Characterization of stage‐specific tumor progression in TMPRSS2‐ERG (fusion)‐driven and non‐fusion‐driven prostate cancer in GEM models

Abstract

In the present study, we performed a comparative stage-specific pathological and molecular marker evaluation of TMPRSS2-ERG fusion and PTEN loss-driven (TMPRSS2-ERG. Pten flox/flox ) versus non-fusion-driven prostate tumorigenesis (Hi-Myc) in mice. Anterior, ventral, and dorsolateral prostates were collected from mice at different ages (or time points post-Cre induction). Results indicated that growth and progression of prostatic intraepithelial lesions to adenocarcinoma stages occurred in both mice models albeit at different rates. In the TMPRSS2-ERG. Pten flox/ flox mice, the initiation of tumorigenesis was slow, but subsequent progression through different stages became increasingly faster. Adenocarcinoma stage was reached early on; however, no high-grade undifferentiated tumors were observed.Conversely, in the Hi-Myc +/− mice, tumorigenesis initiation was rapid; however, progression through different stages was relatively slower and it took a while to reach the more aggressive phenotype stage. Nevertheless, at the advanced stages in the Hi-Myc +/− mice, high-grade undifferentiated tumors were observed compared to the later stage tumors observed in the fusion-driven TMPRSS2-ERG. Pten flox/flox mice. These results were corroborated by the stage specific-pattern in the molecular expression of proliferation markers (PCNA and c-Myc); androgen receptor (AR); fusion-resultant overexpression of ERG; Prostein (SLC45-A3); and angiogenesis

Stage-Specific Effect of Inositol Hexaphosphate on Cancer Stem Cell Pool during Growth and Progression of Prostate Tumorigenesis in TRAMP Model

“…Brown-stained cells were counted as positive cells (among total number of cells) and plotted as % positive cells; these were counted in five randomly selected fields at ×400 magnification. Immunoreactivity (intensity of brown staining was represented by arbitrary values) was noted as 0 (no staining), +1 (weak intensity), +2 (moderate intensity), +3 (strong intensity), and +4 (very strong intensity) [ 25 ]. Immunopositive area was assessed as the proportion area of prostate which is positive for expression and assigned arbitrary scores as 0 (<5% positive area), +1 (5–25% positive area), +2 (26–50% positive area), +3 (51–75% positive area), and +4 (>75% positive area).…”

Effect of nonsteroidal anti‐inflammatory drugs (aspirin and naproxen) on inflammation‐associated proteomic profiles in mouse plasma and prostate during TMPRSS2‐ERG (fusion)‐driven prostate carcinogenesis

“…Pten flox/flox ) we identified that indeed NSAIDs, aspirin and naproxen, have strong efficacy in reducing prostate tumorigenesis in the TMPRSS2-ERG driven PCa model but not in the non-TMPRSS2-ERG driven (Hi-Myc +/− mouse) PCa model. 4 We also established in the same study that the NSAIDs primarily affect proliferation in the TMPRSS2-ERG fusion driven cancers, which could possibly stem from the NSAIDs-mediated decrease in androgen receptor (AR) expression. 4 This is because of the androgen sensitivity of the TMPRSS2 promoter; specifically, after TMPRSS2-ERG fusion, the androgen-bound AR binds to TMPRSS2 regions, and results in ERG overexpression which in turn causes overexpression/activation of proliferative pathways.…”

“…4 We also established in the same study that the NSAIDs primarily affect proliferation in the TMPRSS2-ERG fusion driven cancers, which could possibly stem from the NSAIDs-mediated decrease in androgen receptor (AR) expression. 4 This is because of the androgen sensitivity of the TMPRSS2 promoter; specifically, after TMPRSS2-ERG fusion, the androgen-bound AR binds to TMPRSS2 regions, and results in ERG overexpression which in turn causes overexpression/activation of proliferative pathways. 5 Another important factor that cannot be overlooked is that cancer progression is a complex process; many pathways associated with cancer initiation and progression are similar to inflammation and wound healing.…”

“…4 This is because of the androgen sensitivity of the TMPRSS2 promoter; specifically, after TMPRSS2-ERG fusion, the androgen-bound AR binds to TMPRSS2 regions, and results in ERG overexpression which in turn causes overexpression/activation of proliferative pathways. 5 Another important factor that cannot be overlooked is that cancer progression is a complex process; many pathways associated with cancer initiation and progression are similar to inflammation and wound healing. 5 Tumor inflammation is characterized by the presence of inflammatory cells and cytokines/chemokines in the tumor microenvironment, which contributes to tumor growth and progression, immunosuppression, and chemoresistance.…”

“…5 Another important factor that cannot be overlooked is that cancer progression is a complex process; many pathways associated with cancer initiation and progression are similar to inflammation and wound healing. 5 Tumor inflammation is characterized by the presence of inflammatory cells and cytokines/chemokines in the tumor microenvironment, which contributes to tumor growth and progression, immunosuppression, and chemoresistance. 6 Cytokines, chemokines, and growth factors secreted by prostate tumor cells, stromal cells, and inflammatory cells in the tumor microenvironment promote the epithelial to mesenchyme transition (EMT), angiogenesis, and cancer metastasis.…”