Abstract
BackgroundEffective eradication of high-risk primary prostate cancer (HRPCa) could significantly decrease mortality from prostate cancer. However, the discovery of curative therapies for HRPCa is hampered by the lack of authentic preclinical models.MethodsWe improved upon tumorgraft models that have been shown to predict drug response in other cancer types by implanting thin, precision-cut slices of HRPCa under the renal capsule of immunodeficient mice. Tissue slice grafts (TSGs) from 6 cases of HRPCa were established in mice. Following androgen deprivation by castration, TSGs were recovered and the presence and phenotype of cancer cells were evaluated.ResultsHigh-grade cancer in TSGs generated from HRPCa displayed characteristic Gleason patterns and biomarker expression. Response to androgen deprivation therapy (ADT) was as in humans, with some cases exhibiting complete pathologic regression and others showing resistance to castration. As in humans, ADT decreased cell proliferation and prostate-specific antigen expression in TSGs. Adverse pathological features of parent HRPCa were associated with lack of regression of cancer in corresponding TSGs after ADT. Castration-resistant cancer cells remaining in TSGs showed upregulated expression of androgen receptor target genes, as occurs in castration-resistant prostate cancer (CRPC) in humans. Finally, a rare subset of castration-resistant cancer cells in TSGs underwent epithelial-mesenchymal transition, a process also observed in CRPC in humans.ConclusionsOur study demonstrates the feasibility of generating TSGs from multiple patients and of generating a relatively large number of TSGs from the same HRPCa specimen with similar cell composition and histology among control and experimental samples in an in vivo setting. The authentic response of TSGs to ADT, which has been extensively characterized in humans, suggests that TSGs can serve as a surrogate model for clinical trials to achieve rapid and less expensive screening of therapeutics for HRPCa and primary CRPC.
Highlights
Effective eradication of high-risk primary prostate cancer (HRPCa) could significantly decrease mortality from prostate cancer
The proliferation index in Tissue slice grafts (TSGs) maintained in recombination activating gene-2 (RAG2)−/−γc−/− mice was 97% of the parent tumor. These results suggest that RAG2−/−γc−/− mice provide a more supportive environment for TSGs derived from HRPCa than NIH III mice and should be the host of choice for human PCa tumorgrafts
T) and AMACR (Figure 3U-V), and negative for ERG (Figure 3W-X). These results suggest that androgen-deprivation therapy (ADT) abolished prostatespecific antigen (PSA) expression in cancer cells in castration-resistant TSGs (CR-TSGs) derived from HRPCa but did not affect expression of other markers
Summary
Effective eradication of high-risk primary prostate cancer (HRPCa) could significantly decrease mortality from prostate cancer. Mortality from prostate cancer (PCa) is confined to those men who have either advanced disease (distant metastases at initial presentation) or high-risk localized PCa (HRPCa) [1,2]. The definition of HRPCa is either a Gleason score of 8–10, pre-treatment serum prostatespecific antigen (PSA) > 20 ng/ml, or clinical stage of T3/T4 at diagnosis [3]. Patients with at least two of the following criteria - a Gleason score of 7, pre-. Treatment serum PSA > 10 ng/ml, and a clinical stage of T2b/c - may be considered high-risk [3]. Up to 50% of these high-risk patients will inevitably progress to castration-resistant prostate cancer (CRPC), which is incurable, within 10 years [6,9,10,11]. ADT induces epithelial-mesenchymal transition (EMT), a process that has been associated with aggressive clinical behavior in human PCa [13,14]
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