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Prostate epithelial‐specific expression of activated PI3K drives stromal collagen production and accumulation
Author(s) -
Wegner Kyle A,
Mueller Brett R,
Unterberger Christopher J,
Avila Enrique J,
Ruetten Hannah,
Turco Anne E,
Oakes Steven R,
Girardi Nicholas M,
Halberg Richard B,
Swanson Steven M,
Marker Paul C,
Vezina Chad M
Publication year - 2020
Publication title -
the journal of pathology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.964
H-Index - 184
eISSN - 1096-9896
pISSN - 0022-3417
DOI - 10.1002/path.5363
Subject(s) - stromal cell , prostate cancer , prostate , cancer research , pi3k/akt/mtor pathway , hyperplasia , cancer , pathology , biology , medicine , microbiology and biotechnology , signal transduction
We genetically engineered expression of an activated form of P110 alpha, the catalytic subunit of PI3K, in mouse prostate epithelium to create a mouse model of direct PI3K activation ( Pbsn‐cre4Prb;PI3K GOF/+ ). We hypothesized that direct activation would cause rapid neoplasia and cancer progression. Pbsn‐cre4Prb;PI3K GOF/+ mice developed widespread prostate intraepithelial hyperplasia, but stromal invasion was limited and overall progression was slower than anticipated. However, the model produced profound and progressive stromal remodeling prior to explicit epithelial neoplasia. Increased stromal cellularity and inflammatory infiltrate were evident as early as 4 months of age and progressively increased through 12 months of age, the terminal endpoint of this study. Prostatic collagen density and phosphorylated SMAD2‐positive prostatic stromal cells were expansive and accumulated with age, consistent with pro‐fibrotic TGF‐β pathway activation. Few reported mouse models accumulate prostate‐specific collagen to the degree observed in Pbsn‐cre4Prb;PI3K GOF/+ . Our results indicate a signaling process beginning with prostatic epithelial PI3K and TGF‐β signaling that drives prostatic stromal hypertrophy and collagen accumulation. These mice afford a unique opportunity to explore molecular mechanisms of prostatic collagen accumulation that is relevant to cancer progression, metastasis, inflammation and urinary dysfunction. © 2019 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.