The mammalian target of rapamycin (mTOR) plays an important role in the regulation of protein translation, cell growth and metabolism. The mTOR protein forms two distinct multi-subunit complexes: mTORC1 and mTORC2. The mTORC1 complex is activated by diverse stimuli, such as growth factors, nutrients, energy and stress signals; and essential signalling pathways, such as PI3K and MAPK, in order to control cell growth, proliferation and survival. mTORC1 also activates S6K1 and 4EBP1, which are involved in mRNA translation. The mTORC2 complex is resistant to rapamycin inhibitory activity and is generally insensitive to nutrient-and energy-dependent signals. It activates PKC-α and Akt and regulates the actin cytoskeleton. Deregulation of the mTOR-signalling pathway (PI3K amplification/mutation, PTEN loss of function, Akt overexpression, and S6K1, 4EBP1 and eIF4E overexpression) is common in cancer, and alterations in components of the mTOR pathway have a major role in tumour progression. Therefore, mTOR is an appealing therapeutic target in many tumours. Here we summarize the upstream regulators and downstream effectors of the mTORC1 and mTORC2 pathways, the role of mTOR in cancer, and the potential therapeutic values and issues related to the novel agents targeting the mTOR-signalling pathway. AbbreviationsDeptor, DEP-domain-containing mTOR-interacting protein; EGFR, epidermal growth factor receptor; eIF4E, translation initiation factor 4E; FKBP12, FK506-binding protein; GSK3, glycogen synthase kinase 3; HIF-1α, hypoxia inducible factor-1α; Hsp70, heat shock protein 70-α; IGFR, insulin-like growth factor receptor; mLST8, mammalian lethal with Sec13 protein8 (also known as GβL); mSIN1, mammalian stress-activated protein kinase-interacting protein 1; mTOR, mammalian target of rapamycin; mTORC1 and mTORC2, mTOR complex 1 and 2; PDK1, 3-phosphoinositidedependent protein kinase-1; PI3K, phosphoinositide 3-kinase; PIP3, phosphatidylinositol (3,4,5)-trisphosphate; PRAS40, proline-rich Akt substrate 40 kDa; PTEN, phosphatase and tensin homologue; Raptor, regulatory-associated protein of mTOR; Rictor, Raptor-independent companion of mTOR; RTK, receptor tyrosine kinase; S6K1, S6 kinase 1; TPdIs, mTOR/PI3K dual inhibitors; TSC1 and TSC2, tuberous sclerosis 1 and 2 complex BJP British Journal of Pharmacology

Angiogenesis is a constant hallmark of multiple myeloma progression and has prognostic potential. Multiple myeloma cells interact with surrounding host cells and extracellular matrix, this crosstalk affecting the most important aspects of the malignant phenotype, both at primary and secondary tumor sites. The pathophysiology of multiple myeloma-induced angiogenesis involves both direct production of angiogenic cytokines by plasma cells and their induction within the bone marrow microenvironment cells. A direct involvement of bone marrow macrophages and mast cells in vasculogenic mimicry has been demonstrated, thus contributing together with circulating endothelial cells and endothelial precursor cells to the multiple myeloma neovascularization. The role of host cells or the niche microenvironment and extracellular matrix represents an intense area of research, finalized at a better understanding of the pathophysiological modifications of the complete tumor entity, i.e. malignant cells and microenvironment.

Tumor microenvironment is essential for multiple myeloma (MM) growth, progression, and drug resistance through provision of survival signals and secretion of growth and proangiogenic factors. This paper examines the importance of macrophages within MM bone marrow (BM) microenvironment, referred to as MM-associated macrophages, as a potential niche component that supports tumor plasma cells. These macrophages are derived from peripheral blood monocytes recruited into the tumor. Upon activation by MM plasma cells and mesenchymal stromal cells, macrophages can release growth factors, proteolytic enzymes, cytokines, and inflammatory mediators that promote plasma cell growth and survival. Macrophages promote tumor progression through several mechanisms including angiogenesis, growth, and drug resistance. Indeed, these macrophages are essential for the induction of an angiogenic response through vasculogenic mimicry, and this ability proceeds in step with progression of the plasma cell tumors. Data suggest that macrophages play an important role in the biology and survival of patients with MM, and they may be a target for the MM antivascular management.

In contrast to the pluripotent embryonic stem cells (ESCs) which are able to give rise to all cell types of the body, mammalian adult stem cells (ASCs) appeared to be more limited in their differentiation potential and to be committed to their tissue of origin. Recently, surprising new findings have contradicted central dogmas of commitment of ASCs by showing their plasticity to differentiate across tissue lineage boundaries, irrespective of classical germ layer designations. The present paper supports the plasticity of the bone marrow stem cells (BMSCs), bringing the most striking and the latest evidences of the transdifferentiation properties of the bone marrow hematopoietic and mesenchymal stem cells (BMHSCs, and BMMSCs), the two BM populations of ASCs better characterized. In addition, we report the possible mechanisms that may explain these events, outlining the clinical importance of these phenomena and the relative problems.