Radiotherapy-induced remodeling of the tumor microenvironment by stromal cells

Cancer cells reside amongst a complex milieu of stromal cells and structural features known as the tumor microenvironment. Often cancer cells divert and co-opt functions of stromal cells of the microenvironment to support tumor progression and treatment resistance. During therapy targeting cancer cells, the stromal cells of the microenvironment receive therapy to the same extent as cancer cells. Stromal cells therefore activate a variety of responses to the damage induced by these therapies, and some of those responses may support tumor progression and resistance. We review here the response of stromal cells to cancer therapy with a focus on radiotherapy in glioblastoma. We highlight the response of endothelial cells and the vasculature, macrophages and microglia, and astrocytes, as well as describing resulting changes in the extracellular matrix. We emphasize the complex interplay of these cellular factors in their dynamic responses. Finally, we discuss their resulting support of cancer cells in tumor progression and therapy resistance. Understanding the stromal cell response to therapy provides insight into complementary therapeutic targets to enhance tumor response to existing treatment options.