A comprehensive biological and clinical perspective can drive a patient-tailored approach to multiple myeloma: Bridging the gaps between the plasma cell and the neoplastic niche

There is a broad spectrum of diseases labeled as multiple myeloma (MM). This is due not only to the composite prognostic risk factors leading to different clinical outcomes and responses to treatments but also to the composite tumor microenvironment that is involved in a vicious cycle with the MM plasma cells. New therapeutic strategies have improved MM patients' chances of survival. Nevertheless, certain patients' subgroups have a particularly unfavorable prognosis. Biological stratification can be subdivided into patient, disease, or therapy-related factors. Alternatively, the biological signature of aggressive disease and dismal therapeutic response can promote a dynamic, comprehensive strategic approach, better tailoring the clinical management of highrisk profiles and refractoriness to therapy and taking into account the role played by the MM milieu. By means of an extensive literature search, we have reviewed the state-of-the-art pathophysiological insights obtained from translational investigations of the MM-bone marrow microenvironment. A good knowledge of the MM niche pathophysiological dissection is crucial to tailor personalized approaches in a bench-bedside fashion. The discussion in this review pinpoints two main aspects that appear fundamental in order to gain novel and definitive results from the biology of MM. A systematic knowledge of the plasma cell disorder, along with greater efforts to face the unmet needs present in MM evolution, promises to open a new therapeutic window looking out onto the plethora of scientific evidence about the myeloma and the bystander cells

The anti-vegf(R) drug discovery legacy: Improving attrition rates by breaking the vicious cycle of angiogenesis in cancer

Resistance to anti-vascular endothelial growth factor (VEGF) molecules causes lack of response and disease recurrence. Acquired resistance develops as a result of genetic/epigenetic changes conferring to the cancer cells a drug resistant phenotype. In addition to tumor cells, tumor endothelial cells also undergo epigenetic modifications involved in resistance to anti-angiogenic therapies. The association of multiple anti-angiogenic molecules or a combination of anti-angiogenic drugs with other treatment regimens have been indicated as alternative therapeutic strategies to overcome resistance to anti-angiogenic therapies. Alternative mechanisms of tumor vasculature, including intussusceptive microvascular growth (IMG), vasculogenic mimicry, and vascular co-option, are involved in resistance to anti-angiogenic therapies. The crosstalk between angiogenesis and immune cells explains the efficacy of combining anti-angiogenic drugs with immune check-point inhibitors. Collectively, in order to increase clinical benefits and overcome resistance to anti-angiogenesis therapies, pan-omics profiling is key

Mammalian tumor xenografts induce neovascularization in zebrafish embryos.

The zebrafish (Danio rerio)/tumor xenograft model represents a powerful new model system in cancer. Here, we describe a novel exploitation of the zebrafish model to investigate tumor angiogenesis, a pivotal step in cancer progression and target for antitumor therapies. Human and murine tumor cell lines that express the angiogenic fibroblast growth factor (FGF) 2 and/or vascular endothelial growth factor (VEGF) induce the rapid formation of a new microvasculature when grafted close to the developing subintestinal vessels of zebrafish embryos at 48 h postfertilization. Instead, no angiogenic response was exerted by related cell clones defective in the production of these angiogenic growth factors. The newly formed blood vessels sprout from the subintestinal plexus of the zebrafish embryo, penetrate the tumor graft, and express the transcripts for the zebrafish orthologues of the early endothelial markers Fli-1, VEGF receptor-2 (VEGFR2/KDR), and VE-cadherin. Accordingly, green fluorescent protein–positive neovessels infiltrate the graft when tumor cells are injected in transgenic VEGFR2:G-RCFP zebrafish embryos that express green fluorescent protein under the control of the VEGFR2/KDR promoter. Systemic exposure of zebrafish embryos immediately after tumor cell injection to prototypic antiangiogenic inhibitors, including the FGF receptor tyrosine kinase inhibitor SU5402 and the VEGFR2/KDR tyrosine kinase inhibitor SU5416, suppresses tumor-induced angiogenesis without affecting normal blood vessel development. Accordingly, VE-cadherin gene inactivation by antisense morpholino oligonucleotide injection inhibits tumor neovascularization without affecting the development of intersegmental and subintestinal vessels. These data show that the zebrafish/ tumor xenograft model represents a novel tool for investigating the neovascularization process exploitable for drug discovery and gene targeting in tumor angiogenesis

