Involvement of stromal p53 in tumor-stroma interactions

Abstract

p53 is a major tumor-suppressor gene, inactivated by mutations in about half of all human cancer cases, and probably incapacitated by other means in most other cases. Most research regarding the role of p53 in cancer has focused on its ability to elicit apoptosis or growth arrest of cells that are prone to become malignant owing to DNA damage or oncogene activation, i.e. cell-autonomous activities of p53. However, p53 activation within a cell can also exert a variety of effects upon neighboring cells, through secreted factors and paracrine and endocrine mechanisms. Of note, p53 within cancer stromal cells can inhibit tumor growth and malignant progression. Cancer cells that evolve under this inhibitory influence acquire mechanisms to silence stromal p53, either by direct inhibition of p53 within stromal cells, or through pressure for selection of stromal cells with compromised p53 function. Hence, activation of stromal p53 by chemotherapy or radiotherapy might be part of the mechanisms by which these treatments cause cancer regression. However, in certain circumstances, activation of stromal p53 by cytotoxic anti-cancer agents might actually promote treatment resistance, probably through stromal p53-mediated growth arrest of the cancer cells or through protection of the tumor vasculature. Better understanding of the underlying molecular mechanisms is thus required. Hopefully, this will allow their manipulation towards better inhibition of cancer initiation, progression and metastasis.

Fig. 1. p53 represses SDF-1 expression in cultured adult lung fibroblasts

Lung fibroblasts were prepared from 4 months old wild type (WT) mice or p53 knockout (KO) mice, and maintained in culture for the minimal number of passages required to obtain enough cells for RNA analysis. Cells were either left untreated (control) or treated with the p53-activating drug Nutlin-3a (25μM) for 24 hours. RNA was extracted and subjected to qRT-PCR mRNA analysis of SDF-1, p21, and HPRT as an internal control. p21 (right) and SDF-1 (left) mRNA levels are shown after normalization for the HPRT. As expected, p21 mRNA are high in the wt fibroblasts and are further elevated upon Nutlin treatment, while they are very low in the p53-null fibroblasts. In contrast, SDF-1 mRNA expression is repressed in the wt cells relative to their p53-null counterparts, and is further reduced upon Nutlin treatment in the wild type but not p53-null fibroblasts, implying specific repression of SDF-1 gene expression by wt p53.

Fig. 2. Proposed model for the association between tumor progression and altered p53 function in stromal cells

The cartoon depicts the proposed impact of stromal p53 on the secreted protein profile (“secretome”) of stromal cells, exemplified by fibroblasts. Functional p53 in stromal fibroblasts increases their ability to produce and secrete tumor inhibitory factors, while suppressing the production of tumor promoting factors. Loss or attenuation of p53 function in fibroblasts reverses this pattern, leading to a shift towards an overall tumor-promoting secretome. It is further proposed that, in the course of tumor progression, p53 activity within cancer-associated fibroblasts (CAFs) becomes attenuated through several distinct cell-autonomous and non cell-autonomous mechanisms. This leads to changes in the secretome of CAFs relative to normal fibroblasts, creating a more supportive microenvironment for the cancer cells.