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The pace of prostatic intraepithelial neoplasia development is determined by the timing of Pten tumor suppressor gene excision.

Luchman HA, Benediktsson H, Villemaire ML, Peterson AC, Jirik FR - PLoS ONE (2008)

Bottom Line: Despite evidence of increased Akt/mTOR/S6K axis activity at early time points in Pten-deficient epithelial cells, excisions induced in the post-pubertal (6 wk-old) prostate yielded gradual acquisition of a range of lesions.These progressed from pre-malignant changes (nuclear atypia, focal hyperplasia) and low grade prostatic intraepithelial neoplasia (PIN) at 16-20 wks post-tamoxifen exposure, to overtly malignant lesions by approximately 1 yr of age, characterized by high-grade PIN and microinvasive carcinoma.These results indicate that the developmental stage at which Pten deletions are induced dictates the pace of PIN development.

View Article: PubMed Central - PubMed

Affiliation: Department of Biochemistry and Molecular Biology, and The McCaig Institute for Bone and Joint Health, University of Calgary, Calgary, Alberta, Canada.

ABSTRACT
Loss of the PTEN tumor suppressor is a common occurrence in human prostate cancer, particularly in advanced disease. In keeping with its role as a pivotal upstream regulator of the phosphatidylinositol 3-kinase signaling pathway, experimentally-induced deletion of Pten in the murine prostate invariably results in neoplasia. However, and unlike humans where prostate tumorigenesis likely evolves over decades, disease progression in the constitutively Pten deficient mouse prostate is relatively rapid, culminating in invasive cancer within several weeks post-puberty. Given that the prostate undergoes rapid androgen-dependent growth at puberty, and that Pten excisions during this time might be especially tumorigenic, we hypothesized that delaying prostate-specific Pten deletions until immediately after puberty might alter the pace of tumorigenesis. To this end we generated mice with a tamoxifen-inducible Cre recombinase transgene enabling temporal control over prostate-specific gene alterations. This line was then interbred with mice carrying floxed Pten alleles. Despite evidence of increased Akt/mTOR/S6K axis activity at early time points in Pten-deficient epithelial cells, excisions induced in the post-pubertal (6 wk-old) prostate yielded gradual acquisition of a range of lesions. These progressed from pre-malignant changes (nuclear atypia, focal hyperplasia) and low grade prostatic intraepithelial neoplasia (PIN) at 16-20 wks post-tamoxifen exposure, to overtly malignant lesions by approximately 1 yr of age, characterized by high-grade PIN and microinvasive carcinoma. In contrast, when Pten excisions were triggered in the pre-pubertal (2 week-old) prostate, neoplasia evolved over a more abbreviated time-frame, with a spectrum of premalignant lesions, as well as overt PIN and microinvasive carcinoma by 10-12 wks post-tamoxifen exposure. These results indicate that the developmental stage at which Pten deletions are induced dictates the pace of PIN development.

