Diabetes and Colorectal Cancer Risk: Clinical and Therapeutic Implications

Abstract

Several epidemiological studies have identified diabetes as a risk factor for colorectal cancer (CRC). The potential pathophysiological mechanisms of this association include hyperinsulinemia, insulin-like growth factor (IGF) axis, hyperglycemia, inflammation induced by adipose tissue dysfunction, gastrointestinal motility disorder, and impaired immunological surveillance. Several studies have shown that underlying diabetes adversely affects the prognosis of patients with CRC. This review explores the novel anticancer agents targeting IGF-1R and receptor for advanced glycation end products (RAGE), both of which play a vital role in diabetes-induced colorectal tumorigenesis. Inhibitors of IGF-1R and RAGE are expected to become promising therapeutic choices, particularly for CRC patients with diabetes. Furthermore, hypoglycemic therapy is associated with the incidence of CRC. Selection of appropriate hypoglycemic agents, which can reduce the risk of CRC in diabetic patients, is an unmet issue. Therefore, this review mainly summarizes the current studies concerning the connections among diabetes, hypoglycemic therapy, and CRC as well as provides a synthesis of the underlying pathophysiological mechanisms. Our synthesis provides a theoretical basis for rational use of hypoglycemic therapies and early diagnosis and treatment of diabetes-related CRC.

Figure 1

Schematic review of the tumor-promoting signaling pathways linking hyperinsulinemia and CRC. IGF-1R is comprised of extracellular α-chains, transmembrane β-chains and intracellular tyrosine kinase (IRS-1). Both IGF-1 and insulin are ligands for IGF-1R, and their binding induces autophosphorylation and conformational change of cytoplasmic tyrosine domain, resulting in stimulation of signaling cascades, mainly including PI3K/AKT and MAPK pathways which are closely correlated with protein synthesis, survival, and proliferation. IRS-1: insulin receptor substrate-1; PI3K: phosphatidylinositol 3-kinase; AKT: protein kinase B; mTOR: mammalian target of rapamycin; MAPK: mitogen-activated protein kinase; MEK: mitogen-activated protein kinase; ERK: extracellular signal-regulated kinase; SOS: son of sevenless; FOXO: Forkhead; BAD: proapoptotic member of the Bcl-family; GS3Kβ: glycogen synthase kinase.

Figure 2

Effects of hyperinsulinemia and IGF axis on colorectal carcinogenesis. GLP-1: glucagon-like peptide-1; PI3K: phosphatidylinositol 3-kinase; mTOR: mammalian target of rapamycin; MAPK: mitogen-activated protein kinase; MEK: mitogen-activated protein kinase; ERK: extracellular signal-regulated kinase.

Figure 3

Effects of hyperglycemia on colorectal carcinogenesis. RAGE: receptor for advanced glycation end products; AGEs: advanced glycation end products; ROS: reactive oxygen species; ERK: extracellular signal-regulated kinase; SP1: specificity protein 1; MMP-2: matrix metallopeptidase-2; MAPK: mitogen-activated protein kinase; NF-κB: nuclear factor kappa-B; PI3K: phosphatidylinositol 3-kinase; YAP-1: Yes-associated protein-1; GLUT1: glucose transporter 1; GLUT3: glucose transporter 3.

Figure 4

Effects of obesity and adipose tissue dysfunction on colorectal carcinogenesis. JAK: Janus kinase; STAT3: signal transducer and activator of transcription 3; PI3K: phosphatidylinositol 3-kinase; mTOR: mammalian target of rapamycin; MAPK: mitogen-activated protein kinase; ERK: extracellular signal-regulated kinase; AMPK: adenosine monophosphate-activated protein kinase; IL-1β: interleukin-1β; IL-6: interleukin-6; TNF-α: tumor necrosis factor-α.

Figure 5

Predisposing factors of patients with T2DM for CRC.