Tumor Microenvironment as a Regulator of Radiation Therapy: New Insights into Stromal-Mediated Radioresistance

SIMPLE SUMMARY: Cancer is multifaceted and consists of more than just a collection of mutated cells. These cancerous cells reside along with other non-mutated cells in an extracellular matrix which together make up the tumor microenvironment or tumor stroma. The composition of the tumor microenvironment plays an integral role in cancer initiation, progression, and response to treatments. In this review, we discuss how the tumor microenvironment regulates the response and resistance to radiation therapy and what targeted agents have been used to combat stromal-mediated radiation resistance. ABSTRACT: A tumor is a complex “organ” composed of malignant cancer cells harboring genetic aberrations surrounded by a stroma comprised of non-malignant cells and an extracellular matrix. Considerable evidence has demonstrated that components of the genetically “normal” tumor stroma contribute to tumor progression and resistance to a wide array of treatment modalities, including radiotherapy. Cancer-associated fibroblasts can promote radioresistance through their secreted factors, contact-mediated signaling, downstream pro-survival signaling pathways, immunomodulatory effects, and cancer stem cell-generating role. The extracellular matrix can govern radiation responsiveness by influencing oxygen availability and controlling the stability and bioavailability of growth factors and cytokines. Immune status regarding the presence of pro- and anti-tumor immune cells can regulate how tumors respond to radiation therapy. Furthermore, stromal cells including endothelial cells and adipocytes can modulate radiosensitivity through their roles in angiogenesis and vasculogenesis, and their secreted adipokines, respectively. Thus, to successfully eradicate cancers, it is important to consider how tumor stroma components interact with and regulate the response to radiation. Detailed knowledge of these interactions will help build a preclinical rationale to support the use of stromal-targeting agents in combination with radiotherapy to increase radiosensitivity.