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Dean J. Bacich, PhD

UPMC Content 3

PSMA, Folate and Prostate Cancer
Our lab focuses primarily on the identification and characterization of factors that contribute to the high rate of prostate cancer seen in humans. Notably, only humans and dogs develop prostate cancer at an appreciable rate, suggesting that factors unique to the prostates of these species play a critical role in disease development. Furthermore, unlike other cancers, the mutation of a specific gene, or group of genes, does not mark the early stage of prostate cancer. Therefore, proteins or conditions found in the normal human prostate may be very relevant to disease etiology. These factors should act as targets for prophylactic therapy to significantly reduce the incidence of prostate cancer. Prostate Specific Membrane Antigen (PSMA), a folate hydrolase, is one such protein. PSMA, highly expressed in the normal human prostate, is up-regulated in over 95% of prostate cancers, including metastases. Importantly, only humans and dogs express significant PSMA levels in their prostates. Mice express the PSMA homolog, Fol, but in other organs. We generated a transgenic mouse that expressed human PSMA specifically in the prostate. The majority of these mice eventually developed prostatic lesions characteristic of Prostatic Intraepithelial Neoplasia (PIN), the putative precursor to prostate cancer, while wild-type siblings did not. Moreover, PIN proceeded to invasive carcinoma when prostate tissue from the PSMA mice was mixed with rat urogenital mesenchyme and then implanted under the kidney capsule of an immuno-incompetent host. Tissue recombinants using wild-type prostate did not develop invasive carcinoma. These findings strongly support the hypothesis that PSMA expression contributes to prostate cancer initiation, progression or both. Cells require folate to replicate. While dying cells found in tumors may release polyglutamated folates, only the monoglutamated form can enter cells. Thus, PSMA, as a folate hydrolase, may provide a growth advantage. In fact, PSMA expression did convey a growth advantage for prostate cancer cells cultured in low folate media with polyglutamated folates. We are doing additional studies to determine whether the folate hydrolase activity of PSMA indeed promotes prostate cancer or whether there is another mechanism involved. We are also investigating the possible role of folate consumption in prostate cancer. In 1998, the government mandated folate fortification of the food supply, which led to a three-fold increase in the mean serum folate concentration in the American population. An emerging body of evidence suggests that folic acid supplementation may promote the progression of premalignant lesions to cancer in the colorectum. We have evidence that, in addition to PSMA, a number of other folate-regulating proteins undergo alterations in expression in prostate cancer. Thus, the possibility exists that increased folate consumption may also promote progression of pre-existing prostate lesions.

DNA Repair Pathways and Prostate Cancer
Nucleotide excision repair (NER), a major DNA damage repair pathway, is linked to prostate cancer risk. NER activity correlates with expression levels of the excision repair cross-complementing rodent repair deficiency complementation group 1 (ERCC1), a central component of the NER process. Targeted inactivation of ERCC1 in mice results in genotoxic lesions leading to a limited life span of 21 to 28 days, which prevented the study of ERCC1-inactivation on prostate cancer. To circumvent this problem, we used our tissue recombination model. We consistently observed that recombinants made from ERCC1 -/- prostate epithelial tissue developed invasive cancer, demonstrating the importance of ERCC1 in preventing prostate cancer. We will use this powerful technique to evaluate the roles of the different DNA repair pathways on prostate carcinogenesis, and how these pathways interact with various chemo-preventative agents.

Prostate Stem Cells
Maintenance of the prostate depends upon proliferation and differentiation of prostate stem cells. The current hypothesis states that stem cells undergo asymmetric cell division to produce one copy of the stem cell and one cell committed to further division and differentiation, giving rise to amplifying intermediate cells. The intermediate cells then undergo terminal differentiation to form basal and secretory epithelial cells; cells move in a unidirectional manner through differentiation. However, an alternative hypothesis describes a bidirectional movement of cells through differentiation such that intermediate cells could become stem cells again. Prostate cancer, like other cancers, probably arises from transforming events that occur in the normal stem cell population. If the malignant stem cells move in a unidirectional manner, then we should be able to target them to fully eradicate the cancer. However, the inability to mark stem cells has made it impossible to determine stem cell movement. Thus, we devised a proprietary method to individually mark all prostate cells. This mark is passed onto daughter cells, allowing us to determine fate s of the prostate cell population. By following the pattern and variance of the individual marks over time, we should be able to determine which of the prostate stem cell hypotheses is correct, and — if the unidirectional model holds true — use this technique to identify the stem cells for therapy.

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