Modeling prostate cancer in mice: something old, something new, something premalignant, something metastatic

Irshad, Shazia; Abate‐Shen, Cory

doi:10.1007/s10555-012-9409-1

Cited by 50 publications

(52 citation statements)

References 111 publications

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“…S4 A-E and Table S1). Notably, the essentially 100% penetrance of metastases in the NPK mice differ from the lower frequency of metastases in most other mouse models or prostate cancer (45), including an analogous model based on activated B-Raf oncogene in cooperation with loss of function of Pten (46). The visible metastases in the NPK mice were corroborated by histological analysis, and their prostate origin was verified with markers from the primary tumor (Fig.…”

Section: Resultsmentioning

confidence: 80%

“…Notably, though we detect disseminated cells in the bone marrow, we have not observed bone metastases, which may reflect the unfavorable host environment. Indeed, most genetically engineered mouse models of cancer do not develop consistent metastases to bone (45), and the few mouse models of prostate cancer that have reported metastases to bone (60) have Fig. 2) is robustly expressed in the prostate tumors at both time points, whereas Etv4 is only expressed in the 3-mo prostate as well as in the lung metastases from this time point as well as the micrometastases at 2 mo.…”

Section: Discussionmentioning

confidence: 99%

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ETV4 promotes metastasis in response to activation of PI3-kinase and Ras signaling in a mouse model of advanced prostate cancer

Aytés

Mitrofanova

Kinkade³

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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Combinatorial activation of PI3-kinase and RAS signaling occurs frequently in advanced prostate cancer and is associated with adverse patient outcome. We now report that the oncogenic Ets variant 4 (Etv4) promotes prostate cancer metastasis in response to coactivation of PI3-kinase and Ras signaling pathways in a genetically engineered mouse model of highly penetrant, metastatic prostate cancer. Using an inducible Cre driver to simultaneously inactivate Pten while activating oncogenic Kras and a fluorescent reporter allele in the prostate epithelium, we performed lineage tracing in vivo to define the temporal and spatial occurrence of prostate tumors, disseminated tumor cells, and metastases. These analyses revealed that though disseminated tumors cells arise early following the initial occurrence of prostate tumors, there is a significant temporal lag in metastasis, which is temporally coincident with the up-regulation of Etv4 expression in primary tumors. Functional studies showed that knockdown of Etv4 in a metastatic cell line derived from the mouse model abrogates the metastatic phenotype but does not affect tumor growth. Notably, expression and activation of ETV4, but not other oncogenic ETS genes, is correlated with activation of both PI3-kinase and Ras signaling in human prostate tumors and metastases. Our findings indicate that ETV4 promotes metastasis in prostate tumors that have activation of PI3-kinase and Ras signaling, and therefore, ETV4 represents a potential target of therapeutic intervention for metastatic prostate cancer. M etastasis is a highly inefficient process that involves multiple steps, including invasion of local stroma, intravasation into the bloodstream and/or lymphatic system, and extravasation into a secondary tissue, which is thought to arise as a consequence of multiple molecular/epigenetic alterations in tumor cells, as well as in the microenvironment of metastatic sites (1-4). Nonetheless, despite its inefficiency, most cancer deaths are due to metastases and our current inability to treat them once they arise. In particular, in prostate cancer, the locally invasive disease has a nearly 100% survival rate, whereas metastatic prostate cancer is very often lethal (5).Recent analyses have identified key molecular pathways that are frequently dysregulated during prostate cancer progression, as a consequence of copy number alterations, chromosomal rearrangements, and other aberrant genetic/epigenetic events (6-10). For example, loss of chromosomal region 8p21 and coincident haploinsufficiency for the NKX3.1 homeobox gene occurs frequently in precursor lesions known as prostatic intraepithelial neoplasia (PIN) and are associated with prostate cancer initiation (11,12). Another early event in prostate tumorigenesis is the formation of the TMPRSS2-ERG rearrangement, which fuses the transmembrane protease TMPRSS2 promoter with the coding region of the ETS transcription factor ERG (13, 14). The TMPRSS2-ERG fusion is highly prevalent in prostate cancer and is associated with disease out...

