The Effects of Chemotherapeutics on the Ovarian Cancer Microenvironment

SIMPLE SUMMARY: Cancer cells are the target of most approved therapies. A growing body of evidence suggests that these agents have important roles in modulating the biology of host cells and their interactions with cancer cells, including blood vessels, fibroblasts, immune and fat cells, among others. This review provides an overview of potential roles of commonly used therapeutics in the tumor microenvironment, with a focus on cancer-associated fibroblasts. This includes an emphasis on therapies commonly used for the treatment of high-grade serous ovarian cancers (e.g., platinum, taxanes, PARP inhibitors, and anti-angiogenic agents). In vitro, in vivo, and clinical studies are included, and perspectives offered on how to best interpret the influence of therapeutics on normal cells. ABSTRACT: High-grade serous ovarian cancer (HGSOC) is characterized by a complex and dynamic tumor microenvironment (TME) composed of cancer-associated fibroblasts (CAFs), immune cells, endothelial cells, and adipocytes. Although most approved therapies target cancer cells, a growing body of evidence suggests that chemotherapeutic agents have an important role in regulating the biology of the diverse cells that compose the TME. Understanding how non-transformed cells respond and adapt to established therapeutics is necessary to completely comprehend their action and develop novel therapeutics that interrupt undesired tumor–stroma interactions. Here, we review the effects of chemotherapeutic agents on normal cellular components of the host-derived TME focusing on CAFs. We concentrate on therapies used in the treatment of HGSOC and synthesize findings from studies focusing on other cancer types and benign tissues. Agents such as platinum derivatives, taxanes, and PARP inhibitors broadly affect the TME and promote or inhibit the pro-tumorigenic roles of CAFs by modifying the bidirectional cross-talk between tumor and stromal cells in the tumor organ. While most chemotherapy research focuses on cancer cells, these studies emphasize the need to consider all cell types within the tumor organ when evaluating chemotherapeutics.