Tumor Exosome-Adipose Stem Cell Axis in Racial Disparity of Prostate Cancer
Abstract
Background: African American (AA) men are twice as likely to develop and die of prostate cancer (PC) compared to the Caucasian American (CA) men. Although PC patients respond well to initial treatment (hormone or surgery), some patients inevitably develop resistance to therapy, and tumors progress to a terminal stage (termed castration-resistant prostate cancer [CRPC]), especially among AA men. The CRPC refers to the group of patients who failed all types of therapy and are likely to die because of this. One critical issue is that the underlying mechanisms associated with development and progression of advanced disease state remains elusive. Understanding such mechanisms will allow identifying new therapeutic targets for effective clinical management of the disease. Recent studies show that obesity, which is reported to be high among AA men, is responsible for disease progression. Importantly, fat tissue depots contain stem cells (termed adipose stem cells [pASCs]), which have been implicated in playing pivotal roles in cancer progression. Our proposed studies identified a novel mechanism by which male hormones (androgens) produced by tumor-attracted ASCs can promote growth of aggressive disease in PC patients despite being treated with hormone deprivation drugs. Briefly, our initial studies show that pASCs attracted to the tumor sites in PC patients play a significant role in hormone production at the tumor sites, especially among AA men. Additionally, we identified small bodies (named exosomes) released by PC cells. These exosomes are pivotal to the hormone production by carrying some factors from PC cells to the fat stem cells (pASCs). We also demonstrated that the tumor-attracted pASCs derived from AA men are sufficient to maintain higher growth and survival of the prostate tumors in castrated mice (i.e., without male hormone) in comparison to those derived from CA men. The results suggest that tumor-attracted pASCs are critical to disease progression in AA men despite being treated with hormone deprivation drugs. Importantly, we recently discovered among a group human-approved medications that can be repurposed to target and inhibit exosomes synthesis by PC cells. Our use of one drug, named Tipifarnib, was effective in inhibiting resistant tumor growth in mice when combined with drugs currently used to treat PC in the clinic. Based on our initial studies, we were able to show that a novel combined treatment regimen targeting exosomes and testosterone may be effective against prostate tumor growth and progression, especially among AA men. Hypothesis/Objectives: Based on our initial studies, we hypothesize that interaction between prostate tumor-derived exosomes and tumor-attracted pASC promote aggressive disease progression via testosterone, especially among AA men. Study Design: The hypothesis will be tested by the following aims: (1): examine whether mutual interaction between PC cells and fat stem cells leads (pASCs) to testosterone production. This will be examined using PC cells and pASCs derived from obese AA and CA men in culture under conditions that mimic disease progression in humans; (2) explore the mechanisms by which testosterone is produced by pASCs. The objective is to identify new therapeutic targets for advance disease state among AA men. (3) Finally, we will assess the preclinical efficacy of a novel combination therapeutic strategy of Tipifarnib and currently used drugs (enzalutamide) to reduce prostate tumor growth supported by ASCs derived from obese AA and CA men in castrated mice. Impact: The proposed work is endowed with many innovations, including new ideas and technical approaches. The proposed studies define and narrow the significant gap in the current knowledge linking obesity to PC progression and development of hormone-resistant disease in AA men. In terms of expected outcome, the proposed novel therapeutic strategy could be developed through tumor site-speci
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Nov 19, 2019
- Source ID
- W81XWH1910396
Entities
People
- Asim Abdel-mageed
Organizations
- Tulane University of Louisiana
- United States Army