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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.

SUBMITTER: Hesterberg AB

PROVIDER: S-EPMC8073007 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Simple Summary Primary, organ-confined prostate cancer is treatable with surgery, chemotherapy, radiation, and active surveillance; however, a subset of patients will develop metastatic disease. The main issue in prostate cancer is the need of prognostic tools for identifying patients at risk for lethal metastatic tumor, as well as a lack of curative therapies for such patients. The tissues surrounding the prostate cancer cells consist of a mixture of stromal cells that are structurally and functionally different from stromal cells in normal prostate. The stromal component, as a source of prognostic information for metastatic disease progression, has received little attention. In the present study, we characterized stromal cells from cancer tissues as compared to stromal cells from normal adjacent tumor tissue or human benign prostate. The stroma’s specific profile will allow to predict the presence of aggressive tumors, therapy resistance, and metastasis development. Abstract Background: Stromal components surrounding epithelial cancer cells seem to play a pivotal role during epithelial-to-mesenchymal transition (EMT), tumor invasion, and metastases. To identify the molecular mechanisms underlying tumor–stroma interactions may yield novel therapeutic targets for prostate cancer. Methods: Gene expression profile of prostate-cancer associated fibroblast (PCAF) and prostate non-cancer associated fibroblast (PNAF) cells isolated from radical prostatectomy was performed by Illumina, analyzed, and further processed by Ingenuity®: IPA® software. qRT-PCR was performed on an independent set of 17 PCAF, 12 PNAF, and 12 fibroblast cell lines derived from patients with benign prostatic hyperplasia (BPHF). Results: Using microarray analysis, we found six upregulated genes and two downregulated genes in PCAFs compared to PNAFs. To validate microarray results, we performed qRT-PCR for the most significantly regulated genes involved in the modulation of proliferation and androgen resistance on an independent set of PNAF, PCAF, and BHPF samples. We confirmed the increased expression of SCARB1, MAPK3K1, and TGF-β as well as the decreased expression of S100A10 in PCAFs compared to PNAFs and BPHFs. Conclusions: These results provide strong evidence that the observed changes in the gene expression profile of PCAFs can contribute to functional alteration of adjacent prostate cancer cells.

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

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