The role of fibroblasts in cancer progression, therapy resistance and field cancerization
Chan, Jeremy Soon Kiat
Date of Issue2017-06-08
School of Biological Sciences
Cancer refers to a cluster of diseases that are characterized by uncontrolled neoplastic growth manifesting in a wide variety of tissues and organs. The malignant progression of cancer requires a permissive microenvironment comprising tumor supportive cells embedded within an altered extracellular matrix (ECM), collectively known as the reactive tumor stroma. Cancer-associated fibroblasts (CAFs) are the dominant cell type within the reactive tumor stroma, contributing mitogenic factors, reactive oxygen species (ROS), metabolic intermediates, ECM molecules and matrix remodeling enzymes that profoundly influence the aggressiveness of tumor epithelia and the tumor response to therapy. Most anticancer treatments to date are targeted at the tumor epithelia and neglect the critical roles played by CAFs. Moreover, tumor resistance and relapse are persistent challenges faced by patients and clinicians, suggesting an incomplete understanding of tumor-stroma co-evolution that severely limits the sustained efficacy of existing anticancer drugs. Herein, we explored the transcription-based programs that enable the protumorigenic effects of CAFs. Firstly, we focused on the expression profile of nuclear receptors in CAFs. Because nuclear receptors are a unique class of transcription factors whose activities are directly modulated by small molecule ligands, they hold untapped potential for CAF-directed anticancer therapy. We showed that tumor epithelia are sensitive to the nuclear receptor profile of CAFs. The overexpression or knockdown of specific nuclear receptors in CAFs resulted in the attenuation of one or more aggressive phenotypes in tumor epithelial cells, namely, proliferation, invasiveness, drug resistance, energy metabolism and oxidative stress. Furthermore, we identified androgen receptor and retinoic acid receptor β antagonists as useful adjuvants to cisplatin chemotherapy that attenuated chemoresistance in mice tumor xenografts. Given our observations that CAFs augment oxidative stress within the tumor microenvironment, we investigated whether the readily diffusible ROS, H2O2, could promote oncogenic transformation of adjacent normal epithelia and stromal fibroblasts. Indeed, epithelial cells at various stages of oncogenic transformation exhibited a differential response to H2O2 in terms of proliferation and invasiveness. Fibroblasts exposed to H2O2 also adopted a CAF-like state and became a source of H2O2 due to impaired TGFβ signaling that resulted in a defect in ROS detoxification. Importantly, oxidatively transformed fibroblasts retained their tumor-promoting capacity when adoptively transferred into tumor xenografts. Therefore, the findings reported in this thesis suggest that future anticancer therapies should consider the stromal context of tumors. Druggable features of CAFs such as their nuclear receptor expression and their pro-oxidant status can be targeted in combination with existing cytotoxic agents or antibody-based treatments to potentially improve patient outcomes.