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.

Chromosome position 9p21 encodes three-tumor suppressors p16^INK4a, p14^ARF, and p15^INK4b and the long non-coding RNA ANRIL (antisense non-coding RNA in the INK4 locus). The rs11515 single-nucleotide polymorphism in the p16^INK4a/p14^ARF 3′-untranslated region is associated with glioblastoma, melanoma, and other cancers. This study investigated the frequency and effect of rs11515 genotypes in breast cancer. Genomic DNA samples from 400 women (200 with and 200 without a diagnosis of breast cancer) were genotyped for the rs11515 major (C) and minor (G) alleles. The rs11515 polymorphism was also investigated in 108 heart tissues to test for tissue-specific effects. Four 9p21 transcripts, p16^INK4a, p14^ARF, p15^INK4b, and ANRIL were measured in breast tumors and myocardium using quantitative PCR. Heterozygotes (CG genotype) were more frequent in women with breast cancer compared to the control population (P = 0.0039). In those with breast cancer, the CG genotype was associated with an older age (P = 0.016) and increased lymph node involvement (P = 0.007) compared to homozygotes for the major allele (CC genotype). In breast tumors, the CG genotype had higher ANRIL (P = 0.031) and lower p16^INK4a (P = 0.006) expression compared to the CC genotype. The CG genotype was not associated with altered 9p21 transcripts in heart tissue. In breast cancer, the rs11515 CG genotype is more frequent and associated with a more aggressive tumor that could be due to increased ANRIL and reduced p16^INK4a expression. The absence of association between rs11515 genotypes and 9p21 transcripts in heart tissue suggests this polymorphism has tissue- or disease-specific functions.

We investigated the influence of selected TP53 SNPs in exon 4 and intron 4 on cancer risk, clinicopathological features and expression of TP53 isoforms. The intron 4 SNPs were significantly over-represented in cohorts of mixed cancers compared to three ethnically matched controls, suggesting they confer increased cancer risk. Further analysis showed that heterozygosity at rs1042522(GC) and either of the two intronic SNPs rs9895829(TC) and rs2909430(AG) confer a 2.34–5.35-fold greater risk of developing cancer. These SNP combinations were found to be associated with shorter patient survival for glioblastoma and prostate cancer. Additionally, these SNPs were associated with tumor-promoting inflammation as evidenced by high levels of infiltrating immune cells and expression of the Δ133TP53 and TP53β transcripts. We propose that these SNP combinations allow increased expression of the Δ133p53 isoforms to promote the recruitment of immune cells that create an immunosuppressive environment leading to cancer progression.

Despite significant advances in developing drugs to treat brain tumours, achieving therapeutic concentrations of the drug at the tumour site remains a major challenge due to the presence of the blood–brain barrier (BBB). Several strategies have evolved to enhance brain delivery of chemotherapeutic agents to treat tumours; however, most approaches have several limitations which hinder their clinical utility. Promising studies indicate that ultrasound can penetrate the skull to target specific brain regions and transiently open the BBB, safely and reversibly, with a high degree of spatial and temporal specificity. In this review, we initially describe the basics of therapeutic ultrasound, then detail ultrasound-based drug delivery strategies to the brain and the mechanisms by which ultrasound can improve brain tumour therapy. We review pre-clinical and clinical findings from ultrasound-mediated BBB opening and drug delivery studies and outline current therapeutic ultrasound devices and technologies designed for this purpose.

The p53 isoform, Δ133p53β, is critical in promoting cancer. Here we report that Δ133p53β activity is regulated through an aggregation-dependent mechanism. Δ133p53β aggregates were observed in cancer cells and tumour biopsies. The Δ133p53β aggregation depends on association with interacting partners including p63 family members or the CCT chaperone complex. Depletion of the CCT complex promotes accumulation of Δ133p53β aggregates and loss of Δ133p53β dependent cancer cell invasion. In contrast, association with p63 family members recruits Δ133p53β from aggregates increasing its intracellular mobility. Our study reveals novel mechanisms of cancer progression for p53 isoforms which are regulated through sequestration in aggregates and recruitment upon association with specific partners like p63 isoforms or CCT chaperone complex, that critically influence cancer cell features like EMT, migration and invasion.

BACKGROUND AND PURPOSE: In glioblastoma, tumor-associated macrophages have tumor-promoting properties. This study determined whether routine MR imaging features could predict molecular subtypes of glioblastoma that differ in the content of tumor-associated macrophages. MATERIALS AND METHODS: Seven internally derived MR imaging features were assessed in 180 patients, and 25 features from the Visually AcceSAble Rembrandt Images feature set were assessed in 164 patients. Glioblastomas were divided into subtypes based on the telomere maintenance mechanism: alternative lengthening of telomeres positive (ALT+) and negative (ALT−) and the content of tumor-associated macrophages (with [M+] or without [M−] a high content of macrophages). The 3 most frequent subtypes (ALT+/M−, ALT−/M+, and ALT−/M−) were correlated with MR imaging features and clinical parameters. The fourth group (ALT+/M+) did not have enough cases for correlation with MR imaging features. RESULTS: Tumors with a regular margin and those lacking a fungating margin, an expansive T1/FLAIR ratio, and reduced ependymal extension were more frequent in the subgroup of ALT+/M− (P < .05). Radiologic necrosis, lack of cystic component (by both criteria), and extensive peritumoral edema were more frequent in ALT−/M+ tumors (P < .05). Multivariate testing with a Cox regression analysis found the cystic imaging feature was additive to tumor subtype, and O6-methylguanine methyltransferase (MGMT) status to predict improved patient survival (P < .05). CONCLUSIONS: Glioblastomas with tumor-associated macrophages are associated with routine MR imaging features consistent with these tumors being more aggressive. Inclusion of cystic change with molecular subtypes and MGMT status provided a better estimate of survival.