Model for human tumor sngiogenesis using NOD/SCID mice

血管生成是癌症的关键事件。我们通过将人骨和人乳腺癌（MB-231）或神经母细胞瘤（SK-N-DZ）细胞移植到NOD/SCID小鼠的皮下组织中来检查人肿瘤血管生成。用抗人CD 31和CD 34抗体通过免疫组织化学染色观察人血管。结果，在所有移植的人癌组织中观察到人肿瘤血管生成。将含有Tek/Tie-2或Flt-1-细胞外结构域和人免疫球蛋白Fc结构域的表达载体（Tek-Fc或Flt-Fc）转移到MB-231或SK-N-DZ细胞中。将具有Tek-Fc、Flt-Fc或neor的克隆接种到人骨移植的NOD/SCID小鼠中。结果，不仅由Flt-Fc克隆而且由Tek-Fc克隆形成的肿瘤比由neor克隆形成的肿瘤小。与neor克隆的肿瘤相比，Flt-Fc克隆的肿瘤中的肿瘤血管密度显著降低。另一方面，在Tek-Fc克隆的肿瘤中观察到肿瘤血管畸形和血管密度降低。血液系统恶性肿瘤的血管生成是否是肿瘤发生发展的必要条件尚不清楚。我们通过将人白血病/淋巴瘤或骨髓瘤细胞接种到移植的人骨中来检查是否在这些肿瘤中产生人肿瘤血管生成。结果，白血病或骨髓瘤细胞肿瘤中的微血管由表达人CD 31和CD 34的人内皮细胞形成。肿瘤的微血管密度明显高于不含白血病或骨髓瘤细胞的移植骨（P<0.01）。通过将人骨和人癌细胞移植到NOD/SCID小鼠体内，建立了人肿瘤血管生成的体内模型。这些模型可能有助于开发新的癌症治疗方法。

Angiogenesis is a crucial event for cancer. We examined human tumor angiogenesis using transplantation of human bone and human breast carcinoma (MB-231) or neuroblastoma (SK-N-DZ) cells into subcutaneous tissue of NOD/SCID mice. Human vessels were observed by immunohistochemical stainings with anti-human CD31 and CD34 antibodies. As a result, human tumor angiogenesis was observed in all transplanted human cancer tissues. Expression vectors (Tek-Fc or Flt-Fc) containing Tek/Tie-2 or Flt-1-extracellular domain and human immunoglobulin Fc domain were transferred into MB-231 or SK-N-DZ cells. Clones with Tek-Fc, Flt-Fc, or neor were inoculated into human bone transplanted-NOD/SCID mice. As a result, tumors which formed by not only the Flt-Fc clones but also the Tek-Fc clones were smaller than tumors formed by neor clones. The tumor vessel density in the tumors of Flt-Fc clones was significantly decreased compared with the tumors of neor clones. In the other hand, the deformity of tumor vessels and the decreased density of vessel were observed in the tumors of Tek-Fc clones. It is obscure whether tumor angiogenesis in hematological malignancies is essential for the tumor development. We examined whether human tumor angiogenesis was generated in these tumors by the inoculation of human leukemia/lymphoma or myeloma cells into the transplanted human bone. As a result, the microvessels in tumors of the leukemia or myeloma cells were formed by human endothelia, which expressed human CD31 and CD34. The microvessel density of the tumors was significantly higher than one of the transplanted human bones without leukemic or myeloma cells (p<0.01). The in vivo models for human tumor angiogenesis were established using the transplantation of human bone and human cancer cells into NOD/SCID mice. These models may be useful for the development of new cancer therapies.