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A distinct repertoire of cancer-associated fibroblasts is enriched in cribriform
Hesterberg AB, Rios BL, Wolf EM, Tubbs C, Wong HY, Schaffer KR, Lotan TL,
Giannico GA, Gordetsky JB, Hurley PJ
Submitted Externally on 2/22/2021
The journal of pathology. Clinical research, References
Volume : Pages
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 PDGFRß) 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.
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