Abstract
Oncogenic K-Ras represents the most common molecular change in human lung adenocarcinomas, the major histologic subtype of non–small cell lung cancer (NSCLC). The presence of K-Ras mutation is associated with a poor prognosis, but no effective treatment strategies are available for K-Ras -mutant NSCLC. Epidemiological studies report higher lung cancer mortality rates in patients with type 2 diabetes. Here, we use a mouse model of K-Ras-mediated lung cancer on a background of chronic hyperglycemia to determine whether elevated circulating glycemic levels could influence oncogenic K-Ras-mediated tumor development. Inducible oncogenic K-Ras mouse model was treated with subtoxic doses of streptozotocin (STZ) to induce chronic hyperglycemia. We observed increased tumor mass and higher grade of malignancy in STZ treated diabetic mice analyzed at 4, 12 and 24 weeks, suggesting that oncogenic K-Ras increased lung tumorigenesis in hyperglycemic condition. This promoting effect is achieved by expansion of tumor-initiating lung bronchio-alveolar stem cells (BASCs) in bronchio-alveolar duct junction, indicating a role of hyperglycemia in the activity of K-Ras-transformed putative lung stem cells. Notably, after oncogene K-Ras activation, BASCs show upregulation of the glucose transporter (Glut1/Slc2a1), considered as an important player of the active control of tumor cell metabolism by oncogenic K-Ras. Our novel findings suggest that anti-hyperglycemic drugs, such as metformin, may act as therapeutic agent to restrict lung neoplasia promotion and progression.
Highlights
Lung cancer is the leading cause of cancer mortality in the United States and worldwide: the 5-year relative survival rate has not been significantly improved during the last 30 years and remained limited to about 15%
K-Ras mutation has been identified in atypical adenomatous hyperplasia (AAH) lesions, which are thought to precede the development of lung adenocarcinoma [3,4]
Taking advantage from the K-RasV12 mouse model, we demonstrate that the hyperglycemic status accelerates tumor formation by bronchio-alveolar stem cells (BASCs) amplification
Summary
Lung cancer is the leading cause of cancer mortality in the United States and worldwide: the 5-year relative survival rate has not been significantly improved during the last 30 years and remained limited to about 15%. A growing body of evidence indicates that K-Ras mutation is important in the initiation of lung adenocarcinoma development. K-Ras mutation has been identified in atypical adenomatous hyperplasia (AAH) lesions, which are thought to precede the development of lung adenocarcinoma [3,4]. Beside the genetic factors, other factors are known to influence the high incidence and mortality of lung cancer. Environmental factors, diabetes, may play a role in development and progression of lung cancer. In a recent study, conducted by the independent academic coordinating center of the Emerging Risk Factors Collaboration (ERFC), the hazard ratio for death in lung cancer was found moderately higher among participants with diabetes compared to those without diabetes [5]
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