The ever-evolving role of mTOR in translation.

Control of translation allows for the production of stoichiometric levels of each protein in the cell. Attaining such a level of fine-tuned regulation of protein production requires the coordinated temporal and spatial control of numerous cellular signalling cascades impinging on the various components of the translational machinery. Foremost among these is the mTOR signalling pathway. The mTOR pathway regulates both the initiation and elongation steps of protein synthesis through the phosphorylation of numerous translation factors, while simultaneously ensuring adequate folding of nascent polypeptides through co-translational degradation of misfolded proteins. Perhaps most remarkably, mTOR is also a key regulator of the synthesis of ribosomal proteins and translation factors themselves. Two seminal studies have recently shown in translatome analysis that the mTOR pathway preferentially regulates the translation of mRNAs encoding ribosomal proteins and translation factors. Therefore, the role of the mTOR pathway in the control of protein synthesis extends far beyond immediate translational control. By controlling ribosome production (and ultimately ribosome availability), mTOR is a master long-term controller of protein synthesis. Herein, we review the literature spanning the early discoveries of mTOR on translation to the latest advances in our understanding of how the mTOR pathway controls the synthesis of ribosomal proteins.

Introduction to Brain Tumor Stem Cells.

From stem cells, to the cancer stem cell hypothesis and intratumoral heterogeneity, the following introductory chapter on brain tumor stem cells explores the history of normal and cancerous stem cells, and their implication in the current model of brain tumor development. The origins of stem cells date back to the 1960s, when they were first described as cells capable of self-renewal, extensive proliferation, and differentiation. Since then, many advances have been made and adult stem cells are now known to be present in a very wide variety of tissues. Neural stem cells were subsequently discovered 30 years later, which was shortly followed by the discovery of cancer stem cells in leukemia and in brain tumors over the next decade, effectively enabling a new understanding of cancer. Since then, many markers including CD133, brain cancer stem cells have been implicated in a variety of phenomena including intratumoral heterogeneity on the genomic, cellular, and functional levels, tumor initiation, chemotherapy-resistance, radiation-resistance, and are believed to be ultimately responsible for tumor relapse. Understanding this small and rare population of cells could be the key to solving the great enigma that is cancer.

EMT: Mechanisms and therapeutic implications.

Metastasis, the dissemination of cancer cells from primary tumors, represents a major hurdle in the treatment of cancer. The epithelial-mesenchymal transition (EMT) has been studied in normal mammalian development for decades, and it has been proposed as a critical mechanism during cancer progression and metastasis. EMT is tightly regulated by several internal and external cues that orchestrate the shifting from an epithelial-like phenotype into a mesenchymal phenotype, relying on a delicate balance between these two stages to promote metastatic development. EMT is thought to be induced in a subset of metastatic cancer stem cells (MCSCs), bestowing this population with the ability to spread throughout the body and contributing to therapy resistance. The EMT pathway is of increasing interest as a novel therapeutic avenue in the treatment of cancer, and could be targeted to prevent tumor cell dissemination in early stage patients or to eradicate existing metastatic cells in advanced stages. In this review, we describe the sequence of events and defining mechanisms that take place during EMT, and how these interactions drive cancer cell progression into metastasis. We summarize clinical interventions focused on targeting various aspects of EMT and their contribution to preventing cancer dissemination.