Role of p53 in the Regulation of the Inflammatory Tumor Microenvironment and Tumor Suppression

Abstract

p53 has functional roles in tumor suppression as a guardian of the genome, surveillant of oncogenic cell transformation, and as recently demonstrated, a regulator of intracellular metabolism. Accumulating evidence has shown that the tumor microenvironment, accompanied by inflammation and tissue remodeling, is important for cancer proliferation, metastasis, and maintenance of cancer stem cells (CSCs) that self-renew and generate the diverse cells comprising the tumor. Furthermore, p53 has been demonstrated to inhibit inflammatory responses, and functional loss of p53 causes excessive inflammatory reactions. Moreover, the generation and maintenance of CSCs are supported by the inflammatory tumor microenvironment. Considering that the functions of p53 inhibit reprogramming of somatic cells to stem cells, p53 may have a major role in the inflammatory microenvironment as a tumor suppressor. Here, we review our current understanding of the mechanisms underlying the roles of p53 in regulation of the inflammatory microenvironment, tumor microenvironment, and tumor suppression.

Keywords: cancer metabolism; cancer stem cells; cellular reprograming; inflammation; nuclear factor-κB (NF-κB); oxidative stress; p53; tumor microenvironment.

Figure 1

Role and regulatory mechanism of p53 in the inflammatory tumor microenvironment. p53 is regulated by inflammation and inhibits the generation and maintenance of cancer stem cells (CSCs). In the absence of p53 functions, enhanced inflammatory reactions cause cells to be continuously exposed to inflammatory cytokines, chemokines, and growth factors, resulting in accumulation of DNA damage induced by oxidative stress and enhanced energy metabolism. These conditions might cause reprogramming of the cells to facilitate the production of CSCs, tumor development, and metastasis.