23 S100A4 functions as both intracellular and extracellular forms. 24 , 25 Intracellular S100A4 is involved in a wide range of biological functions, such as the regulation of angiogenesis, cell survival, motility, invasion or metastasis.…”