INFLAMMATION AND PROSTATE CANCER DEVELOPMENT: THE ROLE OF CHEMOKINE (CXC MOTIF) LIGAND 12 AND ITS RECEPTORS CXCR4 AND CXCR7, TUMOR ENVIRONMENTS AND MODULATION BY DIET-DERIVED COMPOUND PHENETHYL ISOTHIOCYANATE

Abstract

Prostate cancer is the most prevalent and the third leading cause of cancer death in men in the United States and effective cure remain elusive. In the etiology of prostate cancer, the mediators and cellular effectors of inflammation are important constituents associated with the regulation of prostate cancer progression but detail mechanisms remain unclear. It would be important to further elucidate the mechanisms to allow for development of effective preventive/therapeutic strategy for prostate cancer. C-X-C motif ligand 12 (CXCL12) is a constitutive and inflammatory chemokine that modulates autoimmune inflammation and homeostasis in the immune system. It is also a pleiotropic chemokine that is expressed in malignant prostate tumors and regulates prostate cancer migration and invasion via interaction with its two receptors CXCR4 and CXCR7. However, regulations of CXCL12 and its receptors in the immune system and prostate cancer are poorly understood. In addition, phenethyl isothiocyanate (PEITC) is a dietary compound from Cruciferae family with an inhibitory effect on prostate cancer progression. The mechanisms that underlie the anti-cancer effects of PEITC on prostate cancer are not well studied. This dissertation elucidated 1) the role of CXCL12 and its receptors in the immune system, specifically during monocyte-macrophage differentiation; 2) the transcriptome alterations in androgen-responsive human prostate cancer LNCaP cells and its xenograft; 3) roles of prostate cancer microenvironment in prostate cancer progression; 4) molecular effects of diet-derived cancer-preventive compound phenethyl isothiocyanate (PEITC) on monocytes. The accomplishment of this dissertation will 1) provide critical mechanistic information of the interaction between inflammation and prostate cancer development and 2) validate the role of CXCL12/CXCR4/CXCR7 chemokine axis and PEITC in the regulation of prostate cancer development and immune response. Ultimately, the study of the mechanisms mentioned above could help identify new strategies for the prevention/treatment of prostate cancer.