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Section: Resultsmentioning

confidence: 80%

Section: Discussionmentioning

confidence: 99%

ETV4 promotes metastasis in response to activation of PI3-kinase and Ras signaling in a mouse model of advanced prostate cancer

Aytés

Mitrofanova

Kinkade³

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

123

129

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“…Overall, we have analyzed a representative sample of widely used mouse models of human prostate cancer (Irshad and Abate-Shen, 2013; Ittmann et al, 2013; Shappell et al, 2004). However, there may be specific caveats associated with each model; for example, tumor initiation might conceivably occur in basal cells prior to seven weeks of age in the transgenic models, resulting in early basal to luminal differentiation that would escape lineage-marking.…”

Section: Discussionmentioning

confidence: 99%

Luminal Cells Are Favored as the Cell of Origin for Prostate Cancer

et al. 2014

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The identification of cell types of origin for cancer has important implications for tumor stratification and personalized treatment. For prostate cancer, the cell of origin has been intensively studied, but it has remained unclear whether basal or luminal epithelial cells, or both, represent cells of origin under physiological conditions in vivo. Here, we use a novel lineage-tracing strategy to assess the cell of origin in a diverse range of mouse models, including Nkx3.1+/–; Pten+/–, Pten+/–, Hi-Myc, and TRAMP mice, as well as a hormonal carcinogenesis model. Our results show that luminal cells are consistently the observed cell of origin for each model in situ; however, explanted basal cells from these mice can generate tumors in grafts. Consequently, we propose that luminal cells are favored as cells of origin in many contexts, whereas basal cells only give rise to tumors after differentiation into luminal cells.

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“…The current breakthroughs in analysis of the prostate cancer genome, have revealed that the gradual accumulation of genome alterations is intimately associated with metastatic disease progression and the derived genome landscape revealed a critical role for copy number changes (3-6). In the past, making sense of putative oncogenic events was made possible due to functional validation of candidate genes by mouse genetic engineering of prostate cancer (7-15). Today however, two major problems have arisen: first, the GEM models have not so far reconstituted highly penetrant metastatic prostate cancer.…”

Section: Introductionmentioning

confidence: 99%

RapidCaP, a Novel GEM Model for Metastatic Prostate Cancer Analysis and Therapy, Reveals Myc as a Driver of Pten-Mutant Metastasis

et al. 2014

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Genetically engineered mouse (GEM) models are a pillar of functional cancer research. Here, we developed RapidCaP, a GEM modeling system that uses surgical injection for viral gene delivery to the prostate. We show that in Pten defi ciency, loss of p53 suffi ces to trigger metastasis to distant sites at greater than 50% penetrance by four months, consistent with results from human prostate cancer genome analysis. Live bioluminescence tracking showed that endogenous primary and metastatic disease responds to castration before developing lethal castration resistance. To our surprise, the resulting lesions showed no activation of Akt but activation of the Myc oncogene. Using RapidCaP, we fi nd that Myc drives local prostate metastasis and is critical for maintenance of metastasis, as shown by using the Brd4 inhibitor JQ1. Taken together, our data suggest that a "MYC-switch" away from AKT forms a critical and druggable event in PTEN -mutant prostate cancer metastasis and castration resistance. SIGNIFICANCE:The RapidCaP system introduces fast and fl exible genetics for functional analysis and therapy for endogenous metastatic prostate cancer. The approach introduces targeting of MYC as a critical strategy against PTEN -defi cient lethal prostate cancer. Cancer Discov; 4(3); 318-33. ©2014AACR.

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Modeling prostate cancer in mice: something old, something new, something premalignant, something metastatic

Cited by 50 publications

References 111 publications

ETV4 promotes metastasis in response to activation of PI3-kinase and Ras signaling in a mouse model of advanced prostate cancer

ETV4 promotes metastasis in response to activation of PI3-kinase and Ras signaling in a mouse model of advanced prostate cancer

Luminal Cells Are Favored as the Cell of Origin for Prostate Cancer

RapidCaP, a Novel GEM Model for Metastatic Prostate Cancer Analysis and Therapy, Reveals Myc as a Driver of Pten-Mutant Metastasis

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