Avoiding Extinction: Cancer-Associated Fibroblasts Help Triple-Negative Breast Cancer Outrun Chemotherapy

Abstract Neoadjuvant chemotherapy is a staple of triple-negative breast cancer (TNBC) treatment. Predicated on the principle of fractional cell killing, chemotherapy regimens are typically cycles of short drug exposure followed by a period of recovery from the toxic side effects. However, many patients experience chemotherapy resistance for a variety of reasons, resulting in tumors that are not sufficiently reduced with treatment. Response to chemotherapy prior to surgical resection is a strong predictor of patient prognosis; therefore, finding ways to improve efficacy is a critical need. Tremendous effort has gone into understanding the relationship between the tumor microenvironment and treatment sensitivity in many tumor types. In this issue of Cancer Research, Miroshnychenko and colleagues investigate how the well-characterized phenomenon of cancer-associated fibroblast (CAF)–induced proliferation of tumor cells allows TNBC to evade extinction after multiple cycles of cytotoxic chemotherapies. Their findings imply CAF-promoted tumor cell proliferation allows tumor cells to push through stressful conditions caused by treatment and to avoid tumor elimination. This mechanism of ‘indirect’ chemoresistance contrasts with the dogma that tumor cell proliferation enhances chemosensitivity. This study opens the door for the discovery of mechanisms and therapeutic targets to limit the ability of CAFs to rescue tumor cells from the brink of extinction. See related article by Miroshnychenko et al., p. 3681