New insights into the prognosis of intraocular malignancy: Interventions for association mechanisms between cancer and diabetes

Abstract

The intraocular malignancies, which mostly originate from the retina and uvea, exhibit a high incidence of blindness and even death. Uveal melanoma (UM) and retinoblastoma (RB) are the most common intraocular malignancies in adults and children, respectively. The high risks of distant metastases lead to an extremely poor prognosis. Nowadays, various epidemiological studies have demonstrated that diabetes is associated with the high incidence and mortality of cancers, such as liver cancer, pancreatic cancer, and bladder cancer. However, the mechanisms and interventions associated with diabetes and intraocular malignancies have not been reviewed. In this review, we have summarized the associated mechanisms between diabetes and intraocular malignancy. Diabetes mellitus is a chronic metabolic disease characterized by prolonged periods of hyperglycemia. Recent studies have reported that the abnormal glucose metabolism, insulin resistance, and the activation of the IGF/insulin-like growth factor-1 receptor (IGF-1R) signaling axis in diabetes contribute to the genesis, growth, proliferation, and metastases of intraocular malignancy. In addition, diabetic patients are more prone to suffer severe complications and poor prognosis after radiotherapy for intraocular malignancy. Based on the common pathogenesis shared by diabetes and intraocular malignancy, they may be related to interventions and treatments. Therefore, interventions targeting the abnormal glucose metabolism, insulin resistance, and IGF-1/IGF-1R signaling axis show therapeutic potentials to treat intraocular malignancy.

Keywords: Warburg effect; insulin resistance; insulin-like growth factor-1 receptor; intraocular malignancy; retinoblastoma; uveal melanoma.

Figure 1

Biological mechanisms linking diabetes and intraocular malignancy. Tumor cells undergo metabolic reprogramming to meet their energy needs for rapid proliferation. Warburg effect and anaerobic glycolysis are involved in the formation and development of intraocular malignancies in the early stage and advanced stage, respectively. Insulin resistance improves carcinogenesis by developing an adiponectin-deficient environment, direct insulin/insulin receptor pathway, and indirect IGF-1/IGF-1R signaling pathway. Both IGF-1/IGF-1R axis and insulin/insulin receptor are involved in the occurrence and development of intraocular malignancy through PI3K/AKT and Ras/Raf/MEK/ERK signaling pathways. →, activation; ⊥, inhibition.

Figure 2

The potential treatments for intraocular malignancy by intervening the pathogenic factors of diabetes. GLUT1 inhibitors as well as GLUT1 antibodies inhibit tumor cell growth by limiting glucose translocated into the cell. Treatments targeting glycolytic enzymes inhibit glucose metabolism and tumorigenesis, including miR-216a-5p (the HK2 inhibitor), SOX-10 knockdown (GAPDHS suppression), and 2-DG and 2-FG (glycolytic inhibitors). Anti-IGF-1R antibody, IGF-1R inhibitor (such as pristimerin), PI3K/AKT inhibitors, FoxO3a overexpression, and miR-98 upregulation exert antitumor function by limiting IGF-1R and IGF-1/IGF-1R signaling pathway. Insulin sensitizer (such as metformin) and adiponectin treatment are considered potential approaches for treating intraocular malignancies by improving insulin resistance. →, activation; ⊥, inhibition.