Establishment of in vivo model for angiogenesis in hematological malignancy and development of anti-angiogenic therapy.

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Angiogenesis plays a critical role in solid tumor development, invasion and metastasis. Recently, a role of angiogenesis in the pathology of leukemia and multiple myeloma has been suggested. The purpose of this work was to generate a model for human leukemia with human angiogenesis and then to study the meaning of angiogenesis in human leukemias. Human cancellous bones, which were irradiated (8 Gy), were transplanted into subcutaneous tissue of NOD/SCID mice (hu-Bone mice). Human microvessels were observed in not only the transplanted bone marrow and bone but also around murine subcutaneous tissues over six months. Human leukemic Raji cells were inoculated into these hu-bone mice. The leukemic cells invaded diffusely into the transplanted human bone marrow within 14 days after innoculation, several days later into murine bone marrow and around the spinal cord. The density of microvessels in human bone narrow with the leukemic infiltration elevated significantly as compared to one of hu … More -bone mice which were inoculated with normal human bone marrow cells or with saline only. The increased density of microvessels associated with leukemic invasion was independent in age or sex of bone donors. The mRNA of vascular endothelial growth factor(VEGF)121,165, angiopoietin-1,2 and angiopoietin-like factor were detected in cultured Raji cells using RT-PCR. Soluble TIE2-Fc chimeric protein inhibited the development of invasion of leukemic cells and angiogenesis. Futhermore the expression of phosphatidylinositol-3 Kinase(p85a) in endothelia of bone marrow which involved with leykemic cells was augmented. The inhibition of p85a signalling resulted impairments of angiogenesis in bone marrow. The gene transfer of dominant negative forms of receptors for Flt-1,FGF and Eph using a tricystronic vector into leukemic cells was done and the alteration of leukamic invasiveness is examined. These observation suggested the angiogenesis in bone marrow by human leukemic infiltration was induced via certain angiogenetic factors produced by leukemic cells. This model for human leukemia with human angiogenesis may be useful for to search novel therapies or to do preclinical tests of drugs. Less