Selection of p53-Deficient Stromal Cells in the Tumor Microenvironment

Abstract

The tumor microenvironment is considered pro-oncogenic for reasons that, among others, involve the stimulation of cancer cell growth. However, little is known regarding how the tumor microenvironment affects the proliferation of stromal cells that coexist with cancer cells in the tumors. In the present study, we show that cancer cells trigger a paracrine response in normal fibroblasts that is not consistently mitogenic but may also become antimitogenic, inhibiting fibroblasts' proliferation in vitro. In vivo experiments on xenografts of MDA-MB-231 breast and A549 lung cancer cells in SCID mice or primary Notch-induced breast cancers that develop in transgenic mice showed that stromal cells frequently undergo senescence, confirming the presence of stress-inducing conditions within the tumor's microenvironment. These antimitogenic responses of the stromal cells were less pronounced in fibroblasts that are p53-deficient, suggesting that p53 plays a role in the execution of these mitogenic stress responses. In addition, they provide a biological basis for the selection of certain stromal cell subpopulations within malignant tumors exemplified by the p53-deficient stromal cells. Indeed, reconstitution of A549 human lung tumors in mice with admixed wild-type and p53-deficient stromal fibroblasts indicates that the selection of p53-deficient stromal cells is more intense when the number of cancer cells, and therefore the intensity of the stress response-inducing signals, is higher. These findings possess implications related to the effects of the cancer cells in the stromal cells and provide hints for the mechanism(s) underlining the transition of the normal stroma to cancer-associated stroma.