Abstract
Background and Aim: Multiple myeloma (MM) is characterized by a clonal proliferation of abnormal plasma cells in bone marrow. Angiogenesis is required by tumor cells to survive, proliferate and metastasize but its role in hematologic malignancies is limited. Central to the angiogenic cascade are endothelial specific receptor tyrosine kinases (RTKs) and their respective ligands such as Angiopoietins and VEGF. Angiogenic factors are known to regulate matrix proteins in solid tumors. It may be possible that these factors function via up‐regulation of ECM proteins such as integrins, laminins and plasminogen activator. Extracellular matrix (ECM) proteins are involved in invasion of myelomic cells to bone marrow microenvironment. The urokinase‐type plasminogen activator (uPA) system and laminin are involved in cell migration, tissue remodeling, angiogenesis and cell adhesion. Angiopoietins (Ang) and their association with ECM proteins which may provide an alternative pathway in angiogenesis and myeloma growth have not been well studied in MM. Therefore, the aim of this study was to investigate the expression of angiogenic factors (Ang‐1, Ang‐2, and VEGF) along with ECM proteins (uPA, Laminin) at the circulatory as well as cellular level and their correlation with the pathogenesis of Multiple Myeloma.
Methods: Fifty patients of MM (Grade II: 33, Grade III: 17) and fifty healthy controls were enrolled. All the patients included were newly diagnosed and staged according to International system of staging, rely on β2 microglobulin levels. The circulatory levels of angiogenic factors (Ang‐1, Ang‐2, and VEGF) and Laminin were measured by commercially available ELISA kits. uPA activity was measured by activity assay kit. The mRNA expression of angiogenic factors and ECM proteins in the Peripheral blood mononuclear cells (PBMC) were further detected by RT‐PCR. The data were analyzed statistically.
Results: The statistical significant (p < 0.001) increase was observed in Ang‐2, VEGF, uPA and laminin levels and found to be significantly correlated with each other, in MM patients. Increased mRNA expression for VEGF, Ang‐2, uPA and laminin has also been observed in the isolated PBMC by RT‐PCR. No significant change was found for Ang‐1 levels at the circulatory and cellular level.
Conclusion: Elevated expression of Ang‐2 and VEGF suggest their involvement in the process of angiogenesis in MM as they both are involved in vessel sprouting and neovessel formation. Increased expression of laminin and plasminogen activator might facilitate the myeloma plasma cells to interact with the bone marrow microenvironment and influence important biological events such as bone matrix degradation, plasma cell invasion and homing. Hence this study suggests that Angiopoietins, VEGF signaling as well as ECM proteins might contribute to the complicated and unregulated process of angiogenesis in MM. Such a study might facilitate the therapies to prevent MM by targeting not only the tumor cell but also the bone marrow microenvironment.
Citation Information: Cancer Prev Res 2010;3(1 Suppl):B43.
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