Beyond molecular tumor heterogeneity: protein synthesis takes control

Ramon y Cajal, Santiago; Castellvi, Josep; Hümmer, Stefan; Peg, Vicente; Pelletier, Jerry; Sonenberg, Nahum

Thus, the eIF4E/4E-BP1 node appears to act as a restriction point for essential oncogenic features such as self-sufficiency in growth signals and should serve as a highly relevant molecular marker of malignant potential. Interestingly, the expression of eIF4E and 4E-BP1 and their phosphorylated forms is apparent even in the presence of upstream receptor or kinase overexpression (e.g., AKT, mTOR, or ERK), suggesting that other mechanisms are involved in their regulation. The expression of p-AKT or p-mTOR is highly heterogeneous within a tumor, whereas the expression of 4E-BP1 and eIF4E is more homogeneous (Fig. 3) [22] . This may be due to the activation status of the global growth signaling and proliferative network in being able to maintain a certain flux threshold rather than the necessity of maintaining activity of a specific player. Even in tumors showing constitutive expression of EGFR and HER2, the global gene expression program is not necessarily permanently fixed or homogeneous in all cells. Interestingly, the geographic context of the tumor cell may impinge on the expression levels of these pathways [72] . For example, some markers are more highly expressed at the invasive front or around necrotic areas, suggesting that ischemia or other microenvironmental factors impinge on their expression or activity (Figs. 3 and 5 ).