A distinct repertoire of cancer‐associated fibroblasts is enriched in cribriform prostate cancer

Abstract

Outcomes for men with localized prostate cancer vary widely, with some men effectively managed without treatment on active surveillance, while other men rapidly progress to metastatic disease despite curative-intent therapies. One of the strongest prognostic indicators of outcome is grade groups based on the Gleason grading system. Gleason grade 4 prostate cancer with cribriform morphology is associated with adverse outcomes and can be utilized clinically to improve risk stratification. The underpinnings of disease aggressiveness associated with cribriform architecture are not fully understood. Most studies have focused on genetic and molecular alterations in cribriform tumor cells; however, less is known about the tumor microenvironment in cribriform prostate cancer. Cancer-associated fibroblasts (CAFs) are a heterogeneous population of fibroblasts in the tumor microenvironment that impact cancer aggressiveness. The overall goal of this study was to determine if cribriform prostate cancers are associated with a unique repertoire of CAFs. Radical prostatectomy whole-tissue sections were analyzed for the expression of fibroblast markers (ASPN in combination with FAP, THY1, ENG, NT5E, TNC, and PDGFRβ) in stroma adjacent to benign glands and in Gleason grade 3, Gleason grade 4 cribriform, and Gleason grade 4 noncribriform prostate cancer by RNAscope ® . Halo ® Software was used to quantify percent positive stromal cells and expression per positive cell. The fibroblast subtypes enriched in prostate cancer were highly heterogeneous. Both overlapping and distinct populations of low abundant fibroblast subtypes in benign prostate stroma were enriched in Gleason grade 4 prostate cancer with cribriform morphology compared to Gleason grade 4 prostate cancer with noncribriform morphology and Gleason grade 3 prostate cancer. In addition, gene expression was distinctly altered in CAF subtypes adjacent to cribriform prostate cancer. Overall, these studies suggest that cribriform prostate cancer has a unique tumor microenvironment that may distinguish it from other Gleason grade 4 morphologies and lower Gleason grades.

Single cell analysis of cribriform prostate cancer reveals cell intrinsic and tumor microenvironmental pathways of aggressive disease

“…However, vascular infiltration patterns and other stromal cells associated with ICC/IDC have not been robustly assessed. A recent study comparing cribriform morphology to other Gleason pattern 4 histologic subtypes, as well as lower Gleason patterns, showed that FAP + ASPN + cancer-associated fibroblasts (CAF) were enriched in regions directly adjacent to cribriform foci 33 . FAP has immunosuppressive functions in the TME 34,35 , yet little has been reported on the immune microenvironment associated with prostate ICC/IDC.…”

Pan-cancer analyses and molecular subtypes based on the cancer-associated fibroblast landscape and tumor microenvironment infiltration characterization reveal clinical outcome and immunotherapy response in epithelial ovarian cancer

“…For example, ACTA2 also serves as a general marker for vascular muscle cells and pericytes. Thus, the selective expression patterns of these markers could be used to characterize the phenotypic heterogeneity and functional diversity of activated CAFs within the specific TME (7,(34)(35)(36)(37)(38). Furthermore, the combination of these markers may enhance the differentiation of CAF subgroups, and different CAF subgroups have specific prognostic significance and exert different roles in efficacy.…”

Cribriform Patterned Lesions in the Prostate Gland with Emphasis on Differential Diagnosis and Clinical Significance

“…This feature leads us to hypothesize that, similar to IDC, tumor cells find a safe haven within cribriform structures, away from the potentially harmful effects of the stroma. In addition, hypoxia that is higher within cribriform formations [75], probably as a result of the limited contact of the cells to the vessel-containing stroma [81], and the effects of a specific type of tumor-associated fibroblast found around cribriform structures that is distinct from fibroblasts associated with other morphologic patterns [82], may account for the aggressive behavior of cribriform-patterned carcinoma.…”