Hypoxia in Prostate Tumor Promotes Premetastatic Niche Formation in Distant Organs through RAB-Mediated Exosomes Release
Abstract
Objective and Rationale for the Proposed Project: Metastasis is the main cause of mortality in prostate cancer (PCA) patients, killing approximately 29,000 men every year in the United States. It is generally believed that PCA could be better managed through early screening and diagnosis. Increasingly we have been successful in diagnosing PCA at early stages, but unfortunately that has not translated into significantly reducing PCA-related morbidity and mortality. This clearly reflects that there is a critical gap in our understanding of prostate carcinogenesis especially the PCA metastasis. Recent evidence in other malignancies has suggested that the primary localized tumors could influence and modify the environment of distant organs by promoting the formation of metastasis supportive microenvironment, termed as "pre-metastatic niches," much prior to the tumor cell metastasis. These pre-metastatic niches could determine the metastatic success of disseminated cancer cells; however, this aspect of PCA metastasis has remained totally unstudied. Our preliminary/published studies have shown that PCA cells under low oxygen conditions (termed as "hypoxia") release exosomes, small vesicles of ~30-100 nm size, filled with growth factors, signaling molecules and proteinases, and could prepare the pre-metastatic niches. Our preliminary results clearly showed that RAB5A is the major molecular regulator of exosomes biogenesis in PCA cells under hypoxic conditions. Based upon these exciting observations, our innovative idea in the present proposal is that "hypoxia in prostate tumor promotes pre-metastatic niches formation and metastasis through RAB5A-mediated exosomes biogenesis." Ultimate Applicability of the Research: The present proposal will benefit all PCA patients. Based upon the presence of hypoxia biomarkers or RAB5A expression in primary tumors or the detection of ExoHypoxic in the blood, it will be feasible to predict the presence/absence of pre-metastatic niches, and on that basis to stratify PCA patients with aggressive or indolent disease, and to decide and monitor treatment success. Furthermore, targeted therapies against premetastatic niche regulators (such as VEGF, TNF1alpha, IL6, TGFbeta, CD11b+) as well as exosomes synthesis regulator RAB5A could be combined with existing therapeutic modalities to effectively target primary tumors and to prevent and treat primary/secondary metastasis. Based upon the outcomes, in future, clinical success against PCA will be determined by both the treatment of primary tumor and the effective elimination of pre-metastatic niches. Importantly, the concept/results from present proposal will be immediately translated into clinic to achieve patient s related outcome. Contributions of This Study to Advancing the Field of Prostate Cancer Research: The treatment of metastasis in clinic will remain unsuccessful and metastasis will remain the cause of most cancer-related fatalities while pre-metastatic niches persist. At present, there is no information available about pre-metastatic niches, hypoxic PCA exosomes and RAB5A role in PCA metastasis, and that is the central focus of present proposal. Overall, our proposed hypothesis is completely untested and novel in the area of PCA research and will bring a paradigm shift in our understanding to reduce PCA-related mortality.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Apr 04, 2016
- Source ID
- W81XWH1510188
Entities
People
- Gagan Deep
Organizations
- United States Army
- University of Colorado Denver