Sarcomas are a heterogeneous group of malignancies arising from mesoderm-derived tissues such as muscle, fat, and connective tissue. They are diagnosed in nearly 20,000 persons in the United States each year, and approximately 40% of patients die of either loco-regional recurrence or distant metastasis. Sarcomas and other solid tumors typically thrive in hypoxic and nutrient-poor conditions to proliferate and metastasize. To survive in such environments, sarcomas hijack two adaptive mechanisms: (1) activation of hypoxia inducible factor 1? (HIF-1?), which enhances the transcription of over 150 genes mediating tumor metabolism, angiogenesis, and metastasis and (2) utilization of aerobic glycolysis (a.k.a. the Warburg effect), which creates energy by means of glycolysis rather than oxidative phosphorylation. HIF-1? appears to be particularly critical for a subset of tumor cells which we will refer to as ?sarcoma stem-like cells? or SSCs, characterized by their ability to self renew and differentiate. In preliminary studies, we have found that SSCs reside preferentially in hypoxic regions of tumors, exhibit elevated levels of HIF-1?, and are likely to promote chemotherapy resistance and metastasis. The reverse reaction of glycolysis is gluconeogenesis, where fructose-1, 6-bisphosphatase (FBP) acts as a rate-limiting enzyme. We also recently determined that FBP2 is consistently downregulated in 8 human sarcoma subtypes compared to normal human mesoderm-derived tissues. The long-term objective of this proposal is to expand the use of agents targeting HIF-1? and FBP2 in patients with sarcomas to reduce recurrence, distant metastasis, and chemotherapy resistance. Consequently, this proposal is designed to test the hypothesis that HIF-1? and FBP2 play critical and inter- related roles in regulating sarcomagenesis, metabolism, metastasis, and chemotherapy resistance. To test this hypothesis, this research proposal will (1) define the role of FBP2 in sarcoma metabolism, progression, and metastasis, and (2) determine the role of HIF-1? in SSC metastasis and chemotherapy resistance. The methods of this proposal include analysis of autochthonous and xenograft mouse models of sarcomas, analysis of sarcoma cell lines in vitro, metabolic studies, and correlative studies of tumor samples from sarcoma patients.
Hypoxia inducible factor 1? (HIF-1?) and HIF-1? target genes are frequently overexpressed in sarcomas, especially those that metastasize and become resistant to chemotherapy. Fructose-1, 6-bisphosphatase 2 (FBP2) is downregulated in nearly all sarcoma subtypes, and decreased expression correlates with poorer overall patient survival. This project will examine the critical and inter-related roles of HIF-1? and FBP2 in regulating sarcomagenesis, metabolism, metastasis, and chemotherapy resistance.
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|Yoon, Changhwan; Chang, Kevin K; Lee, Jun Ho et al. (2016) Multimodal targeting of tumor vasculature and cancer stem-like cells in sarcomas with VEGF-A inhibition, HIF-1? inhibition, and hypoxia-activated chemotherapy. Oncotarget 7:42844-42858|
|Lewis, Daniel M; Park, Kyung Min; Tang, Vitor et al. (2016) Intratumoral oxygen gradients mediate sarcoma cell invasion. Proc Natl Acad Sci U S A 113:9292-7|
|Simon, M Celeste (2016) The Hypoxia Response Pathways - Hats Off! N Engl J Med 375:1687-1689|
|Hayano, Koichi; Tian, Fang; Kambadakone, Avinash R et al. (2015) Texture Analysis of Non-Contrast-Enhanced Computed Tomography for Assessing Angiogenesis and Survival of Soft Tissue Sarcoma. J Comput Assist Tomogr 39:607-12|
|Yoon, C; Lee, H-J; Park, D J et al. (2015) Hypoxia-activated chemotherapeutic TH-302 enhances the effects of VEGF-A inhibition and radiation on sarcomas. Br J Cancer 113:46-56|
|Tan, Marcus C B; Yoon, Sam S (2015) Surgical management of retroperitoneal and pelvic sarcomas. J Surg Oncol 111:553-61|
|Kambadakone, Avinash; Yoon, Sam S; Kim, Tae-Min et al. (2015) CT perfusion as an imaging biomarker in monitoring response to neoadjuvant bevacizumab and radiation in soft-tissue sarcomas: comparison with tumor morphology, circulating and tumor biomarkers, and gene expression. AJR Am J Roentgenol 204:W11-8|
|Lee, Hae-June; Yoon, Changhwan; Park, Do Joong et al. (2015) Inhibition of vascular endothelial growth factor A and hypoxia-inducible factor 1? maximizes the effects of radiation in sarcoma mouse models through destruction of tumor vasculature. Int J Radiat Oncol Biol Phys 91:621-30|
|Yoon, Changhwan; Park, Do Joong; Schmidt, Benjamin et al. (2014) CD44 expression denotes a subpopulation of gastric cancer cells in which Hedgehog signaling promotes chemotherapy resistance. Clin Cancer Res 20:3974-88|
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