Metabolic syndrome and colorectal cancer: Is hyperinsulinemia/insulin receptor-mediated angiogenesis a critical process?

Abstract

Objective Components of metabolic syndrome (MS) have been individually linked to colorectal cancer risk and prognosis; however, an understanding of the dominant mechanisms is lacking. Materials and methods Twenty-one patients (10 MS; 11 non-MS) with resectable colorectal cancer were prospectively enrolled. Patients were classified for MS by the World Health Organization criteria and tested for circulating vascular endothelial growth factor (VEGF), interleukin-6 (IL-6), insulin-like growth factor-1 (IGF-1), fasting insulin, and tumor expression of IGF-1 receptor (IGF-1R), insulin-receptor (IR) and receptor for advanced glycation end-products (RAGE). Circulating markers were re-tested 6 months after surgery. Results The MS group had significantly higher baseline and post-operative fasting insulin levels (p < 0.001 and 0.003). No differences were observed in circulating IL-6, VEGF, IGF-1 and free IGF-1. By immunohistochemistry (IHC), IGF-1R expression was significantly higher in tumor vs. normal tissues (p < 0.001) while IR expression showed no difference. Interestingly, 64% of tumors demonstrated high IR positivity in the vessels within or surrounding the tumor stroma, but not in the vessels away from the tumor. By reverse transcription polymerase chain reaction (RT-PCR), tumor IGF-1R over-expression (80%) was confirmed, but there was no difference between MS and non-MS patients. Tumor RAGE over-expression was found in 67% of patients and was equally distributed between the two groups. Conclusions Hyperinsulinemia was the only significant factor distinguishing patients with colorectal cancer who have MS. The preferential over-expression of IR in the peri-tumoral microvessels suggests that hyperinsulinemia might contribute to colorectal cancer growth by enhancing angiogenesis.

Diabetes Mellitus is Independently Associated with an Increased Risk of Mortality in Patients with Clear Cell Renal Cell Carcinoma

“…5 High plasma insulin results in increased hepatic production of IGF-1, which has a central driving role in cell proliferation and differentiation, protecting against apoptosis. 24 Over expression of IGF-1 and IGF-1 receptor was associated with an increased risk of prostate, cervical, ovarian, breast and colon cancers in clinical studies, 5,25 and with increased tumor growth in vitro 26 and in animal models. 27 Furthermore, there is growing understanding of the role of metabolic dysregulation and reliance on aerobic glycolysis in RCC pathogenesis, known as the Warburg effect.…”

The ColoCare Study: A Paradigm of Transdisciplinary Science in Colorectal Cancer Outcomes

“…Components of the ColoCare Cohort have been leveraged to support initial research; including on biologic determinants of colorectal cancer (e.g., tumor immunity, gut microbiome, epigenome), health behaviors (e.g., physical activity or dietary patterns), components of energy balance (e.g., adipose tissue distribution, accelerometry), clinical endpoints (e.g., surgical complications, quality of life), and novel biomarkers (proteomics, metabolomics, metagenomics). Furthermore, we have published on the interrelations between these factors, specifically in the context of colorectal cancer prognosis (18,(30)(31)(32)(33)(34)(35)(36)(37)(38)(39)(40)(41)(42)(43)(44)(45)(46)(47)(48). Table 3 highlights research contributions using the growing ColoCare Study cohort.…”

Preoperative metabolic syndrome and prognosis after radical resection for colorectal cancer: The Fujian prospective investigation of cancer (FIESTA) study

“…In recent decade, growing evidence suggests that metabolic syndrome plays a carcinogenic role in cancer at some sites, including CRC . However, the precise mechanisms underlying the relationship between metabolic abnormalities and colorectal carcinogenesis are not fully understood, although several explanations have been proposed . Insulin resistance is characteristic of metabolic syndrome, and its resultant chronic hyperinsulinemia and bioavailable insulin‐like growth factor‐1 (IGF‐1) can trigger tumorigenesis and metastasis .…”

“…[16][17][18][19] However, the precise mechanisms underlying the relationship between metabolic abnormalities and colorectal carcinogenesis are not fully understood, although several explanations have been proposed. [20][21][22] Insulin resistance is characteristic of metabolic syndrome, and its resultant chronic hyperinsulinemia and bioavailable insulin-like growth factor-1 (IGF-1) can trigger tumorigenesis and metastasis. 23 The insulin/IGF system is a multifactorial signaling cascade that regulates cell proliferation, differentiation, apoptosis, glucose transport and energy metabolism.…”