Metformin as a Therapeutic Target in Endometrial Cancers

Teresa Y Lee, Ubaldo E Martinez-Outschoorn, Russell J Schilder, Christine H Kim, Scott D Richard, Norman G Rosenblum, Jennifer M Johnson, Teresa Y Lee, Ubaldo E Martinez-Outschoorn, Russell J Schilder, Christine H Kim, Scott D Richard, Norman G Rosenblum, Jennifer M Johnson

Abstract

Endometrial cancer is the most common gynecologic malignancy in developed countries. Its increasing incidence is thought to be related in part to the rise of metabolic syndrome, which has been shown to be a risk factor for the development of hyperestrogenic and hyperinsulinemic states. This has consequently lead to an increase in other hormone-responsive cancers as well e.g., breast and ovarian cancer. The correlation between obesity, hyperglycemia, and endometrial cancer has highlighted the important role of metabolism in cancer establishment and persistence. Tumor-mediated reprogramming of the microenvironment and macroenvironment can range from induction of cytokines and growth factors to stimulation of surrounding stromal cells to produce energy-rich catabolites, fueling the growth, and survival of cancer cells. Such mechanisms raise the prospect of the metabolic microenvironment itself as a viable target for treatment of malignancies. Metformin is a biguanide drug that is a first-line treatment for type 2 diabetes that has beneficial effects on various markers of the metabolic syndrome. Many studies suggest that metformin shows potential as an adjuvant treatment for uterine and other cancers. Here, we review the evidence for metformin as a treatment for cancers of the endometrium. We discuss the available clinical data and the molecular mechanisms by which it may exert its effects, with a focus on how it may alter the tumor microenvironment. The pleiotropic effects of metformin on cellular energy production and usage as well as intercellular and hormone-based interactions make it a promising candidate for reprogramming of the cancer ecosystem. This, along with other treatments aimed at targeting tumor metabolic pathways, may lead to novel treatment strategies for endometrial cancer.

Keywords: endometrial cancer; metabolism; metformin; reverse Warburg; tumor microenvironment.

Figures

Figure 1
Figure 1
(A) Mechanisms of action of metformin within the endometrial cancer cell. (B) Downstream molecular targets of metformin showing differential expression or activity in endometrial cancer.

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