Hyperglycemia Promotes K-Ras-Induced Lung Tumorigenesis through BASCs Amplification
Hyperglycemia Promotes K-Ras-Induced Lung Tumorigenesis through BASCs Amplification
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DOI：
10.1371/journal.pone.0105550
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发表时间：
2014-08-21
期刊：
影响因子：
3.7
通讯作者：
Catalano, Alfonso
中科院分区：
文献类型：
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作者：
Micucci, Carla;Orciari, Silvia;Catalano, Alfonso
致癌性K-Ras代表了人肺腺癌中最常见的分子变化，肺腺癌是非小细胞肺癌（NSCLC）的主要组织学亚型。K-Ras突变的存在与不良预后相关，但对于K-Ras突变的NSCLC没有有效的治疗策略。流行病学研究报告2型糖尿病患者的肺癌死亡率较高。在这里，我们使用K-Ras介导的肺癌的小鼠模型在慢性高血糖的背景下，以确定是否升高的循环血糖水平可能会影响致癌K-Ras介导的肿瘤的发展。用亚毒性剂量的链脲佐菌素（STZ）诱导诱导K-Ras致癌小鼠模型，以诱导慢性高血糖。我们观察到STZ治疗的糖尿病小鼠在4周、12周和24周时的肿瘤质量增加和恶性程度更高，这表明致癌K-Ras增加了高血糖条件下的肺肿瘤发生。这种促进作用是通过支气管肺泡管连接处的肿瘤起始肺支气管肺泡干细胞（BASC）的扩增来实现的，表明高血糖在K-Ras转化的推定肺干细胞的活性中的作用。值得注意的是，在致癌基因K-Ras激活后，BASCs显示葡萄糖转运蛋白（Glut 1/Slc 2a 1）的上调，被认为是致癌K-Ras主动控制肿瘤细胞代谢的重要参与者。我们的新发现表明，抗高血糖药物，如二甲双胍，可能作为治疗剂，以限制肺肿瘤的促进和进展。
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.