Abstract
The microenvironment of metastatic breast cancer is incompletely characterized, despite prior evidence that it plays a key role in the biology of metastasis. A major component of the tumor stroma is the carcinoma-associated fibroblast (CAF), which has been shown to communicate with other stromal and cancer cells to create a protumorigenic milieu. Our study was designed to characterize human CAFs from different metastatic sites. We collected eight carcinoma-associated fibroblasts (mCAFs) from different metastatic sites and compared them with CAFs from primary tumors (pCAFs) and with normal breast fibroblasts (NFs). Molecular profiles and effects on breast cancer cell growth, on response to doxorubicin and on T-cell proliferation were compared. We observed marked differences in mCAFs compared with pCAFs and NFs with respect to in vitro proliferation and effects on breast cancer cell migration, spheroid growth, invasion, response to doxorubicin, and in vivo tumor growth. We found marked transcriptomic differences between mCAFs and pCAFs, including increased expression of IFN-related genes and IGF2 in the former. Cluster analysis revealed two groups of mCAFs, with the liver mCAFs clustering together, with increased PDGFA expression. Treatment with an antibody against insulin-like growth factors (BI836845) inhibited growth of mixed mCAF-tumor cell xenografts in vivo. Also, mCAFs had a suppressive effect on T-cell proliferation. This is the first comparative analysis of a set of CAFs from metastatic sites in breast cancer. It revealed a marked protumorigenic effect in these mCAFs, which occurs in part through increased expression of IGF2.
Highlights
Metastatic breast tumors are almost always incurable: They progressively become resistant to chemotherapy as well as targeted therapies even if there is an initial response
It is well established that carcinoma-associated fibroblast (CAF) from primary breast tumors show significant molecular and phenotypic changes compared to normal fibroblasts (NFs), which confer on them a broad protumorigenic ability, there have been almost no studies of CAFs obtained from metastatic sites, and the contribution of metastatic CAFs to the incurability of metastasis is presently unknown
Stromal fibroblasts were isolated from 16 patients from normal breast tissue or from primary or metastatic breast tumors, and designated NFs, primary tumor CAFs (pCAFs), and mCAFs, respectively (Supplementary Table S1)
Summary
Metastatic breast tumors are almost always incurable: They progressively become resistant to chemotherapy as well as targeted therapies even if there is an initial response. One hypothesis to explain the incurability of metastatic lesions is that the tumor microenvironment protects tumor cells in metastatic lesions, more so than in the primary tumor This protection may vary from metastatic site to site, which may explain the frequent clinical observation of differential response to therapy in different metastatic sites. Extensive differences in tumor stroma compared with normal stroma have been widely observed and several studies have shown that carcinomaassociated fibroblasts (CAFs) may affect tumor cells' sensitivity to cancer therapy. Straussman and colleagues [3] showed that CAFs may cause drug resistance in melanomas via the secretion of HGF They found that coculture with CAFs rescued a HER2þ breast cancer cell line from sensitivity to lapatinib. There was previously no evidence that mCAFs are different from CAFs present within primary www.aacrjournals.org
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