Abstract
There are only a few experimental studies which have investigated effects of glucose alone, and glucose in combination with insulin/insulin-like growth factors (IGF) on the growth of colon cancer. In the present study, we studied in vitro in human colorectal cancer cells originating from four Dukes’ stages of colorectal cancer the effects of glucose, insulin and IGFs on proliferation, migration, cell cycle progression and gene expression of the IGF system. Growth of colon cancer cells originating from a Dukes’ stage A was glucose-dependent, whereas growth of cancer cells from Dukes’ stage B, C and D was glucose-independent. Stimulatory effects of insulin and IGFs on cell growth were observed only in colon cancer cells originating from Dukes’ stage C and D. IGF-II stimulated migration in Dukes’ stage B cells only. The growth stimulatory effects in Dukes’ stage C and D colorectal cancer cells were accompanied by G2/M arrest and associated with an increased IGF-IR/IGF-II receptor ratio. In conclusion, our in vitro data suggest that the stimulating effects of glucose, IGFs and insulin on proliferation differ between colorectal cancer cells from early and late Dukes’ stages. Stimulatory effects of glucose on proliferation appear predominantly present in stage Dukes’ stage A colorectal cancer cells, while in contrast growth factor-mediated stimulation of cell proliferation is more pronounced in Dukes’ late stage (metastasized) colorectal cancer cells. Moreover, our study suggests that a stringent glucose control may be important to control tumor growth in early stages of colorectal cancer, while inhibition of the endocrine actions of the IGFs and insulin become more important in the late (metastasized) stages of colorectal cancer to restrain growth of colon cancer cells.
Highlights
Colorectal cancer and type 2 diabetes mellitus are main causes of morbidity and mortality worldwide [1,2,3]
At 25 mmol/L a slightly different pattern of cell growth was observed in SW620 cells (Dukes C), and stimulation by insulin-like growth factors (IGF)-II appeared more potent compared to IGF-I (Supplementary Figure 1)
To the best of our knowledge, there are no previous studies which systematically have studied 1] whether cell proliferation, cell cycle progression and migration in cells from different stages of colon cancer are modified by glucose and 2] whether effects of IGF-I, IGF-II and insulin on cell proliferation, cell cycle progression and migration change during different stages of colon cancer
Summary
Colorectal cancer and type 2 diabetes mellitus are main causes of morbidity and mortality worldwide [1,2,3]. Epidemiologic evidence suggests an association between diabetes mellitus and an increased risk of colorectal cancer [4,5,6,7]. Several studies have suggested that hyperinsulinemia and elevated glucose levels increase the risk for colorectal cancer [4, 7,8,9,10,11,12,13,14,15]. Hyperinsulinemia may Glucose, IGFs, Insulin, and Colon Cancer stimulate insulin receptors (IR) and/or insulin-like growth factor receptors (IGFIR/IGFIIR) and thereby induce cell proliferation and suppress apoptosis [16,17,18]. Elevated circulating levels of IGF-I and IGF-II have been associated with an increased risk on colorectal cancer [25, 26]. Overexpression of IGF-II mRNA has been observed in colorectal cancer tumors compared with normal tissue [30]
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