1. Altieri, Dario C. MD

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The American Cancer Society estimates one in seven men will be diagnosed with prostate cancer in his lifetime. In fact, prostate cancer is second only to skin cancer as the most prevalent type of cancer in American men. How are prostate tumors maintained, and what factors accelerate the disease? The answer may lie in the regulation of mitochondria.

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A key mitochondrial chaperone, TNF receptor associated protein 1 (TRAP1), is involved in many aspects of protein homeostasis, primarily in the regulation of proper protein folding. It has been shown that the expression of TRAP1 is heightened in the mitochondria of tumor cells as compared with normal tissue, suggesting a role for aberrant protein folding in cancer (Cell 2007;131:257-270). However, the role of TRAP1 in disease has remained controversial. While some data indicate TRAP1 is utilized for tumor maintenance (Nature Commun 2013;4:239), other studies suggest the protein may act as a tumor suppressor (Proc Natl Acad Sci 2013;110:E1604-1612).


TRAP1 Model

To resolve these opposing views surrounding TRAP1 and elucidate the function of mitochondrial protein folding in disease, we generated the first transgenic mouse with tissue-specific expression of TRAP1 in the prostate. This breakthrough model simulates the human disease, as TRAP1 is only overexpressed in the prostatic epithelium in primary or metastatic prostate cancer.


Perhaps surprisingly, the overexpression alone of prostatic TRAP1 did not result in an overt phenotype in the mice, and the animals did not develop prostatic tumors during the 18-month observation period. However, these mice displayed an increase in cellular irregularities upon histological examination of the prostatic epithelium, laying the groundwork for a potential cancer model.


To further understand the role of TRAP1 in prostate tumorigenesis, we next bred our novel model with mice heterozygous for the known tumor suppressor phosphate and tensin homolog (Pten). Pten is often compromised in human cancer, and roughly 70 percent of men diagnosed with prostate cancer have only one copy of the PTEN gene when diagnosed with the disease (Nature 2005;436:725-730). The mice from these experiments developed invasive prostatic adenocarcinoma within 6 months, and tumor formation was seen in all prostatic lobes. In a rescue experiment, we crossed Pten+/- mice with TRAP1 knockout mice. These mice displayed a reduction in prostatic adenocarcinoma, further highlighting the role of TRAP1 in tumor formation.


Beyond increased tumor development, how does the overexpression of TRAP1 affect the microenvironment of the cell? To answer this question, we performed RNA sequencing experiments on the TRAP1 transgenic mice. We found that more than 350 genes had altered expression as compared with the Pten+/- mice, and the gene signature had shifted to reflect an invasive, cytoprotective, and angiogenic setting. These genes foster tumor maintenance and disease progression, providing additional evidence for the capacity of TRAP1 to contribute to cancer.


Future of a Biomarker

While many studies have identified TRAP1 as an important player in cancer, its role in disease progression has remained elusive. In generating our transgenic mouse model, we sought to definitively determine if TRAP1 was involved in tumor suppression or tumor maintenance using prostate cancer as a disease paradigm. Our findings preclude the view that TRAP1 functions as a tumor suppressor; indeed, our model suggests that TRAP1 is involved in tumor formation and maintenance.


Is this biomarker for prostatic cancer a viable therapeutic target for the disease? Preclinical studies with inhibitors for Hsp90, a homolog of TRAP1, appear promising (Clin Cancer Res 2010;16:4779-4788).


DARIO C. ALTIERI, MD, is President & Chief Executive Officer, Director of The Wistar Institute Cancer Center and Robert and Penny Fox Distinguished Professor.


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