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A Bioluminescent and Fluorescent Orthotopic Syngeneic Murine Model of Androgen-dependent and Castration-resistant Prostate Cancer
Published on: March 6, 2018
X-linked inhibitor of apoptosis deficiency in the TRAMP mouse prostate cancer model
C Hwang1, K A Oetjen, D Kosoff
1Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI 48109-2200, USA.
Abstract:
Deregulation of apoptotic pathways plays a central role in cancer pathogenesis. X-linked inhibitor of apoptosis protein (XIAP), is an antiapoptotic molecule, whose elevated expression has been observed in tumor specimens from patients with prostate carcinoma. Studies in human cancer cell culture models and xenograft tumor models have demonstrated that loss of XIAP sensitizes cancer cells to apoptotic stimuli and abrogates tumor growth. In view of these findings, XIAP represents an attractive antiapoptotic therapeutic target for prostate cancer. To examine the role of XIAP in an immunocompetent mouse cancer model, we have generated transgenic adenocarcinoma of the mouse prostate (TRAMP) mice that lack XIAP. We did not observe a protective effect of Xiap deficiency in TRAMP mice as measured by tumor onset and overall survival. In fact, there was an unexpected trend toward more aggressive disease in the Xiap-deficient mice. These findings suggest that alternative mechanisms of apoptosis resistance are playing a significant oncogenic role in the setting of Xiap deficiency. Our study has implications for XIAP-targeting therapies currently in development. Greater understanding of these mechanisms will aid in combating resistance to XIAP-targeting treatment, in addition to optimizing selection of patients who are most likely to respond to such treatment.
Insights
X-linked inhibitor of apoptosis protein (XIAP) deficiency did not prevent prostate cancer in mice. Instead, Xiap loss unexpectedly accelerated tumor progression, suggesting alternative survival pathways in cancer.
Area of Science:
- Oncology
- Molecular Biology
- Apoptosis Research
Background:
- Deregulation of apoptotic pathways is crucial in cancer development.
- Elevated X-linked inhibitor of apoptosis protein (XIAP) expression is linked to prostate carcinoma.
- XIAP inhibition shows promise as a cancer therapy by sensitizing cells to apoptosis.
Purpose of the Study:
- To investigate the role of XIAP in prostate cancer using a TRAMP mouse model.
- To determine if XIAP deficiency impacts tumor onset and survival in immunocompetent mice.
- To explore alternative apoptosis resistance mechanisms in the absence of XIAP.
Main Methods:
- Generation of transgenic adenocarcinoma of the mouse prostate (TRAMP) mice lacking XIAP.
- Assessment of tumor onset and overall survival in XIAP-deficient TRAMP mice.
- Comparative analysis of tumor progression between XIAP-deficient and wild-type TRAMP mice.
Main Results:
- XIAP deficiency did not confer a protective effect against prostate cancer in TRAMP mice.
- XIAP-deficient TRAMP mice exhibited a trend towards more aggressive disease.
- Tumor onset and overall survival were not improved by the absence of XIAP.
Conclusions:
- Alternative mechanisms of apoptosis resistance play a significant role in prostate cancer pathogenesis, even when XIAP is absent.
- Findings challenge the universal efficacy of XIAP-targeting therapies and highlight the need to understand resistance mechanisms.
- Further research is needed to identify these alternative pathways for optimizing patient selection and treatment strategies for XIAP-targeted therapies.
