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

Abstract

A novel set of integrated procedures for quantification of fibroblast‐rich stroma and vascular characteristics has recently been presented allowing discovery of novel perivascular and stromal biomarkers in colorectal, renal cell, and ovarian cancer. In the present study, data obtained through these procedures from clinically well‐annotated collections of these three tumour types have been used to address two novel questions. First, data have been used to investigate if the three tumour types demonstrate significant differences regarding features such as vessel diameter, vessel density, and perivascular marker expression. Second, analyses of the cohorts have been used to explore the prognostic significance of a novel vascular metric, ‘vessel distance inter‐quartile range (IQR)’ that describes intra‐case heterogeneity regarding vessel distribution. The comparisons between the three tumour types demonstrated a set of significant differences. Vessel density of renal cell cancer was statistically significantly higher than in colorectal and ovarian cancer. Vessel diameter was statistically significantly higher in ovarian cancer. Concerning perivascular status, colorectal cancer displayed significantly higher levels of perivascular PDGFR‐β expression than the other two tumour types. Intra‐case heterogeneity of perivascular PDGFR‐β expression was also higher in colorectal cancer. Notably, these fibroblast‐dominated stroma phenotypes matched previously described experimental tumour stroma characteristics, which have been linked to differential sensitivity to anti‐VEGF drugs. High ‘vessel distance IQR’ was significantly associated with poor survival in both renal cell cancer and colorectal cancer. In renal cell cancer, this characteristic also acted as an independent prognostic marker according to multivariate analyses including standard clinico‐pathological characteristics. Explorative subset analyses indicated particularly strong prognostic significance of ‘vessel distance IQR’ in T stage 4 of this cancer type. Together, these analyses identified tumour‐type‐specific vascular‐stroma phenotypes of possible functional significance, and suggest ‘vessel distance IQR’ as a novel prognostic biomarker.

Prognostic and predictive impact of stroma cells defined by PDGFRb expression in early breast cancer: results from the randomized SweBCG91RT trial

“…Furthermore, PDGFRb scoring was performed manually by two independent raters and despite a moderate interrater agreement, unbiased digital approaches may be more sensitive. Initial digital approaches have been described [ 26 , 51 , 52 ] but are still under refinement given the fact that especially in early stage breast cancers, normal tissue regions very often are present and need to be excluded. Of note, in this retrospective study, the patients were categorized into PDGFRb score groups based on tertiles as a predefined cut-off.…”

Fibroblasts in urothelial bladder cancer define stroma phenotypes that are associated with clinical outcome

“…FAP positive fibroblasts were linked to immunosuppressive functions within the tumor microenvironment [28][29][30][31][32] . Stromal PDGFRa was found to decrease with tumor progression [33][34][35] , while a high expression of stromal PDGFRb was associated with a worse prognosis in different solid tumors [36][37][38][39][40][41][42] and drug resistance 43 . Likewise, CD90 defined fibroblasts were adversely associated with clinical outcome 44,45 but were also discussed as immune-regulatory fibroblasts [46][47][48] .…”

PDGF-BB/PDGFRβ induces tumour angiogenesis via enhancing PKM2 mediated by the PI3K/AKT pathway in Wilms’ tumour

“…In addition to maintaining vascular homeostasis in pericytes, PDGFRβ is highly expressed in a variety of tumours, such as colorectal cancer, ovarian carcinoma, and hepatocellular carcinoma. The PDGFRβ expression is increased in the perivascular area of colorectal cancer, and the inpatient heterogeneity of PDGFRβ expression is also high [18][19][20]. In a xenograft mouse model of human WT [21], PDGFRβ was found in the blood vessels of recurrent tumours.…”