Date of Graduation

5-2014

Document Type

Dissertation (PhD)

Program Affiliation

Cancer Biology

Degree Name

Doctor of Philosophy (PhD)

Advisor/Committee Chair

Mong-Hong Lee, Ph.D.

Committee Member

Sai-Ching Jim Yeung, M.D., Ph.D.

Committee Member

Paul Chiao, Ph.D.

Committee Member

Huamin Wang, M.D., Ph.D.

Committee Member

Michele Forman, Ph.D.

Abstract

Pancreatic cancer is one of the most aggressive types of cancer, with poor prognosis that lacks effective diagnostic markers and therapies. It is expected that in 2014 the incidence and the mortality of pancreatic cancer in the United States will be 46,420 and 39,590 respectively. Diabetes and obesity are modifiable risk factors associated with accelerated pancreatic carcinogenesis and tumor progression, but the biological mechanisms are not completely understood. The purpose of this study is to demonstrate direct evidence for the mechanisms mediating these epidemiologic phenomena. Our hypothesis is that obesity and diabetes mellitus type 2 (DM2) accelerate pancreatic cancer and that metformin treatment has a beneficial impact. To determine the effect of glucose, insulin and adipocytes in pancreatic cancer proliferation we used conditioned media to mimic DM2 and obese conditions. Also, we studied the effect of anti-diabetic drugs, particularly metformin and rosiglitazone on pancreatic cancer. We established orthotopic/syngeneic mouse models to evaluate the effect of obesity (Ay/a) and diabetes (Leprdb/Leprdb) on pancreatic tumor growth and aggressiveness. Our results showed that both obesity and diabetes promote pancreatic tumor growth. Furthermore, enhanced tumor growth and aggressiveness (e.g., EMT) was explained by functional transcriptomic and metabolomic changes in the mice with obesity and diabetes, namely via activation of the AKT/mTOR pathway. Metformin treatment decreased the obesity-induced and diabetes-induced AKT/mTOR pathway activation and tumor growth. Adipokine profile array showed an induced secretion of several adipokines in the obese and diabetic mice compared with lean mice. Our co-culture system showed a direct impact of adipocytes on the growth of pancreatic cancer cells. In conclusion, obesity and diabetes have adverse effects that promote pancreatic cancer progression by enhancing proliferation and aggressiveness via transcriptomic and metabolomic changes. Adipocytes affect tumor microenvironment and cancer cell proliferation through the secretion of adipokines targeting cancer cells’ survival and proliferation. Our animal models provide strong evidence for the causal relationship between obesity, diabetes and accelerated pancreatic cancers. This study sheds a new insight of the effects of metformin and its potential as part of therapeutic interventions for pancreatic cancer in obese/diabetic patients.

Keywords

Metabolism, Type 2 diabetes mellitus, Metformin, PancO2, Mouse model

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