Elevation of the TP53 isoform Δ133p53β in glioblastomas: an alternative to mutant p53 in promoting tumor development

Abstract

As tumor protein 53 (p53) isoforms have tumor‐promoting, migration, and inflammatory properties, this study investigated whether p53 isoforms contributed to glioblastoma progression. The expression levels of full‐length TP53α (TAp53α) and six TP53 isoforms were quantitated by RT‐qPCR in 89 glioblastomas and correlated with TP53 mutation status, tumor‐associated macrophage content, and various immune cell markers. Elevated levels of Δ133p53β mRNA characterised glioblastomas with increased CD163‐positive macrophages and wild‐type TP53. In situ‐based analyses found Δ133p53β expression localised to malignant cells in areas with increased hypoxia, and in cells with the monocyte chemoattractant protein C‐C motif chemokine ligand 2 (CCL2) expressed. Tumors with increased Δ133p53β had increased numbers of cells positive for macrophage colony‐stimulating factor 1 receptor (CSF1R) and programmed death ligand 1 (PDL1). In addition, cells expressing a murine ‘mimic’ of Δ133p53 (Δ122p53) were resistant to temozolomide treatment and oxidative stress. Our findings suggest that elevated Δ133p53β is an alternative pathway to TP53 mutation in glioblastoma that aids tumor progression by promoting an immunosuppressive and chemoresistant environment. Adding Δ133p53β to a TP53 signature along with TP53 mutation status will better predict treatment resistance in glioblastoma. © 2018 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

The Emerging Landscape of p53 Isoforms in Physiology, Cancer and Degenerative Diseases

“…In HCT116 cells, ∆133p53β expression was found to promote the acquisition of an amoeboid-like phenotype associated with epithelial mesenchymal transition and cell invasiveness [76]. Recently Kazantseva et al showed that the expression of ∆133p53β, which was increased in glioblastoma tissues with WT p53, promoted an immunosuppressive tumour microenvironment by increasing CCL2 expression and subsequent CD163 macrophage infiltration [102]. Taken together, it is becoming apparent that ∆133p53β co-expression with other p53 isoforms could be associated with poorer cancer outcomes.…”

“…Therefore, given the significance of p53 isoforms in multiple biological processes, it would be a logical endeavour to investigate p53 isoform expression and their spatiotemporal distribution in normal, precancerous and cancer tissues by IHC. Several groups have attempted to identify p53 isoforms with IHC with varying degrees of success [92,102,128]. Significant limitations experienced include the paucity of p53 isoform-specific antibodies and weak signal intensity.…”

“…Additionally, as p53α is notorious for extensive PTMs, one would expect p53 isoforms to also be similarly modified, thus potentially affecting the target epitope of the isoform-specific antibodies. Other methods to study isoform expression in situ include RNAscope in situ hybridisation which has been employed to study ∆133p53β expression in formalin-fixed paraffin-embedded glioblastoma tissue [102]. Targeted proteomics with liquid chromatography-tandem mass spectrometry (LC-MS/MS) is emerging as a reliable method to quantify p53 isoform expression at the protein level.…”

Targeting Tumor Associated Macrophages to Overcome Conventional Treatment Resistance in Glioblastoma

“…Tumor protein 53 (p53) is involved in promoting the development of the tumor. GB with the p53 isoform D133p53b had increased CD163 + macrophages (Kazantseva et al, 2018). Moreover, D133p53b supports cancer stemness (Arsic et al, 2015).…”

“…Moreover, D133p53b supports cancer stemness (Arsic et al, 2015). In addition, it is correlated with resistance to TMZ (Kazantseva et al, 2018). GB is able to evade the toxic effects of chemotherapy, but it can equally evade the action of the immune system.…”