Diabetes mellitus contribution to the remodeling of the tumor microenvironment in gastric cancer

Abstract

Compelling pieces of evidence derived from both clinical and experimental research has demonstrated the crucial contribution of diabetes mellitus (DM) as a risk factor associated with increased cancer incidence and mortality in many human neoplasms, including gastric cancer (GC). DM is considered a systemic inflammatory disease and therefore, this inflammatory status may have profound effects on the tumor microenvironment (TME), particularly by driving many molecular mechanisms to generate a more aggressive TME. DM is an active driver in the modification of the behavior of many cell components of the TME as well as altering the mechanical properties of the extracellular matrix (ECM), leading to an increased ECM stiffening. Additionally, DM can alter many cellular signaling mechanisms and thus favoring tumor growth, invasion, and metastatic potential, as well as key elements in regulating cellular functions and cross-talks, such as the microRNAs network, the production, and cargo of exosomes, the metabolism of cell stroma and resistance to hypoxia. In the present review, we intend to highlight the mechanistic contributions of DM to the remodeling of TME in GC.

The crosstalk within the breast tumor microenvironment in type II diabetes: Implications for cancer disparities

“…HIF1α stability and function are dysregulated by hyperglycemia, and disruption of this aberrant signaling can improve insulin sensitivity ( 101 – 104 ). Within the diabetic breast TME, higher levels of HIF1α and subsequent oxidative stress contribute to hypoxia ( 101 , 103 , 105 ). Hypoxia is a driving force of tumor progression as it stimulates vascularization (VEGF, ANG1, ANG2, MMPs, LOX, CAIX, CXCR4) , upregulates EMT/CSC signatures (SNAI1, SNAI2, TWIST1, SOX9, SOX2, OCT4, NANOG) , and contributes to drug resistance ( 106 – 109 ).…”