Cargando…
Hyperglycemia Promotes K-Ras-Induced Lung Tumorigenesis through BASCs Amplification
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 NSC...
Autores principales: | , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2014
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4140809/ https://www.ncbi.nlm.nih.gov/pubmed/25144301 http://dx.doi.org/10.1371/journal.pone.0105550 |
_version_ | 1782331568778379264 |
---|---|
author | Micucci, Carla Orciari, Silvia Catalano, Alfonso |
author_facet | Micucci, Carla Orciari, Silvia Catalano, Alfonso |
author_sort | Micucci, Carla |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-4140809 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2014 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-41408092014-08-25 Hyperglycemia Promotes K-Ras-Induced Lung Tumorigenesis through BASCs Amplification Micucci, Carla Orciari, Silvia Catalano, Alfonso PLoS One Research Article 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. Public Library of Science 2014-08-21 /pmc/articles/PMC4140809/ /pubmed/25144301 http://dx.doi.org/10.1371/journal.pone.0105550 Text en © 2014 Micucci et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited. |
spellingShingle | Research Article Micucci, Carla Orciari, Silvia Catalano, Alfonso Hyperglycemia Promotes K-Ras-Induced Lung Tumorigenesis through BASCs Amplification |
title | Hyperglycemia Promotes K-Ras-Induced Lung Tumorigenesis through BASCs Amplification |
title_full | Hyperglycemia Promotes K-Ras-Induced Lung Tumorigenesis through BASCs Amplification |
title_fullStr | Hyperglycemia Promotes K-Ras-Induced Lung Tumorigenesis through BASCs Amplification |
title_full_unstemmed | Hyperglycemia Promotes K-Ras-Induced Lung Tumorigenesis through BASCs Amplification |
title_short | Hyperglycemia Promotes K-Ras-Induced Lung Tumorigenesis through BASCs Amplification |
title_sort | hyperglycemia promotes k-ras-induced lung tumorigenesis through bascs amplification |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4140809/ https://www.ncbi.nlm.nih.gov/pubmed/25144301 http://dx.doi.org/10.1371/journal.pone.0105550 |
work_keys_str_mv | AT micuccicarla hyperglycemiapromoteskrasinducedlungtumorigenesisthroughbascsamplification AT orciarisilvia hyperglycemiapromoteskrasinducedlungtumorigenesisthroughbascsamplification AT catalanoalfonso hyperglycemiapromoteskrasinducedlungtumorigenesisthroughbascsamplification |