METAZOAN CELLS LACK THE CELL AUTONOMOUS ABILITY TO TAKE UP NUTRIENTS Over the last decade, we have been studying the de- pendency of cells on lineage-specific growth factors. Al- though this paper focuses on hematopoietic cells, addi- tional data suggest that the findings are equally true of neuronal cells, epithelial cells, and fibroblasts. In all of these cells, the lineage-specific receptors that promote cell survival regulate the ability of the cell to express the transporters needed to take up nutrients from the extra- cellular environment. Every cell in the human body has an adequate supply of extracellular nutrients to maintain its survival. However, it appears that the cells in multi- cellular organisms lack the cell-autonomous ability to take up nutrients from the extracellular space. For exam- ple, glucose uptake depends on signal transduction that directs the cell to produce glucose transporters, hexoki- nase, and phosphofructokinase (Vander Heiden et al. 2001). These proteins are required to maintain the supply of glucose utilized by the glycolytic pathway to produce substrates for mitochondrial oxidative phosphorylation. When a cell is deprived of survival signals, the ability of the cell to take up, capture, and metabolize sufficient nu- trients to maintain ATP production disappears. In every cell lineage in which this experiment has been done, after 48–96 hours in the absence of the signal transduction that maintains nutrient uptake and metabolism, the cell initi- ates apoptosis. This apoptotic response depends on the activity of the proapoptotic Bcl-2-related proteins, Bax and Bak (see, e.g., Lindsten et al. 2000). Bcl-2 PROTEINS REGULATE THE DURATION OF CELL SURVIVAL FOLLOWING GROWTH FACTOR WITHDRAWAL The first question we have addressed concerns the role of antiapoptotic Bcl-2 proteins in maintaining cell sur- vival following growth factor withdrawal. Surprisingly, we found that Bcl-2 proteins play no role in regulating nutrient uptake. Cells overexpressing antiapoptotic Bcl-2 family members such as Bcl-2 and Bcl-x L still need sur- vival signal transduction to maintain nutrient trans- porters. For example, interleukin-3 (IL-3)-dependent cells deprived of IL-3 lose the ability to express both glu- cose and amino acid transporters. Despite this, antiapo- ptotic Bcl-2 proteins can keep the cell alive several weeks in the absence of nutrient transporter expression (Rath- mell et al. 2000). Alternative explanations for the decline of nutrient transporters following growth factor withdrawal have been suggested. For example, it could be that the decline in transporters results simply from the cell withdrawing from the cell cycle and no longer requiring a high level of nutrients to support growth. This concept would suggest that changes in nutrient transporter expression are a com- pensatory response to withdrawal from the cell cycle. In this view, survival receptors regulate cell survival through altering the expression/function of Bcl-2 family members. If Bax and Bak are in excess, apoptosis is ini- tiated by cytochrome c release into the cytosol and acti- vation of caspase 9. If Bcl-2 or other antiapoptotic family members dominate, the cell can survive for a long period of time. How Do Cancer Cells Acquire the Fuel Needed to Support Cell Growth? C.B. THOMPSON, D.E. BAUER, J.J. LUM, G. HATZIVASSILIOU, W.-X. ZONG, D. DITSWORTH, F. ZHAO, M. BUZZAI, AND T. LINDSTEN Abramson Family Cancer Research Institute, Department of Cancer Biology and Department of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104 Cold Spring Harbor Symposia on Quantitative Biology, Volume LXX. © 2005 Cold Spring Harbor Laboratory Press 0-87969-773-3. 357 In this paper we consider whether the dependency of metazoan cells on extracellular signals to maintain cell survival results in an important barrier that must be overcome during carcinogenesis. It is now generally accepted that a major barrier to can- cer comes from the inability of cells to enter and progress through the cell cycle in a cell-autonomous fashion. Most of the oncogenes studied over the last two decades contribute to the ability of the cancer cell to enter and progress through the cell cycle in the absence of the instructional signals normally imparted by extracellular growth factors. Over the last two decades, it has begun to be appreciated that there is a second potential barrier to transformation. It appears that all cells in multicellu- lar organisms need extracellular signals not only to initiate proliferation, but also to maintain cell survival. Every cell in our body expresses the proteins necessary to execute its own death by apoptosis. A cell will activate this apoptotic program by default unless it receives signals from the extracellular environment that allow the cell to suppress the apoptotic machinery it expresses. It now appears that the molecular basis of this suppression lies in the signaling pathways that regulate cellular nutrient uptake and direct the metabolic fate of those nutrients.