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


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.
Department of Hematology and Medical Oncology, Moffitt Cancer Center, United States.
Jane Jijun
JJ
Liu
Department of Hematology and Medical Oncology, Moffitt Cancer Center, United States.
Mihaela
M
Druta
Department of Gastrointestinal Oncology, Moffitt Cancer Center, United States.
David
D
Shibata
Department of Anatomic Pathology, Moffitt Cancer Center, United States; Experimental Therapeutics, Moffitt Cancer Center, United States.
Domenico
D
Coppola
Senior Adult Oncology Program, Moffitt Cancer Center, United States.
Ivette
I
Boler
Department of Gastrointestinal Oncology, Moffitt Cancer Center, United States.
Abul
A
Elahi
Department of Biostatistics, Moffitt Cancer Center, United States; College of Arts and Sciences, University of South Florida Sarasota-Manatee, United States.
Richard R
RR
Reich
Department of Cancer Prevention and Control, Moffitt Cancer Center, United States.
Erin
E
Siegel
Senior Adult Oncology Program, Moffitt Cancer Center, United States. Electronic address: martine.extermann@moffitt.org.
Martine
M
Extermann
D000368:Aged; D014408:Biomarkers, Tumor / Q000378:metabolism; D015179:Colorectal Neoplasms / Q000098:blood supply / Q000209:etiology* / Q000378:metabolism / Q000601:surgery; D005260:Female; D006801:Humans; D006946:Hyperinsulinism / Q000150:complications* / Q000378:metabolism; D007150:Immunohistochemistry; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D008297:Male; D024821:Metabolic Syndrome / Q000150:complications* / Q000378:metabolism; D008875:Middle Aged; D009389:Neovascularization, Pathologic / Q000209:etiology* / Q000378:metabolism; D011182:Postoperative Care; D011300:Preoperative Care; D011446:Prospective Studies; D000067759:Receptor for Advanced Glycation End Products; D017526:Receptor, IGF Type 1 / Q000378:metabolism; D011972:Receptor, Insulin / Q000378:metabolism; D011971:Receptors, Immunologic / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D042442:Vascular Endothelial Growth Factors / Q000378:metabolism
D014408:Biomarkers, Tumor; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic; D042442:Vascular Endothelial Growth Factors; D007334:Insulin-Like Growth Factor I; D017526:Receptor, IGF Type 1; D011972:Receptor, Insulin
Colorectal cancer; Elderly; Hyperinsulinemia; IGF-1; Insulin receptor; Metabolic syndrome; Tumor vasculature