Prostate cancer (CaP) is the second leading cause of cancer death in men. Advanced prostate tumors often contain neuroendocrine differentiation, which correlates with androgen-independent progression and poor prognosis. Currently, androgen deprivation is the first line of therapy for metastatic CaP. However, CaP often progresses to an androgen-independent bone-metastatic stage, at which point chemotherapy and radiotherapy become the primary therapeutic options. Despite recent advances in therapeutic strategies, many cancers still develop resistance to radiation and therapies, making the identification of new therapies essential to improve the lives and survival rates of patients.
We have studied neuroendocrine cancer progression in the cryptdin-2 SV40-TAg (CR2-TAg) mouse model of CaP. Since these cancers do not express androgen receptor, they are refractory to androgen therapy. Therefore, we sought new potential targets. We previously found that matrix metalloproteinases (MMPs), which are capable of degrading many extracellular matrix proteins and cell surface receptors, are upregulated during CR2-Tag tumor progression. In the present study, we examined expression of a family of a disintegrin and metalloproteinases (ADAMs) that is actively involved in these signaling pathways due to their role in releasing the extracellular domain of transmembrane proteins. ADAMs contain features of both adhesive proteins and proteinases. ADAM10 activates the epidermal growth factor receptor (EGFR) and NOTCH signaling systems controlling cell growth, invasion, and metastasis. We found that ADAM10 expression increased during tumor progression and was highly penetrant. We are quantifying the expression levels and localization patterns of ADAM10 in these samples over time. Since MMPs, like ADAMs, are capable of degrading many extracellular matrix proteins and cell surface receptors, we determined if MMPs (MMP 2, 7, and 9) contribute to ADAM10 expression or localization in aggressive hormone refractory CaP. We have stained for ADAM10 in tissue sections from the CR2-TAg mice that are each missing expression of MMPs to determine if that particular MMP contributes to ADAM10 expression or localization. Our research using ADAM10 localization as a potential biomarker and therapeutic target has potential clinical value to identify aggressive CaP earlier in patients. Our study of MMPs and their role in ADAM10 expression will offer insight into the mechanisms of advanced prostate tumor progression.
Note: This abstract was not presented at the meeting.
Citation Format: Brian D. Shannon, Laurie E. Littlepage. ADAM10/Kuzbanian is upregulated during neuroendocrine prostate carcinogenesis. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4212. doi:10.1158/1538-7445.AM2014-4212