Vasculogenesis in Ewing's Sarcoma: Implications for Therapy

尤文肉瘤的血管发生：对治疗的影响

基本信息

批准号：
7368263
负责人：
Eugenie S Kleinerman
金额：
$ 25.4万
依托单位：
UNIVERSITY OF TX MD ANDERSON CAN CTR
依托单位国家：
美国
项目类别：
财政年份：
2004
资助国家：
美国
起止时间：
2004-07-01 至 2013-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7368263
关键词：
Address Adjuvant Adriamycin PFS Area Arteries Binding Blood Vessels Bone Marrow Bone Marrow Cells Bone Marrow Stem Cell CD34 gene Cell Line Cells Chemotherapy-Oncologic Procedure Combination Chemotherapy Confocal Microscopy Cyclophosphamide Data Depth Development Disease Endothelial Cells Ewings sarcoma Goals Grant Growth Growth and Development function Human Infiltration Investigation Knock-out Laboratories Ligands Localized Lung Membrane Metastatic Neoplasm to the Bone Metastatic Neoplasm to the Lung Modeling Mus Neoplasm Metastasis Neoplasms in Vascular Tissue Numbers Patients Pattern Pericytes Phenotype Play Process Protein Isoforms Protein Overexpression Published Comment Role Sampling Signal Transduction Site Small Interfering RNA Solid Neoplasm Specimen Stem cells Stromal Cell-Derived Factor 1 Survival Rate Technology Therapeutic Transplantation Tumor Biology Tumor Expansion Tumor Tissue VEGF165 VEGF189 Vascular Endothelial Growth Factors Vincristine Week angiogenesis bone cancer type cell motility chemotherapy gene therapy human stem cells improved macrophage migration mouse model neoplastic cell notch protein novel novel therapeutics tumor tumor growth vasculogenesis

项目摘要

DESCRIPTION (provided by applicant): Despite multiple changes in chemotherapy over the past 15-20 years, the 2-year metastasis- free survival for Ewing's sarcoma remains at 40% with a 3-year overall survival of 50%. Understanding the mechanisms that contribute to the growth of Ewing's sarcoma may assist in the development of new therapeutic approaches. We demonstrated that Ewing's tumor cell lines and primary patient tumor specimens overexpress VEGF with a shift from the membrane- bound 189 isoform to the soluble 165 isoform. VEGF165 has been shown to chemoattract stem cells. Using our Ewing's sarcoma nude mouse model in a transplant setting we demonstrated that bone marrow (BM) cells migrate into the tumor, differentiate into endothelial cells and contribute to the formation of the tumor vasculature. We demonstrated that there are 2 distinct patterns of stem cell infiltration and 2 different phenotypes that migrate into the tumor. Murine Sca1+Gr1+ stem cells and human CD34+ cells co-localized to tumor vessels and differentiate into endothelial cells and pericytes. Murine Sca1-Gr1+ and human CD34- cells migrated deep in the tumor tissue away from tumor vessels and differentiated into macrophages. We demonstrated that pericytes and VEGF165 is responsible for the chemoattraction of these stem cells. This activity was not duplicated by VEGF189. Further investigations using VEGF165-siRNA support our hypothesis that these migrated stem cells play an important role in tumor growth and tumor vessel development. Taken together our data indicate that vasculogenesis, in addition to angiogenesis is involved in the expansion of the tumor vasculature contributing to about 10% of the vessels during the first week of tumor growth. We wish to continue investigating the vasculogenesis process, determine the importance of this process in both primary and metastatic tumor growth and investigate the mechanism(s) by which stem cells are attracted to specific tumor vascular areas. We propose to (1) determine whether BM-derived cells are integrated together with local endothelial cells to form tumor vessels and whether this is modified in the absence of VEGF165; (2) determine the importance of vasculogenesis to tumor growth and whether vasculogenesis can restore growth and vessel development in the absence of VEGF165; (3) determine whether NOTCH signaling, in specific DLL4, plays a role in the chemoattraction of stem cells to the Ewing's tumor; (4) determine whether BM stem cells participate in the growth of Ewing's metastases in the lung and bone. Understanding how vasculogenesis contributes to the growth and metastasis of Ewing's sarcoma and ascertaining the chemotactic signals involved in this process may open up new therapeutic approaches to treat patients with this disease. This application will investigate how bone marrow (BM) stem cells contribute to the vasculature expansion that supports the growth of Ewing's sarcoma and the mechanisms that control the migration of BM cells into the tumor. We will also determine whether BM stem cells contribute to the growth of Ewing's metastases in the lung and bone. The survival rates for Ewing's sarcoma have not improved for >20 years. Understanding how tumor vessels are formed may identify new therapeutic approaches for this type of cancer.

描述（由申请人提供）：尽管在过去 15-20 年中化疗发生了多次变化，尤文氏肉瘤的 2 年无转移生存率仍保持在 40%，3 年总生存率为 50%。了解导致尤文氏肉瘤生长的机制可能有助于开发新的治疗方法。我们证明尤文氏肿瘤细胞系和原发性患者肿瘤标本过度表达 VEGF，并从膜结合型 189 亚型转变为可溶性 165 亚型。 VEGF165 已被证明能够吸引干细胞。在移植环境中使用我们的尤文氏肉瘤裸鼠模型，我们证明骨髓（BM）细胞迁移到肿瘤中，分化为内皮细胞并有助于肿瘤脉管系统的形成。我们证明了干细胞浸润有两种不同的模式，并且迁移到肿瘤中的有两种不同的表型。小鼠 Sca1+Gr1+ 干细胞和人 CD34+ 细胞共定位于肿瘤血管并分化为内皮细胞和周细胞。鼠Sca1-Gr1+和人CD34-细胞在肿瘤组织深处迁移远离肿瘤血管并分化为巨噬细胞。我们证明周细胞和 VEGF165 负责这些干细胞的化学吸引。 VEGF189 未重复该活性。使用 VEGF165-siRNA 的进一步研究支持我们的假设，即这些迁移的干细胞在肿瘤生长和肿瘤血管发育中发挥重要作用。总而言之，我们的数据表明，除了血管生成之外，血管生成还参与肿瘤脉管系统的扩张，在肿瘤生长的第一周期间贡献了约 10% 的血管。我们希望继续研究血管发生过程，确定该过程在原发性和转移性肿瘤生长中的重要性，并研究干细胞被吸引到特定肿瘤血管区域的机制。我们建议（1）确定BM来源的细胞是否与局部内皮细胞整合在一起形成肿瘤血管，以及在没有VEGF165的情况下这是否被改变； (2)确定血管生成对肿瘤生长的重要性以及血管生成是否可以在VEGF165缺失的情况下恢复生长和血管发育； (3)确定特定DLL4中的NOTCH信号传导是否在干细胞对尤文氏肿瘤的化学吸引中发挥作用； (4)确定BM干细胞是否参与尤文氏肺和骨转移瘤的生长。了解血管生成如何促进尤文氏肉瘤的生长和转移，并确定该过程中涉及的趋化信号可能会为治疗这种疾病的患者开辟新的治疗方法。该应用将研究骨髓 (BM) 干细胞如何促进支持尤文氏肉瘤生长的脉管系统扩张，以及控制 BM 细胞迁移到肿瘤中的机制。我们还将确定骨髓干细胞是否有助于尤因氏肺和骨转移瘤的生长。尤文氏肉瘤的生存率在 20 年多的时间里都没有提高。了解肿瘤血管的形成方式可能会为此类癌症找到新的治疗方法。