Perivascular PDGFR-β is an independent marker for prognosis in renal cell carcinoma

Abstract

Background:Renal cell carcinoma (RCC) is a highly vascularised tumour, where anti-angiogenic treatment with multi-tyrosine-kinase-inhibitor, is used for first-line treatment of metastatic disease. Variations in vascular characteristics are likely to contribute to variations in intrinsic aggressiveness of the disease. Emerging studies are identifying perivascular status, including perivascular PDGFR-β, as a determinant of prognosis in other tumour types.Methods:This work explored the impact on prognosis of vascular characteristics in RCC through analyses of a population-based collection of tumours from surgery-alone-treated patients. The quantitative data from a panel of vascular metrics were obtained through computerised image analysis of sections double-stained for expression of the endothelial cell marker CD34 together with perivascular markers α-SMA or PDGFR-β.Results:Perivascular expression of PDGFR-β and α-SMA were positively correlated to each other, and negatively correlated to vessel density. High expression of PDGFR-β and α-SMA as well as low vessel density was significantly associated with short survival in uni- and multivariate analyses. Subgroup analyses demonstrated that the prognostic impact of the perivascular markers was particularly prominent in the T4-subgroup. A novel metric, related to PDGFR-β perivascular heterogeneity, was also associated with prognosis in uni-and multi-variate analyses. This novel metric also acted as a prognosis marker in ovarian cancer.Conclusions:The study demonstrates previously unrecognised associations between RCC survival and the absolute levels, and variability, of perivascular PDGFR-β. This marker should be further explored in other RCC cohorts. Findings also suggest mechanistic analyses and studies on the relationship between perivascular status and efficacy of multi-tyrosine-kinase-inhibitors.

Involvement of platelet‐derived growth factor ligands and receptors in tumorigenesis

“…In contrast, animal models with xenografted B16 melanoma cells expressing high levels of PDGF-BB had a higher pericyte coverage and a faster growth rate [340]. Furthermore, high pericyte coverage measured by PDGFRb expression in serous ovarian cancer and renal cell carcinoma has demonstrated correlations with poor prognosis [341][342][343].…”

Multi‐parametric profiling of renal cell, colorectal, and ovarian cancer identifies tumour‐type‐specific stroma phenotypes and a novel vascular biomarker

“…Initial analyses focused on comparing different vascular and fibroblast‐dominated stroma features between colorectal cancer (CRC), renal cell cancer (RCC) and ovarian cancer (OC; Figure A–D,G). Data were also used to compare intra‐case heterogeneity of vascular and perivascular features (Figure E,F,H; see Materials and Methods and for details concerning the metrics ‘vessel size IQR’ and ‘perivascular intensity [PVI] IQR’).…”

“…Previous analyses of the OC and RCC cohort have demonstrated that high heterogeneity of the perivascular status is associated with poor prognosis . In the present study, we introduced a novel metric denoted ‘vessel distance IQR’, which describes the variation in distance to the closest located vessel for each vessel in a tumour sample.…”

“…Marker‐positive stroma fraction was defined as the fraction of the analyzed sample, excluding perivascular regions (see above) and vessel regions, that displayed an expression level above a threshold level. (see Frodin et al for more details ).…”

“…Most prognosis studies with vascular markers have used case‐based mean‐values of the marker‐of‐interest as the basis for scoring of individual tumours. Recent analyses in ovarian and kidney cancer have demonstrated that the inside‐case heterogeneity regarding expression of a perivascular marker acts as a prognostic factor . This suggests the possibility of prognostic significance also of heterogeneity of other tumour vasculature characteristics.…”