Obesity and Diabetes: The Increased Risk of Cancer and Cancer-Related Mortality

Gallagher, Emily J.

doi:10.1152/physrev.00030.2014

Cited by 632 publications

(501 citation statements)

References 216 publications

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“…Inflammation Interleukin-6 (IL-6) [1], [8] Many cell types such as immune cells, fibroblasts, and endothelial cells There is a complex relationship between IGF-1 and obesity or obesity-related diseases [16], [17], [18]. However, regarding the pathogenesis of obesity-related cancers, a plausible explanation has been proposed [18], [19], [20].…”

Section: Chiefly Produced By Receptor Functionmentioning

confidence: 99%

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Tumor-linked HER2 expression: association with obesity and lipid-related microenvironment

Ray

2017

Hormone Molecular Biology and Clinical Investigation

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Abstract:Obesity is associated with the risk of several health disorders including certain cancers. Among obesity-related cancers, postmenopausal breast carcinoma is a well-studied one. Apart from an increase in certain types of lipids in obesity, excess adipose tissue releases many hormone-like cytokines/adipokines, which are usually pro-inflammatory in nature. Leptin is one of such adipokines and significantly linked with the intracellular signaling pathways of other growth factors such as insulin-like growth factor-1 (IGF-1), vascular endothelial growth factor (VEGF), human epidermal growth factor receptor 2 (HER2). In general, HER2 is overexpressed in roughly 30% of breast carcinomas; its presence indicates aggressive tumor behavior. Conversely, HER2 has certain effects in normal conditions such as differentiation of preadipocytes, cardiovascular health and vitamin D metabolism. HER2 has no known endogenous ligand, but it may form dimers with other three members of the epidermal growth factor receptor (EGFR) family and can activate downstream signaling pathways. Furthermore, HER2 is intimately connected with several enzymes, e.g. fatty acid synthase (FASN), phosphatidylinositol 3-kinase (PI3K), AKT and mechanistic target of rapamycin (mTOR), all of which play significant regulatory roles in lipogenic pathways or lipid metabolism. In obesity-related carcinogenesis, characteristics like insulin resistance and elevated IGF-1 are commonly observed. Both IGF-1 and leptin can modulate EGFR and HER2 signaling pathways. Although clinical studies have shown mixed results, the behavior of HER2+ tumor cells including HER2 levels can be altered by several factors such as obesity, leptin and fatty acids. A precise knowledge is useful in new therapeutic approaches against HER+ tumors.

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Section: Chiefly Produced By Receptor Functionmentioning

confidence: 99%

“…However, regarding the pathogenesis of obesity-related cancers, a plausible explanation has been proposed [18], [19], [20]. The inflammatory situation in obesity perhaps creates a state of insulin resistance where cells cannot utilize glucose appropriately due to the defective response to insulin.…”

Section: Chiefly Produced By Receptor Functionmentioning

confidence: 99%

Tumor-linked HER2 expression: association with obesity and lipid-related microenvironment

Ray

2017

Hormone Molecular Biology and Clinical Investigation

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“…Insulin resistance appears to play a central role in endometrial carcinogenesis. Therefore, treatment with insulin-sensitizing agents that act through reducing insulin levels could offer a general approach to prevent the development of cancer and reduce metastasis (10,11).…”

Section: Introductionmentioning

confidence: 99%

Proliferation and metastatic potential of endometrial cancer cells in response to metformin treatment in a high versus normal glucose environment

et al. 2016

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Abstract. In order to improve our understanding of the potential preventive and therapeutic role of metformin, the present study aimed to investigate the capability of low-dose metformin in the efficient inhibition of cancer development and the reduction of the metastasis of endometrial adenocarcinoma type I and primary endometrial epithelial cells (eEPs), with the drug acting as a treatment in a hyperinsulinemic environment exposed to high and normal glucose conditions. The Ishikawa endometrial adenocarcinoma cell line and primary eEPs were exposed to an environment with high (17 mM) or normal glucose (5 mM) and treated with insulin, low-dose metformin (0.1 mM) or a combined treatment. Metastatic potential was assessed by migration and invasion assays, and relative cell proliferation was determined. Metformin at a low dose potently inhibited the insulin action, decreasing the ability of the endometrial cancer (EC) cell line to migrate and invade in a high and normal glucose environment, and decreasing the migration ability of the primary eEPs. In the EC cell line, the insulin treatment increased the proliferation, without any subsequent reduction of proliferation by the addition of 0.1 mM metformin; however, relative cell proliferation sensitivity to metformin was observed in the range between 1 and 5 mM regardless of the glucose concentration present. Overall, metformin at 0.1 mM is not efficient enough to decrease the proliferation in an EC cell line. However, at this concentration, metformin can inhibit the insulin action in endometrial epithelial cancer cells, demonstrating an anti-metastatic effect in high and normal glucose environments.

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“…Although hyperinsulinemia, hyperglycemia and chronic inflammation may be significant mechanisms in the neoplastic process of a number of types of cancer, the carcinogenic mechanisms induced by DM in NETs remain to be elucidated (23). A Taiwanese population-based study revealed that diabetes was associated with a significantly higher risk of lung cancer (24).…”

Section: Discussionmentioning

confidence: 99%

Metformin use and young age lung cancer: A case series report

et al. 2016

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Abstract. Metformin, a widely-prescribed antihyperglycemic drug for the treatment of diabetes mellitus type 2 (DM-II), has been demonstrated to be antineoplastic in vivo and in vitro. However, various preclinical and epidemiological studies investigating the effects of metformin on lung cancer have obtained inconclusive results. The aim of the present study was to retrospectively investigate the effects of metformin, for the treatment of diabetes mellitus type 2 (DM-II), on the onset of lung cancer. In the present study, the pathological features of ten consecutive young age lung cancer cases, aged between 15 and 45 years old at the time of diagnosis and exhibiting existing primary DM, were investigated using the Mayo Clinic Lung Cancer Cohort database. Amongst this cohort, there were 2 cases of DM type 1 (DM-I) and 8 cases of DM-II. Of these patients, two exhibiting adenocarcinoma and DM-II had not been administered metformin; however, 1 patient exhibiting lymphoma and 4 patients with pulmonary neuroendocrine tumors (NETs) had been administered metformin at least 12 months prior to lung cancer diagnosis. The remaining 3 patients exhibiting NETs and DM-II had been treated with insulin therapy. The present study hypothesized that the high proportion of NETs observed in the cases of metformin-treated DM-II was unlikely to be a random event. It was suggested that metformin treatment was not effective in the prevention of pulmonary NETs, and that metformin may instead induce the occurrence of NETs via as yet unknown signaling pathways. The present hypothesis may potentially serve as a novel indicator for the requirement to monitor young patients with diabetes, who are being treated with metformin, for the occurrence of pulmonary NETs.

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Obesity and Diabetes: The Increased Risk of Cancer and Cancer-Related Mortality

Cited by 632 publications

References 216 publications

Tumor-linked HER2 expression: association with obesity and lipid-related microenvironment

Tumor-linked HER2 expression: association with obesity and lipid-related microenvironment

Proliferation and metastatic potential of endometrial cancer cells in response to metformin treatment in a high versus normal glucose environment

Metformin use and young age lung cancer: A case series report

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