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Related in: MedlinePlus

Transition from the earliest stages of transformation to occur progressively in ARR2PBCreER(T2)×Ptenfl/fl mice following OHT exposure.(A) Nuclear enlargement with prominent and multiple nucleoli is seen in the luminal epithelial layer at different times post-OHT; in single cells at 4 wks post-OHT (arrows (i)); becoming more widespread at 8–10 wks post-OHT (arrows (iii)) and in the majority of cells in PIN lesions at 16–20 wks post-OHT (iv). Low grade hyperplasia is seen in the luminal layer at 4 wks post-OHT (rectangle (ii)). At 10 wks post-OHT, hyperplasia became more pronounced and nuclear enlargement with prominent nucleoli and hyperchromasia became more prevalent (arrows (iii)). Early stages of PIN, such as nuclear overlapping and mild tufting are noticeable by 10 wks post-OHT (iii). At 16–20 wks post-OHT more advanced PIN stages were evident (iv), with overt tubular dysplasia while basement membranes remained unbreached. PIN was prominent and most cells within these lesions showed nuclear enlargement, prominent nucleoli, hyperchromasia, and abnormal morphology (iv). (B) High grade PIN lesions were present in mice at 16–20 wks post-OHT. (i) While Ptenfl/fl controls showed normal morphology after OHT treatment, PIN lesions are seen 16–20 wks post-OHT administration in ARR2PBCreER(T2)×Ptenfl/fl mice, with different categories of high grade PIN being evident; including as tufting, micropapillary and flat atypia (ii), and cribriform structures (iii) and (iv) were seen in both focal intra-tubular as well as the more widespread lesions in the experimental animals. Scale bars: 50 µm.
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pone-0003940-g001: Transition from the earliest stages of transformation to occur progressively in ARR2PBCreER(T2)×Ptenfl/fl mice following OHT exposure.(A) Nuclear enlargement with prominent and multiple nucleoli is seen in the luminal epithelial layer at different times post-OHT; in single cells at 4 wks post-OHT (arrows (i)); becoming more widespread at 8–10 wks post-OHT (arrows (iii)) and in the majority of cells in PIN lesions at 16–20 wks post-OHT (iv). Low grade hyperplasia is seen in the luminal layer at 4 wks post-OHT (rectangle (ii)). At 10 wks post-OHT, hyperplasia became more pronounced and nuclear enlargement with prominent nucleoli and hyperchromasia became more prevalent (arrows (iii)). Early stages of PIN, such as nuclear overlapping and mild tufting are noticeable by 10 wks post-OHT (iii). At 16–20 wks post-OHT more advanced PIN stages were evident (iv), with overt tubular dysplasia while basement membranes remained unbreached. PIN was prominent and most cells within these lesions showed nuclear enlargement, prominent nucleoli, hyperchromasia, and abnormal morphology (iv). (B) High grade PIN lesions were present in mice at 16–20 wks post-OHT. (i) While Ptenfl/fl controls showed normal morphology after OHT treatment, PIN lesions are seen 16–20 wks post-OHT administration in ARR2PBCreER(T2)×Ptenfl/fl mice, with different categories of high grade PIN being evident; including as tufting, micropapillary and flat atypia (ii), and cribriform structures (iii) and (iv) were seen in both focal intra-tubular as well as the more widespread lesions in the experimental animals. Scale bars: 50 µm.

Mentions: As Pten gene deletions in the prostate have been shown to lead to rapid onset of tumorigenesis, we investigated the effects of delaying Pten excisions until after the gland had developed. Thus, ARR2PBCreER(T2)×Ptenfl/fl or Ptenfl/fl control mice were injected with OHT daily for 5 consecutive days starting at 6 wks of age and then sacrificed at either 4–10,16–20, or 30–40 wks p.i. In the 4–10 wks p.i. group, ARR2PBCreER(T2)×Ptenfl/fl mice treated with OHT demonstrated nuclear atypia and increased prominence of nucleoli in sporadic cells within the prostatic epithelium (arrows - Figure 1A(i) and (iii)), as well as early hyperplastic lesions at 4-wks post-OHT mice (rectangle- Figure 1A(ii)) with these being more obvious at 10-wks post-OHT mice (Figure 1A(iii)). At 16–20 wks p.i. the premalignant phenotype became much more evident, such that experimental animals displayed increased cellular size and nuclear atypia, as well as abnormal cellular morphology of luminal epithelial cells (Figure 1A(iv)). Of the 13 experimental animals, 11 contained focal areas with hyperplastic lesions ranging from mild to pronounced, and 6 out the mice exhibited advanced PIN lesions (Figure 1B(ii–iv) and Table 1). Control animals did not display these phenotypic changes (Figure 1B(i)) except perhaps for two mice with mild focal thickening of the luminal epithelium likely due to hyperplasia (Table 1). There was no additional progression past PIN lesions in 4 experimental animals when these were aged to 30–40 wks p.i., however, the PIN lesions became more prominent, and showed a wider area of distribution within the prostate (data not shown). Furthermore, none of the non-OHT exposed ARR2PBCreER(T2)×Ptenfl/fl, control Ptenfl/fl, or the ARR2PBCreER(T2) mice developed any evidence of premalignant lesions in their prostates (data not shown).


