Hypoxia is a non-physiological level of oxygen tension, a phenomenon common in a majority of malignant tumors. Tumor-hypoxia leads to advanced but dysfunctional vascularization and acquisition of epithelial-to-mesenchymal transition phenotype resulting in cell mobility and metastasis. Hypoxia alters cancer cell metabolism and contributes to therapy resistance by inducing cell quiescence. Hypoxia stimulates a complex cell signaling network in cancer cells, including the HIF, PI3K, MAPK, and NFĸB pathways, which interact with each other causing positive and negative feedback loops and enhancing or diminishing hypoxic effects. This review provides background knowledge on the role of tumor hypoxia and the role of the HIF cell signaling involved in tumor blood vessel formation, metastasis, and development of the resistance to therapy. Better understanding of the role of hypoxia in cancer progression will open new windows for the discovery of new therapeutics targeting hypoxic tumor cells and hypoxic microenvironment.

BM mesenchymal stromal cells (BM-MSCs IntroductionThe BM microenvironment plays a crucial role in multiple myeloma (MM) pathogenesis by supporting plasma cell growth, survival, and drug resistance, which has been partially attributed to the ability of MM BM mesenchymal stromal cells (BM-MSCs) to secrete growth factors and cytokines such as IL-6, IGF-1, VEGF, and many others (1-3). These observations are indicative of paracrine growth circuits between BM-MSCs and clonal plasma cells and vice versa, which suggests that the BM niche provides an optimal substrate for MM cell localization and growth. Nevertheless, little is known about the putative mechanisms by which the BM microenvironment can lead to initiation or progression of oncogenesis in this disease.It was recently reported that cell-cell communication is mediated by exosomes. Exosomes are small nanometer-sized (50-100 nm) vesicles of endocytic origin that are released in the extracellular milieu by several cell types (4-11) under physiological and pathological conditions, including antigen presentation, transmission of infectious agents, and tumors (12, 13). The role of exosomes in tumor progression is due to the ability of tumor cell-derived exosomes to modulate and mold the host microenvironment, thereby promoting tumor cell growth and disease progression (14-17).

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