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Genes and Proteins of Myeloma Endothelial Cells to Search Specific Targets of the Tumor Vasculature

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Advances in Biology and Therapy of Multiple Myeloma

Abstract

Multiple myeloma (MM) mainly progresses in the bone marrow (BM). Therefore signals from BM microenvironment are thought to play a critical role in maintaining plasma cell growth, migration, and survival. Reciprocal positive and negative interactions between plasma cells and BM stromal cells, namely endothelial cells (ECs), ECs progenitor cells, hematopoietic stem cells, osteoblasts/osteoclasts, chondroclasts, fibroblasts, macrophages, and mast cells, are mediated by an array of cytokines, receptors, and adhesion molecules. BM neovascularization is a constant hallmark of MM, and goes hand in hand with progression until leukemic phase. MM neovessels form through angiogenesis and vasculogenesis, and are endowed with the overangiogenic phenotype of ECs (MMECs). Induction of the vascular phase in MM is sustained by angiogenic cytokines, such as vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), hepatocyte growth factor (HGF), platelet derived growth factor (PDGF) and metalloproteinases, secreted by the BM plasma cells, and overexpressed in MMECs. BM microenvironmental factors induce MMECs to become functionally different from MGUS ECs (MGECs), i.e., to be characterized by an overangiogenic phenotype, and be similar to transformed cells. In fact, MMECs down- or up-regulate some genes like tumor cells. The induced phenotypic and genotypic modifications of MMECs entail at least 22 different genes that are ivolved in specific pathways which control apoptosis, extracellular matrix formation and bone remodeling, cell adhesion, angiogenesis, and cell proliferation. These alterations play an important role in MM progression and may represent new molecular markers for prognostic stratification of patients and prediction of the response to antiangiogenic drugs as well as new potential therapeutic targets.

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Acknowledgments

This work was supported by Associazione Italiana per la Ricerca sul Cancro AIRC (National and Regional Funds) Milan, Fondazione Italiana per la Lotta al Neuroblastoma, Genoa, MIUR – FIRB 2001, PRIN 2005, and PRIN 2007, Rome, and Fondazione Cassa di Risparmio di Puglia, Bari, Italy. European Union Seventh Framework Programme (FPT7/2007–2013) under grant agreement n° 278570 to DR and n° 278706 to AV.

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Authors and Affiliations

  1. Department of Basic Medical Sciences, Section of Human Anatomy and Histology, University of Bari Medical School, Policlinico – Piazza Giulio Cesare, 11, I-70124, Bari, Italy

    Domenico Ribatti M.D.

  2. Department of Internal Medicine and Clinical Oncology, University of Bari Medical School, Policlinico – Piazza Giulio Cesare, 11, I-70124, Bari, Italy

    Angelo Vacca M.D.

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  1. Domenico Ribatti M.D.
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Correspondence to Angelo Vacca M.D. .

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  1. Dana-Farber Cancer Institute, Harvard Medical School, Binney St. 44 44, Boston, 02115, Massachusetts, USA

    Nikhil C. Munshi

  2. Dana-Farber Cancer Institute, Dept. Medical Oncology, Harvard Medical School, Binney St. 44, Boston, 02115, Massachusetts, USA

    Kenneth C. Anderson

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Ribatti, D., Vacca, A. (2013). Genes and Proteins of Myeloma Endothelial Cells to Search Specific Targets of the Tumor Vasculature. In: Munshi, N., Anderson, K. (eds) Advances in Biology and Therapy of Multiple Myeloma. Springer, New York, NY. https://doi.org/10.1007/978-1-4614-4666-8_13

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