News & Research

    University of Louisville, Louisville, Kentucky

Sesquiterpenoids abolish hepatocellular carcinoma stem cells in the compromised liver by diabetes

General Research Subject: Both Type 1 And Type 2 Diabetes

Focus: Complications, Complications\Hypoglycemia, Integrated Physiology, Integrated Physiology\Liver, Signal Transduction (Non-Insulin Action), Signal Transduction (Non-Insulin Action)\Transcriptional Regulation

Type of Grant: Basic Science

Project Start Date: January 1, 2013

Project End Date: December 31, 2015

Research Description

Cancer stem cells (CSC) generate tumors through the stem cell processes of self-renewal and differentiation into multiple cell types. The tumor microenvironment affects carcinogenesis by interfering with the CSC signaling pathways. The characteristics of type 2 diabetes are the metabolic abnormalities such as hyperglycemia and hyperinsulinemia. This diabetic condition may provide a tumor microenvironment to facilitate CSC self-renewal and differentiation for hepatocellular carcinoma (HCC) initiation and progression. The emerging idea for this proposed study is based on the current observations and our own pilot studies.

Recent studies have shown that nature compounds could be promising agents in targeting CSC. Sesquiterpenoids from natural products have been shown to abolish CSC in experimental HCC models in our preliminary data. The risk for HCC is significantly greater in diabetics, and HCC risk has not been linked to the presence of underlying liver disease or other risk factors. Diabetes is clearly established as an independent risk factor for HCC. The purpose of this proposal is to explore a natural compound(s)-based strategy for HCC prevention and therapy. It is tremendously important to gain novel insights into the molecular mechanisms underlying the development of HCC in patients with diabetes, which will help uncover new therapeutic targets.

Research Profile

What area of diabetes research does your project cover? What role will this particular project play in preventing, treating, and curing diabetes?

Diabetes often coexists with cancer. In fact, diabetes is the most common risk factor for liver cancer in the United States, In our study, treating diabetes-associated liver cancer, while challenging, is very important. Our particular project takes into account a complex relationship between diabetes and cancer, focusing on the mechanisms that initiate liver cancer in the diabetic animal and ameliorating the diabetic microenvironment that leads to liver cancer. We will explore the use of our natural product-based therapeutic method to target therapy.

Our preliminary studies have shown promising results with our therapy using the natural compounds, sesquiterpenoids, which can abolish cancer stem cells in diabetes. Our proposed study sheds light on cancer stem cell activation in the diabetic condition, thereby providing a novel therapeutic strategy for diabetes and liver cancer.

If a person with diabetes were to ask you how your project will help them in the future, how would you respond?

Our diabetic research involves complex studies on the association between diabetes and cancer in general. Our aims are designed to gain insight into the mechanisms behind this association and to provide a novel strategy for prevention and treatment. The more that we understand about the mechanisms at work, the more successful we will be at treating a diabetic patient who has an increased risk for liver cancer and a liver cancer patient who has diabetes.

This study builds upon our preliminary findings. We have found that the diabetic condition could be a tumor microenvironment in the liver for the signaling of cancer stem cell activation, which may promote tumor initiation and invasiveness. We also found that natural products could be a promising agent to kill the cancer stem cells.

Why is it important for you, personally, to become involved in diabetes research? What role will this award play in your efforts?

The reason why I became involved in diabetic research is because, as a young physician in China, I saw numerous diabetic patients struggling with the complications from this disease clinically. In my opinion, the worst cases were those that involved complications from diabetes, when the diabetes was not controlled. My previous medical experience centered around the care and treatment of diabetic patients as well as the establishment of a diabetic care training program for patients. In that program, I trained patients on how to set up their own personal schedules for food and exercise. That effort only scratched the surface of the problem for diabetic patients. It is my current belief that I can be more helpful to the diabetic patient by understanding the mechanisms of diabetes and providing effective therapeutic strategies rather than giving them a training program.

Diabetes research has been important to me ever since my early years of research, and my current work complements these efforts. Since 2000, I have been working on the esophageal and liver cancer research, with my focus on cancer stem cells and the tumor microenvironment. Recent studies show that diabetes is the most common risk factor for liver cancer. Therefore, diabetes could create a unique tumor microenvironment for cancer stem cells activation. Our preliminary data supports this hypothesis. This award is very important for me and allows me to re-focus my work on the diabetes research. This award also opens an new opportunity for my career development in the diabetes research as well as fulfills my wishes to provide a meaningful contribution to diabetes research.

In what direction do you see the future of diabetes research going?

In my opinion, the future direction of diabetes research is the prevention of diabetic complications. This should be a priority for future research. The direction that I am focusing on is diabetes-associated liver cancer, which is becoming an area of extreme interest to researchers—a hot topic. The National Cancer Institute reported in 2010 that diabetes is now associated with a greater percentage of liver cancer cases than any other factor. I believe that, while treatment and prevention are important, it appears to me that we could learn a lot more about how to effectively deal with diabetes by putting more research emphasis on the mechanisms of the diabetes and liver cancer at in vivo levels.

It is imperative that we better understand the mechanism and develop novel therapeutic strategies, so that patients can be treated and managed in the best way possible. For example, insulin can lower the glucose level but also increase the incidence of liver cancer. In our current research proposal, we will investigate a natural product-based prevention and therapeutic approach for both the diabetes-associated liver cancer. Ours is a promising idea, because we use a natural agent for diabetes and liver cancer. We believe that natural products are a worthwhile future direction for diabetes research.