African-American (AA) men have higher incidence of prostate cancer (PCa) than European American (EA). Furthermore, PCa in AA men is characterized by poor prognosis and dismal therapeutic outcomes. However, the mechanism/s associated with this health disparity remain unclear. Thus, identification of molecular mechanisms underlying such disparity is greatly desired in order to develop effective therapeutic and management approaches. It is becoming well appreciated that the chemokine-ligand axis is crucially involved in tumor cell trafficking and the development of organ-specific metastases, which is the major cause of PCa associated deaths. Our laboratory is the first to show that CC chemokine receptor 9 (CCR9) is selectively overexpressed in prostate cancers with negligible expression in normal prostate epithelia. Our exciting preliminary data show significantly higher expression of CCR9 in AA PCa cell lines and clinical samples compared to cell lines and clinical samples derived from EA. Furthermore, serum CCL25, which is natural ligand for CCR9 was higher in AA and PCa cell lines from AA (MDA-PCa-2b) and showed higher invasive and migratory potential as well as less response to chemotherapeutics in vitro compared to EA cell lines (C4-2b). Based upon these encouraging data, we hypothesize that CCR9-CCL25 axis underlies the poor prognosis and therapeutic outcome in AA men with PCa. To test our hypothesis, we propose to investigate the CCR9- CCL25 mediated mechanism associated with (i) aggressive cell phenotype in AA samples, (ii) homing and tumor growth in bone and the potential role of this chemokine-receptor axis in improving chemotherapeutic efficacy of clinical regimens in AA patients. We further aim to establish CCR9 as a biomarker for PCa progression and aggressive disease. To accomplish our aims, we have generated CCR9 anti-body against CCR9 and CCL25, which will be used to block this axis during in vitro assays to determine its role in migration, invasion, survival and chemoresistance;determining its potential role in metastasis as well as determining therapeutic efficacy of Docetaxel in vivo using AA and EA cell lines. In addition, siRNA duplexes or specific pharmacological inhibitors against CCR9 driven signaling molecules will be used to dissect the CCR9 mediated mechanism involved in migration, invasion, survival and chemoresistance. We are optimistic that the successful completion of these studies will define the role of this newly identified chemokine in PCa health disparity. Furthermore, it will enable the design and development of rational therapies directed against the CCR9-CCL25 to reduce/eliminate disparity in therapeutic outcomes.
Our goal is to determine the potential involvement of CC chemokine receptor-9 in disparity associated with poor disease and therapeutic outcome in African American patients. The outcomes of our study will (i) allow to determine the CCR9-mediated molecular pathways involved in PCa graveness and chemo resistant phenotypes, (ii) determine the CCR9-mediated mechanisms metastasis and (iii) establish the clinico- pathological significance of CCR9 in PCa health disparity. Our project will impact 1) development CCR9 expression as a new biomarker for aggressive disease and 2) therapeutic outcome of AA patients.
|Gupta, Pranav; Sharma, Praveen K; Mir, Hina et al. (2014) CCR9/CCL25 expression in non-small cell lung cancer correlates with aggressive disease and mediates key steps of metastasis. Oncotarget 5:10170-9|