The pace of prostatic intraepithelial neoplasia development is determined by the timing of Pten tumor suppressor gene excision.

Luchman HA, Benediktsson H, Villemaire ML, Peterson AC, Jirik FR - PLoS ONE (2008)

Transition from the earliest stages of transformation to occur progressively in ARR2PBCreER(T2)×Ptenfl/fl mice following OHT exposure.(A) Nuclear enlargement with prominent and multiple nucleoli is seen in the luminal epithelial layer at different times post-OHT; in single cells at 4 wks post-OHT (arrows (i)); becoming more widespread at 8–10 wks post-OHT (arrows (iii)) and in the majority of cells in PIN lesions at 16–20 wks post-OHT (iv). Low grade hyperplasia is seen in the luminal layer at 4 wks post-OHT (rectangle (ii)). At 10 wks post-OHT, hyperplasia became more pronounced and nuclear enlargement with prominent nucleoli and hyperchromasia became more prevalent (arrows (iii)). Early stages of PIN, such as nuclear overlapping and mild tufting are noticeable by 10 wks post-OHT (iii). At 16–20 wks post-OHT more advanced PIN stages were evident (iv), with overt tubular dysplasia while basement membranes remained unbreached. PIN was prominent and most cells within these lesions showed nuclear enlargement, prominent nucleoli, hyperchromasia, and abnormal morphology (iv). (B) High grade PIN lesions were present in mice at 16–20 wks post-OHT. (i) While Ptenfl/fl controls showed normal morphology after OHT treatment, PIN lesions are seen 16–20 wks post-OHT administration in ARR2PBCreER(T2)×Ptenfl/fl mice, with different categories of high grade PIN being evident; including as tufting, micropapillary and flat atypia (ii), and cribriform structures (iii) and (iv) were seen in both focal intra-tubular as well as the more widespread lesions in the experimental animals. Scale bars: 50 µm.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC2597775&req=5

pone-0003940-g001: Transition from the earliest stages of transformation to occur progressively in ARR2PBCreER(T2)×Ptenfl/fl mice following OHT exposure.(A) Nuclear enlargement with prominent and multiple nucleoli is seen in the luminal epithelial layer at different times post-OHT; in single cells at 4 wks post-OHT (arrows (i)); becoming more widespread at 8–10 wks post-OHT (arrows (iii)) and in the majority of cells in PIN lesions at 16–20 wks post-OHT (iv). Low grade hyperplasia is seen in the luminal layer at 4 wks post-OHT (rectangle (ii)). At 10 wks post-OHT, hyperplasia became more pronounced and nuclear enlargement with prominent nucleoli and hyperchromasia became more prevalent (arrows (iii)). Early stages of PIN, such as nuclear overlapping and mild tufting are noticeable by 10 wks post-OHT (iii). At 16–20 wks post-OHT more advanced PIN stages were evident (iv), with overt tubular dysplasia while basement membranes remained unbreached. PIN was prominent and most cells within these lesions showed nuclear enlargement, prominent nucleoli, hyperchromasia, and abnormal morphology (iv). (B) High grade PIN lesions were present in mice at 16–20 wks post-OHT. (i) While Ptenfl/fl controls showed normal morphology after OHT treatment, PIN lesions are seen 16–20 wks post-OHT administration in ARR2PBCreER(T2)×Ptenfl/fl mice, with different categories of high grade PIN being evident; including as tufting, micropapillary and flat atypia (ii), and cribriform structures (iii) and (iv) were seen in both focal intra-tubular as well as the more widespread lesions in the experimental animals. Scale bars: 50 µm.
Mentions: As Pten gene deletions in the prostate have been shown to lead to rapid onset of tumorigenesis, we investigated the effects of delaying Pten excisions until after the gland had developed. Thus, ARR2PBCreER(T2)×Ptenfl/fl or Ptenfl/fl control mice were injected with OHT daily for 5 consecutive days starting at 6 wks of age and then sacrificed at either 4–10,16–20, or 30–40 wks p.i. In the 4–10 wks p.i. group, ARR2PBCreER(T2)×Ptenfl/fl mice treated with OHT demonstrated nuclear atypia and increased prominence of nucleoli in sporadic cells within the prostatic epithelium (arrows - Figure 1A(i) and (iii)), as well as early hyperplastic lesions at 4-wks post-OHT mice (rectangle- Figure 1A(ii)) with these being more obvious at 10-wks post-OHT mice (Figure 1A(iii)). At 16–20 wks p.i. the premalignant phenotype became much more evident, such that experimental animals displayed increased cellular size and nuclear atypia, as well as abnormal cellular morphology of luminal epithelial cells (Figure 1A(iv)). Of the 13 experimental animals, 11 contained focal areas with hyperplastic lesions ranging from mild to pronounced, and 6 out the mice exhibited advanced PIN lesions (Figure 1B(ii–iv) and Table 1). Control animals did not display these phenotypic changes (Figure 1B(i)) except perhaps for two mice with mild focal thickening of the luminal epithelium likely due to hyperplasia (Table 1). There was no additional progression past PIN lesions in 4 experimental animals when these were aged to 30–40 wks p.i., however, the PIN lesions became more prominent, and showed a wider area of distribution within the prostate (data not shown). Furthermore, none of the non-OHT exposed ARR2PBCreER(T2)×Ptenfl/fl, control Ptenfl/fl, or the ARR2PBCreER(T2) mice developed any evidence of premalignant lesions in their prostates (data not shown).