Erythropoietin/erythropoietin-receptor system is involved in angiogenesis in human hepatocellular carcinoma

Ribatti D, Marzullo A, Gentile A, Longo V, Nico B, Vacca A & Dammacco F (2007) Histopathology 50, 591–596 Erythropoietin/erythropoietin-receptor system is involved in angiogenesis in human hepatocellular carcinom

Nutraceuticals and their role in tumor angiogenesis

Angiogenesis plays a pivotal role in cancer initiation, maintenance, and progression. Diet may inhibit, retard or reverse these processes affecting angiogenesis (angioprevention). Nutraceuticals, such as omega-3 fatty acids, amino acids, proteins, vitamins, minerals, fibers, and phenolic compounds, improve health benefits as they are a source of bioactive compounds that, among other effects, can regulate angiogenesis. The literature concerning the pro-angiogenic and/or anti-angiogenic nutraceuticals and the possible activated pathways in cancer and other non-neoplastic diseases by in vivo and in vitro experiments are reviewed

AQP4 (aquaporin 4)

Review on AQP4 (aquaporin 4), with data on DNA, on the protein encoded, and where the gene is implicated

Erythropoietin/erythropoietin receptor system is involved in angiogenesis in human neuroblastoma

Ribatti D, Poliani P L, Longo V, Mangieri D, Nico B & Vacca A (2007) Histopathology50, 636–641 Erythropoietin/erythropoietin receptor system is involved in angiogenesis in human neuroblastom

Involvement of vascular endothelial growth factor in schizophrenia

Vascular endothelial growth factor (VEGF), which acts as an angiogenic and neurotrophic factor, is involved the regulation of cerebral blood volume and flow in Schizophrenia (SCZ). Several evidence indicates that modification of brain blood circulation due to alterations in the VEGF system affects cognitive performance and brain function in patients with SCZ. The aim of this study is: 1) To analyze the literature data concerning the role of VEGF in modulating the angiogenic response in SCZ. These data are controversial because some studies found elevated VEGF serum levels of VEGF in patients with SCZ, whereas others demonstrated no significant differences between SCZ patients and controls. 2)To analyze the role of VEGF as a predictive factor on the effects of antipsychotics agents used in the treatment of SCZ. In this context, high VEGF levels, associated to better responses to antipsychotics, might be predictive of the use of first generation antipsycotic drugs, whereas low VEGF levels, expression of resistance to therapy, might be predictive for the use of second generation antipsycotic drugs

Do mast cells help to induce angiogenesis in B-cell non-Hodgkin's lymphomas?

Morphological and morphometric data showing a higher number of mast cells (MCs) in the stroma of B-cell non-Hodgkin's lymphomas (B-NHL) than in benign lymphadenopathies are presented in support of the suggestion that angiogenesis during the progression of B-NHL may be partly mediated by angiogenic factors in their secretory granules

Angiogenesis and Progression in Human Melanoma

In tumor growth, angiogenesis, the process of new-formation of blood vessels from pre-existing ones, is uncontrolled and unlimited in time. The vascular phase is characterized by the new-formation of vascular channels that enhances tumor cell proliferation, local invasion and hematogenous metastasis. Human malignant melanoma is a highly metastatic tumor with poor prognosis, and high resistance to treatment. Parallel with progression, melanoma acquires a rich vascular network, whereas an increasing number of tumor cells express the laminin receptor, which enables their adhesion to the vascular wall, favouring tumor cell extravasation and metastases. Melanoma neovascularization has been correlated with poor prognosis, overall survival, ulceration and increased rate of relapse. Secretion of various angiogenic cytokines, i.e. VEGF-A, FGF-2, PGF-1 and -2, IL-8, and TGF-1 by melanoma cells promote the angiogenic switch and has been correlated to transition from the radial to the vertical growth phase, and to the metastatic phase. Moreover, melanoma cells overexpress αvβ3, αvβ5, α2β1 and α5β1 integrins and release, together with stromal cells, higher amount of metalloproteases that increasing their invasive potential and angiogenesis. Basing on these observations, different molecular targets of antiangiogenic molecules has be recognized and various antiangiogenic agents are currently in preclinical and clinical trials for melanoma