Tumor suppressor genes in the tumor microenvironment.

Tumor suppressor genes (TSGs) are thought to suppress tumor development primarily via cancer cell-autonomous mechanisms. However, the tumor microenvironment (TME) also significantly influences tumorigenesis. In this context, a role for TSGs in the various cell types of the TME in regulating tumor growth is emerging. Indeed, expression analyses of TSGs in clinical samples, along with data from mouse models in which TSGs were deleted selectively in the TME, indicate a functional role for them in tumor development. In this Perspective, using TP53 and PTEN as examples, we posit that TSGs play a significant role in cells of the TME in regulating tumor development, and postulate both a 'pro-active' and 'reactive' model for their contribution to tumor growth, dependent on the temporal sequence of initiating events. Finally, we discuss the need to consider a 2-in-1 cancer-treatment strategy to improve the efficacy of clearance of cancer cells and the cancer-promoting TME.