Abstract IA-13: Mechanisms regulating anchorage independent survival

Abstract

Abstract One of the earliest recognized features of tumor cells in culture is their ability to proliferate and survive without attachment to extracellular matrix. This ‘anchorage independence’ of tumor cells distinguishes their behavior from normal cells and is believed to be important to allow tumor cells to proliferate outside of their natural niches during early stages of tumor formation as well as during invasion and metastasis. My presentation will focus on findings from our laboratory on the mechanisms responsible for death of cells deprived of matrix and how oncogenes and other factors promote anchorage independence. We have found that three distinct death processes — apoptosis, metabolic impairment, and a novel non-apoptotic mechanism, referred to as entosis, involving invasion of one cell within another and lysosomal degradation — contribute to death of cells deprived of their appropriate matrix. The major topic of my presentation will be new unpublished findings on metabolic pathways that are regulated by matrix attachment. We have found that detachment of mammary epithelial cells from ECM causes an ATP deficiency due to loss of glucose transport. Overexpression of ErbB2 rescues the ATP deficiency by restoring glucose uptake through PI(3)K activation. Interestingly, we found that the ATP deficiency could also be rescued by antioxidant treatment without rescue of glucose uptake. This restoration was found to be dependent on stimulation of fatty acid oxidation (FAO), which is inhibited by detachment-induced reactive oxygen species (ROS). The significance of these findings was supported by studies in 3D acinar cultures and anchorage-independent colony formation. These results reveal both the importance of matrix attachment in regulating metabolic activity and an unanticipated mechanism for cell survival in altered matrix environments through antioxidant restoration of ATP generation. Citation Information: Cancer Res 2009;69(23 Suppl):IA-13.