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The double trouble of metabolic diseases: the diabetes-cancer link.

ABSTRACT: The recent recognition of the clinical association between type 2 diabetes (T2D) and several types of human cancer has been further highlighted by reports of antidiabetic drugs treating or promoting cancer. At the cellular level, a plethora of molecules operating within distinct signaling pathways suggests cross-talk between the multiple pathways at the interface of the diabetes-cancer link. Additionally, a growing body of emerging evidence implicates homeostatic pathways that may become imbalanced during the pathogenesis of T2D or cancer or that become chronically deregulated by prolonged drug administration, leading to the development of cancer in diabetes and vice versa. This notion underscores the importance of combining clinical and basic mechanistic studies not only to unravel mechanisms of disease development but also to understand mechanisms of drug action. In turn, this may help the development of personalized strategies in which drug doses and administration durations are tailored to individual cases at different stages of the disease progression to achieve more efficacious treatments that undermine the diabetes-cancer association.

SUBMITTER: Tudzarova S

PROVIDER: S-EPMC4569306 | biostudies-literature | 2015 Sep

REPOSITORIES: biostudies-literature

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The double trouble of metabolic diseases: the diabetes-cancer link.

Tudzarova Slavica S Osman Mahasin A MA

Molecular biology of the cell 20150901 18

The recent recognition of the clinical association between type 2 diabetes (T2D) and several types of human cancer has been further highlighted by reports of antidiabetic drugs treating or promoting cancer. At the cellular level, a plethora of molecules operating within distinct signaling pathways suggests cross-talk between the multiple pathways at the interface of the diabetes-cancer link. Additionally, a growing body of emerging evidence implicates homeostatic pathways that may become imbalan ...[more]

PMID: 26371080

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Project description:Epidemiological studies have revealed concurrence of specific cancers with other disease states such as metabolic syndrome, inflammatory disease and autoimmune disease. Patients with these chronic conditions have a higher incidence of various cancers, more aggressive tumors, and a higher mortality rate. It has been proposed that obesity, inflammation and chronic disease should be correlated with cancer at the molecular level, but common gene signatures or networks have yet to be described. Here, we identify genes regulated during the process of cellular transformation in both a breast epithelial cell line and a set of isogenic fibroblastic cell lines. The resulting gene signature strongly mimics those of many different cancer types, thereby validating these experimental systems as models of oncogenesis. Furthermore, it uncovers transcriptional factors and common gene regulatory networks linking cancer with other disease states such as atheroscelorsis, type II diabetes, obesity, lupus, and cardiomyopathy. We suggest that this common transcriptional program can contribute to the concurrence of different diseases, and that the interplay between this program and cell-type specific factors can give rise to a variety of human diseases. Two isogenic cell lines were used to model transformation. The first employed an inducible oncogene: src fused to the ligand binding domain of the estrogen receptor. ER-src and pBABE control cells were dosed with Tamoxifen or Etoh control across several time points to monitor gene expression during transformation. The other model consists of three isogenic cell lines derived from primary fibroblasts in a serial manner. The first is immortalized by overexpression of telomerase (hTERT), and exhibits normal fibroblast morphology. The second expresses hTERT along with both large and small T antigens of Simian virus 40, and it displays an altered morphology but is not transformed. The third cell line expresses hTERT, T antigens, and an oncogenic derivative of Ras (H-RasV12); it is morphologically transformed and has tumorigenic potential in soft agar and nude mice. Thus, three stages of transformation are represented by these cells.

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The double trouble of metabolic diseases: the diabetes-cancer link.

Publications

The double trouble of metabolic diseases: the diabetes-cancer link.

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