Tobacco smoke-induced lung inflammation is a risk factor for lung cancer development. Interleukin-1 beta (IL-1) and prostaglandin E2 (PGE2) are two particularly potent inflammation-associated proteins induced by tobacco smoke exposure. We have found that IL-1 and PGE2 operate by increasing levels of a protein called Snail. Snail functions by decreasing levels of E-Cadherin, a protein critical for maintenance of contacts between cells lining the lungs. Without E-Cadherin, cells lining the airways break apart and are able to move around freely in a process known as epithelial-mesenchymal transition (EMT). EMT is often activated during cancer invasion and metastasis. To date, the roles of inflammation, Snail, and EMT in early lung cancer development have not been defined. Our substantial early results indicate that high levels of Snail cause EMT, driving otherwise normal lung cells to invade or move around more freely. Our results also indicate that Snail causes a highly specialized cell type found in the lung, lung stem cells, to proliferate more than they should. Though stem cells are helpful in many settings, in the context of cancer, they almost always have negative implications. We are the first to report the link between lung inflammation and EMT in the setting of early lung cancer development, and we are the first to report the presence of Snail in human lungs at the very earliest stages of lung cancer development. Additionally, our findings linking EMT with stem cell biology in the development of lung cancer are consistent with the “migrating cancer stem cell” concept recently described. The concept suggests that cancer stem cells residing in the lungs become mobile and much more harmful when conditions in the lung cause them to undergo EMT. Because it takes into consideration both the genetic events common to cancer development and the influence of the location where the tumor cells reside, we expect this concept is relevant in the development of lung cancer. In the proposed studies, we will use cells derived from normal lung tissue that we have engineered to produce high levels of Snail, and we will grow the cells in a cell culture model that closely mimics a precancerous condition of the lung called squamous metaplasia. Our findings will be confirmed in human lungs that are about to develop cancers. In these studies, we will investigate genes downstream of Snail that drive mobility and increase the numbers of lung stem cells. We believe that the addition of Snail causes early lung cancer associated lesions to become more aggressive, possibly resulting in frank cancer. We will attempt to reverse this progression and to explain how the process works.
In Specific Aim 1, we will determine how the protein CD44 contributes to increased invasion and increased numbers of lung stem cells caused by high levels of Snail in normal lung tissues. By blocking CD44, we will determine the importance of the protein to the cancer-associated changes caused by Snail. In several proposed studies, we will also attempt to explain how the process works. In Specific Aim 2, we will determine how two specific lung stem cell populations, ALDH+ and CD44+CD24-, contribute to increased numbers of lung stem cells caused by high levels of Snail in normal lung tissues. By removing the two stem cell populations identified as most problematic, we will determine the importance of those populations to the cancer-associated changes caused by Snail. In several proposed studies, we will also attempt to explain how the process works.
Understanding the interactions of proteins and cell types involved in the development of lung cancer may provide new opportunities for preventing the disease and/or for detecting it at an early stage when cure is possible. Our novel findings thus far combined with funding for the more detailed studies proposed will allow us to make a significant contribution to the fields of EMT and stem cells, to knowledge about the early events that drive lung cancer development, and to the research mission of the TRDRP. |