Amplifying Tumor–Stroma Communication: An Emerging Oncogenic Function of Mutant p53

Abstract

TP53 mutations are widespread in human cancers. An expanding body of evidence highlights that, in addition to their manifold cell-intrinsic activities boosting tumor progression, missense p53 mutants enhance the ability of tumor cells to communicate amongst themselves and with the tumor stroma, by affecting both the quality and the quantity of the cancer secretome. In this review, we summarize recent literature demonstrating that mutant p53 enhances the production of growth and angiogenic factors, inflammatory cytokines and chemokines, modulates biochemical and biomechanical properties of the extracellular matrix, reprograms the cell trafficking machinery to enhance secretion and promote recycling of membrane proteins, and affects exosome composition. All these activities contribute to the release of a promalignant secretome with both local and systemic effects, that is key to the ability of mutant p53 to fuel tumor growth and enable metastatic competence. A precise knowledge of the molecular mechanisms underlying the interplay between mutant p53 and the microenvironment is expected to unveil non-invasive biomarkers and actionable targets to blunt tumor aggressiveness.

The Role of p53 Dysfunction in Colorectal Cancer and Its Implication for Therapy

“…Besides an immunomodulatory function, p53 mutations dictate the composition of the tumor secretome, which consists of extracellular matrix (ECM) components, remodeling enzymes, exosomes and soluble mediators like growth factors, cytokines and chemokines (Figure 2). Stromal cells are corrupted by these signals and give rise to cancer-associated fibroblasts (CAFs), which are strong allies of the tumor in the TME [152][153][154][155][156][157]. They are the most abundant cell type of the TME and promote multiple aspects of tumor development and growth by three mechanisms: firstly, they remodel the ECM to increase its stiffness and thus inhibit immune cells from infiltrating the tumor stroma [158]; secondly, CAFs stimulate neo-angiogenesis via proangiogenic factors (e.g., ang1, 2; angiopoietin 1 and 2), securing the supply of oxygen and nutrients to the tumor [159]; and thirdly, together with tolerogenic cells of the adaptive and inherent immune system, CAFs sustain an immunosuppressive TME, also antagonizing the anti-tumor effect of checkpoint inhibitors [159][160][161][162][163][164].…”

“…Mirroring their mesenchymal heritage, CAFs highly express α-smooth muscle actin (α-SMA), fibroblast activation protein (FAP), type I collagen, platelet derived growth factor receptor-alpha/beta (PDGFRα/β), vimentin, and the cell cycle regulating protein FSP-1 (fibroblast-specific protein, S100A4), which could be exploited for cell-specific drug targeting in the context of anti-stromal therapy [160]. There is rising evidence that the inhibition of p53 in stromal cells, including CAFs, causes immune escape and sustains tumorigenesis [152,165]. p53 is inhibited in stromal cells by onco-miRNA-30d, which is expressed in primarily hypoxic cells in the TME due to tumor triggered hypoxia (Figure 2) [166].…”

The Role of p53 in Progression of Cutaneous Squamous Cell Carcinoma

“…Moreover, the availability of mutant p53 interacting proteins can be context-dependent and vary not only by cell type but also based on the surrounding tumor microenvironment. Indeed, the GOF p53 mutant can mediate several oncogenic functions of the cancer cell itself, and increasing evidence shows that mutant p53 proteins can alter the cancer cell secretome to regulate the tumor microenvironment and promote cancer progression [ 133 ]. Matrix metalloproteinases (MMPs) play an important role in tumor invasion by proteolytic remodeling of the ECM, and they can be produced by the tumor cells, surrounding stromal fibroblasts, and by tumor-associated inflammatory cells [ 134 ].…”

HSP90-stabilized proteins as therapeutic targets in cancer

“…In the past couple of years, it became more evident that mutp53 can influence the crosstalk between cancer cells and the components of the tumor microenvironment [305]. It is thought that the interaction of mutp53 variants with different transcription factors (e.g., NF-𝜅B, pSTAT3, see section 4.2.1) can trigger a pro-tumorigenic response of stromal cells either by specific secretion of soluble bioactive mediators (e.g.…”

“…It is thought that the interaction of mutp53 variants with different transcription factors (e.g., NF-𝜅B, pSTAT3, see section 4.2.1) can trigger a pro-tumorigenic response of stromal cells either by specific secretion of soluble bioactive mediators (e.g. cytokines, angiogenic factors) or the transcription of proteins which are necessary for interaction between tumor and stromal cells [305][306][307]. In that way, mutp53 can DISCUSSION regulate the exact composition of the cancer secretome in order to acquire new tumorigenic functions and to promote tumor progression [305].…”