Access Type

Open Access Dissertation

Date of Award

January 2017

Degree Type

Dissertation

Degree Name

Ph.D.

Department

Cancer Biology

First Advisor

Izabela Podgorski

Abstract

Bone is a preferential site of metastasis from prostate cancer (PCa). Although there have been many advances in therapeutic options for patients suffering from metastatic PCa, this disease remains incurable with an estimated five-year survival of 33%. To design effective therapeutic interventions for metastatic PCa, it is essential that we elucidate the molecular mechanisms responsible for tumor cell adaptation to and the ability to thrive within the bone metastatic niche. Age and obesity, conditions that increase adipocyte numbers in bone marrow, are risk factors for skeletal metastases from PCa; therefore, our laboratory is focused on the interactions between marrow adipocytes and PCa cells.

We initially detailed the metabolic alterations that occur in prostate cancer cells in response to interactions with bone marrow adipocytes in multiple in vivo and in vitro models. The following conclusions were drawn as a result of these experiments: 1) Patients with metastatic disease have increased expression of glycolytic and hypoxic genes compared to primary PCa tumors; 2) tumors grown intratibially in vivo in diet induced models of high marrow adiposity have increased expression of glycolytic and hypoxic genes compared to mice with fewer marrow adipocytes; 3) paracrine interactions between tumor cells and adipocytes in vitro induce expression of glycolytic and hypoxic proteins in tumor cells; 4) PCa cells exposed to adipocytes with increased expression of glycolytic markers exhibit enhanced Warburg metabolism with increases in lactate production, decreases in oxidative phosphorylation, and decreases in ATP production without perturbation of mitochondrial integrity or cellular viability; 5) tumor cells stimulate lipolysis within adipocytes but the inhibition of lipolysis does not affect adipocyte-driven changes in PCa cell metabolism due to possible compensatory mechanisms; 6) metabolic effects are driven through the activation of HIF-1α in PCa cells as shown by increased expression of hypoxia-responsive genes and the reversal of adipocyte-induced metabolic changes upon knockdown of tumor cell HIF-1α.

Additionally, we found novel signaling pathways are activated in tumor cells due to cross talk between tumor cells and adipocytes. We observed a regulation of COX-2 in adipocytes by tumor-secreted IL-1β that leads to increased PGE2 synthesis and release and this PGE2 signals through the EP receptors on the tumor cells to elicit downstream GSK3β/β-catenin signaling and subsequent HIF-1α activation.

We also observed increased SPHK1 in adipocytes exposed to tumor cells as an effect of tumor-stimulated lipolysis within adipocytes, but that S1P was not sufficient to activate HIF-1α signaling in tumor cells or downstream metabolic alterations.

In summary, we have discovered novel crosstalk between metastatic prostate tumor cells and bone marrow adipocytes that cause activation of many pathways involved in tumor survival and growth within the bone. We have revealed a functional contribution of bone marrow adipocytes to altered tumor metabolism and signaling in bone. The expected outcome of this research is the validation of the significance of adipocyte-derived lipids in growth and aggressiveness of metastatic PCa in bone. The ultimate goal is utilize findings from this study to explore whether adipocyte-driven metabolic adaptation contributes to chemoresistance of skeletal tumors and whether targeting tumor metabolism offers new options for improved therapy and/or prevention of aggressive disease.

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