Abstract
Endometrial cancer (EC) is one of the most common malignancies of the female reproductive organs. The most characteristic feature of EC is the frequent association with metabolic disorders. However, the components of these disorders that are involved in carcinogenesis remain unclear. Accumulating epidemiological studies have clearly revealed that hyperinsulinemia, which accompanies these disorders, plays central roles in the development of EC via the insulin-phosphoinositide 3 kinase (PI3K) signaling pathway as a metabolic driver. Recent comprehensive genomic analyses showed that over 90% of ECs have genomic alterations in this pathway, resulting in enhanced insulin signaling and production of optimal tumor microenvironments (TMEs). Targeting PI3K signaling is therefore an attractive treatment strategy. Several clinical trials for recurrent or advanced ECs have been attempted using PI3K-serine/threonine kinase (AKT) inhibitors. However, these agents exhibited far lower efficacy than expected, possibly due to activation of alternative pathways that compensate for the PIK3-AKT pathway and allow tumor growth, or due to adaptive mechanisms including the insulin feedback pathway that limits the efficacy of agents. Overcoming these responses with careful management of insulin levels is key to successful treatment. Further interest in specific TMEs via the insulin PI3K-pathway in obese women will provide insight into not only novel therapeutic strategies but also preventive strategies against EC.
Highlights
Endometrial cancer (EC) is the most common gynecologic malignancy in the Western world
A novel category stated by The Cancer Genome Atlas (TCGA) is the ultramutated POLE subgroup, which consists of 7% of ECs with unusually high mutation rates (232 × 10−6 mutations/Mb), generating extremely frequent mutations in cancer-associated genes such as phosphatase and tensin homologue (PTEN) (94%), PIK3CA (71%), PIK3R1 (65%), FBXW7 (82%), ARID1A (75%), KRAS (53%), and AIRD1B (47%) [10]
microsatellite instability (MSI) represents a specific phenotype caused by a defective DNA mismatch repair (MMR) system composed of four representative MMR proteins (MLH1, MSH2, MSH6, and PMS2) [10]
Summary
Endometrial cancer (EC) is the most common gynecologic malignancy in the Western world. In 10 years, the incidence of EC is expected to dramatically increase to over 120,000 cases, becoming the third most common malignancy affecting women in the US after lung and colorectal cancers [2]. Over 75% of women diagnosed with EC have stage I or II disease, and have good clinical outcomes with five-year overall survival of 75–90% [4,5]. Further therapeutic developments are needed for these patients, hopefully combined with molecular-targeted agents, based on novel aspects of precise molecular pathogenesis and carcinogenesis of this tumor. In 2013, a new classification of EC was proposed by The Cancer Genome Atlas (TCGA) [10], based on the genomic status of the patients. This review article introduces the metabolic TMEs of EC, describes how the genomic status of EC and insulin-PI3K signaling direct TMEs, and suggests important clues for developing novel therapeutic and preventive strategies
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