Abstract
Lung cancer is the cause of most cancer-related deaths in the Western world. Non-small cell lung cancer accounts for almost 80% of all lung cancers, and 50% of this type are adenocarcinomas. The cellular and molecular origin of this type of lung cancer remains elusive and the mechanisms are poorly known. It is known that K-Ras mutations appear in 25–30% of lung adenocarcinomas and it is the best known single mutation that can be related to lung cancers. Recently, it has been suggested that a putative population of mouse bronchioalveolar stem cells could be considered as the cell of origin of adenocarcinomas. These cells are expanded in the early stages of lung tumorigenesis. We have isolated a population of mouse bronchioalveolar stem cells and induced their transformation by oncogenic K-RasG12. Different approaches have shown that an intracellular network linking the p38α MAPK and the PI3K-Pdk1 pathways is involved in regulating the survival and malignant progression of the transformed cells. Absence of p38α catalytic activity leads to further Pdk1 activation (independent of Akt and Erk activity), enhancing the survival and proliferation of the more malignant lung cancer cells. This specifically selects high Sca-1/Sox9 cells that harbour a stronger colonizing potential, as they maintain their capacity to produce secondary tumors after serial transplantations.
Highlights
Lung cancer is the main cause of all cancer deaths in the world [1]
To further study the progression of lung cancer and define the mediators of that repressive role by p38a, we have isolated putative stem cells from mouse lungs with a specific expression profile (Sca-1+/E-Cadherin+/CD312/CD342/CD452/CD732). These cells can be indefinitely expanded in culture and transformed by expression of a K-RasG12 mutant. In this manuscript we have studied, in vitro and in vivo, the process of transformation of the lung stem cells and the mechanisms involved in the selection of tumour cells with low levels of p38a, and the functional advantages that low p38 activity provides to the progression of lung cancer to more malignant stages
Loss of differentiation markers and morphology are some of the hallmarks of lung cancer development [11]
Summary
After many years of research, very little is known about the cellular and molecular mechanisms involved in this type of cancer. The existence of a population of lung cells that could be the source of the major types of lung cancers has been studied in recent years, but still remains elusive and very controversial. Different studies in animal models have suggested the existence of a population of bronchioalveolar stem cells that could act as the cell of origin [3,4]. These cells are expanded in the first stages of lung tumorigenesis induced by oncogenes. The mechanisms that promote these cells to transformation, and their progression to malignant stages are still poorly understood [5]
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