Tumor Microenvironment and Differential Responses to Therapy

Abstract

Cancer evolution plays a key role in both the development of tumors and their response to therapy. Like all evolutionary processes, tumor evolution is shaped by the environment. In tumors, this consists of a complex mixture of nontransformed cell types and extracellular matrix. Chemotherapy or radiotherapy imposes further strong selective pressures on cancer cells during cancer treatment. Here, we review how different components of the tumor microenvironment can modulate the response to chemo- and radiotherapy. We further describe how therapeutic strategies directly alter the composition, or function, of the tumor microenvironment, thereby further altering the selective pressures to which cancer cells are exposed. Last, we explore the consequences of these interactions for therapy outcomes and how to exploit our increasing understanding of the tumor microenvironment for therapeutic benefit.

Figure 1.

Major components of the tumor microenvironment. Illustration of the main cellular types found within tumors alongside a table listing their main roles within the tumor.

Figure 2.

Major mechanisms by which the tumor microenvironment modulates the response to therapy. Stromal cells, including macrophages, endothelial cells, and fibroblasts, can produce growth factors, cytokines, and chemokines that locally promote cancer cell survival. Fibroblasts also play a major role in shaping the tumor extracellular matrix and this can promote prosurvival signals via integrins. The production and activation of transforming growth factor β (TGF-β) by stromal cells can lead to immune suppression that further protects cancer cells; this can be both local and systemic. In addition, the reduction in leukocyte numbers caused by cytotoxic and radiotherapy can lead to further immune suppression.