Bottom Line: Despite evidence of increased Akt/mTOR/S6K axis activity at early time points in Pten-deficient epithelial cells, excisions induced in the post-pubertal (6 wk-old) prostate yielded gradual acquisition of a range of lesions.These progressed from pre-malignant changes (nuclear atypia, focal hyperplasia) and low grade prostatic intraepithelial neoplasia (PIN) at 16-20 wks post-tamoxifen exposure, to overtly malignant lesions by approximately 1 yr of age, characterized by high-grade PIN and microinvasive carcinoma.These results indicate that the developmental stage at which Pten deletions are induced dictates the pace of PIN development.

View Article: PubMed Central - PubMed

Affiliation: Department of Biochemistry and Molecular Biology, and The McCaig Institute for Bone and Joint Health, University of Calgary, Calgary, Alberta, Canada.

ABSTRACT
Loss of the PTEN tumor suppressor is a common occurrence in human prostate cancer, particularly in advanced disease. In keeping with its role as a pivotal upstream regulator of the phosphatidylinositol 3-kinase signaling pathway, experimentally-induced deletion of Pten in the murine prostate invariably results in neoplasia. However, and unlike humans where prostate tumorigenesis likely evolves over decades, disease progression in the constitutively Pten deficient mouse prostate is relatively rapid, culminating in invasive cancer within several weeks post-puberty. Given that the prostate undergoes rapid androgen-dependent growth at puberty, and that Pten excisions during this time might be especially tumorigenic, we hypothesized that delaying prostate-specific Pten deletions until immediately after puberty might alter the pace of tumorigenesis. To this end we generated mice with a tamoxifen-inducible Cre recombinase transgene enabling temporal control over prostate-specific gene alterations. This line was then interbred with mice carrying floxed Pten alleles. Despite evidence of increased Akt/mTOR/S6K axis activity at early time points in Pten-deficient epithelial cells, excisions induced in the post-pubertal (6 wk-old) prostate yielded gradual acquisition of a range of lesions. These progressed from pre-malignant changes (nuclear atypia, focal hyperplasia) and low grade prostatic intraepithelial neoplasia (PIN) at 16-20 wks post-tamoxifen exposure, to overtly malignant lesions by approximately 1 yr of age, characterized by high-grade PIN and microinvasive carcinoma. In contrast, when Pten excisions were triggered in the pre-pubertal (2 week-old) prostate, neoplasia evolved over a more abbreviated time-frame, with a spectrum of premalignant lesions, as well as overt PIN and microinvasive carcinoma by 10-12 wks post-tamoxifen exposure. These results indicate that the developmental stage at which Pten deletions are induced dictates the pace of PIN development.

Show MeSH
Related in: MedlinePlus