Abstract
p53 is an important tumor suppressor, and the complexities of p53 function in regulating cancer cell behaviour are well established. Many cancers lose or express mutant forms of p53, with evidence that the type of alteration affecting p53 may differentially impact cancer development and progression. It is also clear that in addition to cell-autonomous functions, p53 status also affects the way cancer cells interact with each other. In this review, we briefly examine the impact of different p53 mutations and focus on how heterogeneity of p53 status can affect relationships between cells within a tumor.
Highlights
While some cancer-associated somatic mutations in TP53 result in the loss of protein expression, many cancers ex
Li-Fraumeni syndrome (LFS) patients carry germline p53 mutations and are highly likely to develop a variety of different cancers at a young age (Bougeard et al 2015)
While this loss of function can clearly contribute to tumor development, the high incidence of missense mutation compared with nonsense mutation or gene deletion has raised the possibility that there is a selective advantage to tumors in maintaining the expression of mutant p53 proteins
Summary
In addition to inhibiting the function of WT p53, mutant p53 proteins can acquire novel gains of function (GOFs) that contribute to tumor development independently of WT p53. The retention of WT p53 in cancer cells can affect the tumor-stroma interaction, most clearly by supporting the activation of an anti-tumor immune response (Bezzi et al 2018; Wellenstein et al 2019; Blagih et al 2020b) In these studies, loss of p53 in cancer cells was shown to increase expression of cytokines and factors that blunt various arms of the immune response to the tumor and enhance metastasis. Expression of various p53 mutants (including R175H, M237I, R273H, and R280K) supported invasive behavior and cancer cell survival in response to the inflammatory cytokine TNFα by promoting the secretion of proinvasive molecules such as MMP9 and CXCL10 These cells showed mutant p53-dependent secretion of the lymphocyte-attracting chemokines CX3CL1 and LTB, suggesting that the increased motility was accompanied by an induction of a potentially tumor-limiting immune response (Di Minin et al 2014). The ability of cancer cells to induce changes in macrophages was shown to be dependent on the type of p53 mutation in the tumor cells, with R273H and R249S, but not p53 V157F and R175H, able to induce a tumor-promoting shift in the profile of M2 macrophages (Cooks et al 2018)
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
