Beyond molecular tumor heterogeneity: protein synthesis takes control

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

The microenvironment has a key role in selecting the bestadapted cancer clone and can alter communication networks between different cancer cell types. The aberrant information flow in cancer cells leads to alterations in gene regulatory networks that support the cancer hallmarks [73] and can be influenced by features such as cytokines, exosomes, hypoxia, starvation, and oxidative stress (Fig. 5) . In this Fig. 4 a-d Low-grade lung adenocarcinoma (×400). e-h High-grade lung squamous carcinoma (×200). Immunohistochemistry for p-ERK1/2 (a, e), p-S6 (b, f), p-4E-BP1 (c, g), and p-eIF4E (d, h). Immunohistochemistry was performed as described previously [58] respect, modulating the translational program is thought to ensure the expression of factors, which confer resistance to cellular stress [74] (Fig. 3) . In most malignant cells, the capdependent pathway is highly upregulated and interference with this translational program has been shown to be an attractive venue for novel therapeutics that ultimately prevent the adaptation of tumor cells to stress conditions. The main therapeutic approaches targeting the 5′ cap-dependent translational machinery (summarized in ref. [33] ) are directed against, the expression of eIF4E [75, 76] , the interaction between eIF4E-4G [77, 78] , the binding of eIF4F complex to the 5′-cap structure [79, 80] , the eIF4A helicase activity [81] [82] [83] [84] , the phosphorylation status of eIF2α [85, 86] , and the kinase activity of MNK1/2 [87] [88] [89] [90] [91] . Among the different strategies that prevent 5′ capdependent translation under stress conditions, it is believed that inhibition of MNKs may be a powerful way to increase the efficacy of other anti-tumor agents, as phosphorylation of its downstream target eIF4E has been shown to confer resistance to cellular stress, genomic damage, lack of nutrients, and oxidative stress (Fig. 5) [92, 93] . In fact, several companies are developing inhibitors of MNK1/2 activity [94] , and at least one of them (eFT508) is already being studied in a clinical phase II trial. Impressive data 4E-BP1 is an independent prognostic factor and is associated a poor response to endocrine therapy Karlsson et al. [98] eIF4E predicts survival after anthracycline chemotherapy in breast cancer patients Heikkinen et al. [99] eIF4E expression is related to breast cancer survival and it is modulated by 4E-BP1 Coleman et al. [100] p-4E-BP1 correlates with grade and prognosis in breast cancer Rojo et al. [60] High eIF4E is an independent predictor of recurrence in breast cancer. Li et al. [101] Cervix Overexpression of p-4E-BP1 predicts recurrence and reduced survival in cervical carcinoma Benavente et al. [55] CNS p-eIF4E is an independent prognostic factor in astrocytoma Martínez-Saez et al. [58] p-4E-BP1 expression increase with tumor grade and predicts survival in astrocytomas Korkolopoulou et al. [102] Colon High 4E-BP1 expression is associated with poor prognosis Chen et al. [103] High expression of eIF4E is associated with advanced stage and poor prognosis Chao et al. [61] Endometrium p-4E-BP1 is associated with high-grade endometrial carcinomas and worse prognosis Castellvi et al. [57] p-4E-BP1 is associated with stage and high-grade tumors Darb-Esfahani et al. [104] Esophagus p-4E-BP1 expression after chemoradiotherapy is a predictor for recurrence and worse survival in esophageal carcinoma