This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Prostate cancer is the second leading cause of cancer death in U.S. men. Over 80% of mortality results from complications of bone metastasis. Our lab studies mechanisms by which extracellular components regulate tumor development and metastatic dissemination. Our upcoming R01 application centers on hyaluronan (HA), a polymeric glycosaminoglycan essential for cell growth and migration in development. HA is negligible in normal prostate, but abundant in prostate tumors and bone metastases. Quantification of tumor-associated HA and its turnover enzyme, Hyal1, predicts invasive progression and provides a clinical readout for prostate cancer patient prognosis. Tumor-associated HA polymers are synthesized by HA synthases (HAS) and cleaved by hyaluronidases (i.e.;Hyal1). Response to HA at the cellular and tissue level is controlled by HA size and by specific distribution of HA receptors such as CD44 and the HA receptor for endocytosis (HARE). Our hypothesis for this application is built on three key results from our previous data: (1) exogenous HA has no effect on tumor cells, while induced endogenous HA production lowers surface expression of integrins, and cadherins, which reduces growth rate and motility of tumor cells;(2) induced expression of Hyal1, which is both a secreted and a lysosomal enzyme, increases the rate of endocytic HA intake in tumor cells;and (3) systemic administration of an antibody against HARE, found in endothelial cells of liver, lymph node and bone, blocks spontaneous metastasis of prostate tumor cells in mice. From these observations, we postulate that surface HA borne by tumor cells increases metastatic efficiency by facilitating arrest in HARE-expressing vasculature and/or entry of the tumor cells into lymph and marrow tissue. In addition, we suggest excess tumor-borne HA can accelerate tumor cell endocytosis and/or endocytic recycling if Hyal1 is present, activating lymphatic remodeling. Rate of endocytic recycling determines the surface density of cell adhesion receptors and thereby impacts tumor cell motility and metastatic survival. This hypothesis is novel, innovative and parsimonious: no previous explanation has incorporated the complex actions of HA in tumor growth and metastasis under the common process of endocytosis, triggered by distinct receptor classes on tumor cells versus stromal cells, leading to different but concurrent outcomes. Positively defining these unique mechanisms could open avenues of therapy through antagonism of endocytic uptake or recycling pathways more heavily relied upon by tumor cells. Our goal in the bridge funding period is to collect additional preliminary data to support the following aims:
Aim 1 : Determine how HA controls lymphatic navigation and bone metastasis. HA is a likely factor in metastatic preference of prostate tumor cells, while Hyal1 is important for metastasis initiation. We know the size and quantity of HA polymers, on which HA receptor ligation depends, are determined by the relative expression of HAS and Hyal1 enzymes. HARE is not expressed in prostate, but is present on endothelial cells in lymph node and bone, tissues to which HA-enveloped tumor cells show increased frequency of metastasis. We have inducible systems that allow us to stimulate or inhibit either HAS or Hyal1 in an experimentally controlled fashion and we have developed non-invasive near-infrared imaging methods for monitoring tumor growth in mice. We will use orthotopic and intracardiac injection in mice to quantify effects of HA, Hyal1 and HARE manipulation on the metastatic process

National Institute of Health (NIH)
National Center for Research Resources (NCRR)
Exploratory Grants (P20)
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Special Emphasis Panel (ZRR1-RI-6 (01))
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University of Nebraska Medical Center
Schools of Dentistry
United States
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