Presentation Authors: Courtney Yong*, Devon Moose, Nadine Bannick, Marion Vanneste, James A. Brown, Iowa City, IA, Michael B. Cohen, Winston-Salem, NC, Michael D. Henry, Iowa City, IA
Introduction: We previously described a prostate-specific Pten knockout mouse with a genetically engineered luciferase reporter to monitor disease progression with BLI (Svensson et al, 2011, Am J Path). Here, we describe two Pten/Trp53 DOKO models of prostate cancer with genetically engineered luciferase reporters to monitor disease progression with BLI.
Methods: We generated 3 cohorts of Probasin (Pb)-Cre mediated Pten -/- combined with either Trp53 +/+ (WT), Trp53 +/- (HET), or Trp53 -/- (DOKO) mice on an albino C57BL/6 background with a Cre-activatable luciferase reporter allele. An additional inducible DOKO model was created by intraprostatic injection of CMV-Cre or Keratin-5 (K5)-Cre adeno-associated virus. The virus with the CMV promoter will induce broad Cre expression in the prostate, while the K5 will be targeted to the basal cells. BLI was measured biweekly starting at 5 weeks of age for the Pb-Cre mice and after injections for the viral Cre mice. We analyzed BLI data and histopathology for each of the cohorts.
Results: The Pb-Cre DOKO mice develop large, locally invasive tumors that grow more quickly than the HET or WT genotypes. This difference is evident on BLI at 21 weeks of age (p=0.0009). The DOKO mice also have shorter survival compared to the HET or WT, with a median survival of 26.5 weeks compared to 50 and 41 weeks for WT and HET mice (p < 0.0001). Pathologic analysis of the 3 groups showed sarcomatoid carcinoma in all DOKO mice, 41% of HET mice, and none of WT mice; high grade murine prostatic intraepithelial neoplasia (mPIN) in 35% of HET and 73% of WT mice; and low grade mPIN in 11% of HET and 13% of WT mice. There was invasion around pelvic lymphatics, but there was no pathologic confirmation of metastasis. To test androgen sensitivity, we castrated a separate cohort of Pb-Cre DOKO mice at age 10 weeks. BLI signal reached a nadir at 14 weeks but increased steadily to levels comparable to their non-castrate, age-matched counterparts. The Pten/Trp53 DOKO mouse cohorts with virally induced Cre are still active. Three out of five CMV-Cre mice have developed tumors evident on BLI at week 9; 2 of these were fatal at week 11. Of the K5-Cre mice, 2 out of 7 have tumors evident on BLI at week 11, and all are alive at present.
Conclusions: The Pten/Trp53 DOKO mouse model of prostate cancer develops large, locally advanced, and fatal prostate tumors of high-grade pathology that are initially castrate sensitive but develop castrate resistance. Our model also demonstrates the use of noninvasive BLI to monitor tumor progression.
Source of Funding: NIH Grant R21CA137490