The ability of cancer cells to survive in the absence of normal matrix is critical for tumor progression and metastasis. Normal (non-tumorigenic) cells that detach from the extracellular matrix (ECM) undergo caspase-dependent death (known as anoikis), a phenomenon that is frequently defective in cancer cells, thereby contributing to tumor progression. Interestingly, recent studies have revealed that inhibiting anoikis is not sufficient to allow for cell survival in abnormal matrix environments, as detached cells can die by an alternative death pathway. Preliminary work from our laboratory and correlative studies by other groups suggest that alterations in cellular metabolism may underlie the induction of this alternative death pathway in the absence of normal matrix and that oncogenes can modulate cellular metabolism to protect from non- apoptotic death. Thus, the modulation of cellular metabolism to induce non-apoptotic cell death in tumor cells may be a useful and important chemotherapeutic strategy. Therefore, we propose the following specific aims to address the role of metabolic changes in anchorage-independent survival. I. To analyze the basis for low metabolic activity in cells that have detached from the extracellular matrix. II. To understand how oncogenes rescue metabolic defects in cells that detach from the extracellular matrix. III. To characterize the importance of oncogene-mediated modifications in metabolism on tumor progression. Relevance One of the many things that differentiates cancer cells from normal cells is their inability to commit """"""""cellular suicide"""""""" (known as apoptosis) when they migrate to an inappropriate environment. Recently, it has been discovered that cancer cells must also avoid an alternative form of cell death (distinct from apoptosis) in order to survive outside of their normal environment, and this death seems to be dependent on the way cancer cells process nutrients. Therefore, an understanding of how cancer cells process nutrients outside of their normal environment will provide valuable information that may identify novel ways to kill cancer cells that have inappropriately left their environments through the induction of this alternative form of cell death. ? ? ?
| Schafer, Zachary T; Brugge, Joan S (2007) IL-6 involvement in epithelial cancers. J Clin Invest 117:3660-3 |
