Role of vascular mimicry in tumor escape from anti-angiogenic therapy

血管拟态在肿瘤逃避抗血管生成治疗中的作用

• 批准号: 8457567
• 负责人: James Michael Dunleavey
• 金额: $ 2.97万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-07-01 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8457567
• 关键词: Allografting; Angiogenesis Inhibition; Angiogenesis Inhibitors; Antibodies; Apoptosis; Biological; Biopsy; Blood Vessels; Cell Line; Cells; Characteristics; Clinical Research; Collaborations; Combined Modality Therapy; Cytotoxic Chemotherapy; Development; Drug resistance; Endothelial Cells; Endothelium; Enzymes; Exhibits; Figs - dietary; Frequencies; Goals; Human; Immunotherapy; In Vitro; Individual; Label; Letters; Magnetism; Malignant Neoplasms; Measures; Mediating; Melanins; Melanoma Cell; Methodology; Minor; Modeling; Molecular; Monophenol Monooxygenase; Mus; Nutrient; Operative Surgical Procedures; Outcome; Oxygen; PECAM1 gene; Patients; Phenotype; Play; Population; Production; Prostatic Neoplasms; Radiation Oncology; Refractory; Research; Resistance; Resistance development; Role; Staging; Surgical Oncology; Testing; Tumor Biology; Tumor Escape; Vascular Endothelial Growth Factor Receptor-2; Vascular Endothelial Growth Factors; Vascular Endothelium; Work; Xenograft procedure; bevacizumab; cadherin 5; cancer cell; cancer therapy; chemotherapy; improved; in vivo; interest; irradiation; melanoma; mimicry; mortality; neoplastic cell; new therapeutic target; novel; novel strategies; outcome forecast; public health relevance; receptor; research study; response; therapeutic target; tumor; tumor growth

DESCRIPTION (provided by applicant): A novel approach for cancer treatment is to target the blood vessels (anti-angiogenic therapies) responsible for supplying the tumor with oxygen and nutrients. However, these treatments have not been as effective in clinical studies as originally hoped. It is apparent that tumors are able to evade and escape angiogenesis inhibition, but the mechanism by which this occurs is unknown. We have identified a novel population of tumor cells we hypothesize mediate resistance to anti-angiogenic drugs. These tumor cells express CD31, an endothelial selective marker, and lack the receptors typically targeted by angiogenesis inhibitors. Our lab specializes in studies of tumor endothelial cells (TEC). However, while isolating CD31+ TEC from a model of aggressive melanoma we discovered a unique population of tumor cells which express this endothelial-selective marker. We have determined these cells appear to collaborate with blood vessels in tumors, have endothelial-like characteristics in vitro, yet are positive for melanoma markers. This proposal aims to examine this subpopulation of melanoma and its contribution to the vasculature both in normal tumor settings as well as in tumors which exhibit resistance to anti-angiogenic inhibition. There are two project aims: 1) To further clarify the biological significance of CD31 expression in tumor cells. The goal is to determine the role these cells play in the tumor vasculature as well as elucidate the molecular mechanisms controlling CD31 expression in these cells. 2) To determine how CD31+ tumor cells mediate resistance to anti-VEGF therapies. The goal is to induce anti-angiogenic resistance in models of aggressive melanoma and study the role CD31+ cells play in the induction of this resistance phenotype. This work will undertake a comprehensive study of the significance of these cells in anti-angiogenic resistance using a multi-faceted research strategy. We will examine the characteristics of individual CD31+ cells in vitro to better understand their cellular phenotypes while also conducting in vivo studies of tumor growth and vascular development in conjunction with drug resistance studies. Through the collaboration with Dr. Janiel Shields in the Department of Radiation Oncology at UNC (see letter) we will examine human melanoma cell lines for the expression of CD31. Through another collaboration with Dr. David Ollila in the Division of Surgical Oncology (see letter) we will identfy these CD31+ cells in xenografts of primary human melanoma, and induce anti-angiogenic resistance in these xenografts to examine the role CD31+ melanoma cells play in human models of this phenotype. Overall this study should provide novel therapeutic targets which could be used in conjunction with current anti-angiogenic therapies to improve cancer outcomes.

描述（由申请人提供）：一种新的癌症治疗方法是靶向负责为肿瘤提供氧气和营养的血管（抗血管生成疗法）。然而，这些治疗在临床研究中并不像最初希望的那样有效。很明显，肿瘤能够逃避和逃脱血管生成抑制，但发生这种情况的机制尚不清楚。我们已经确定了一种新的肿瘤细胞群体，我们假设介导抗血管生成药物的耐药性。这些肿瘤细胞表达内皮选择性标记物CD31，并且缺乏血管生成抑制剂通常靶向的受体。 我们实验室专门从事肿瘤内皮细胞（TEC）的研究。然而，在从侵袭性黑色素瘤模型中分离CD31+ TEC时，我们发现了表达这种内皮选择性标志物的独特肿瘤细胞群。我们已经确定这些细胞似乎与肿瘤中的血管合作，在体外具有内皮样特征，但对黑色素瘤标记物呈阳性。该提案旨在检查黑色素瘤的该亚群及其在正常肿瘤环境中以及在对抗血管生成抑制表现出抗性的肿瘤中对脉管系统的贡献。 本课题的目的有两个：1）进一步阐明肿瘤细胞中CD31表达的生物学意义。目的是确定这些细胞在肿瘤血管系统中的作用，以及阐明控制这些细胞中CD31表达的分子机制。2)确定CD31+肿瘤细胞如何介导抗VEGF治疗的耐药性。目的是在侵袭性黑色素瘤模型中诱导抗血管生成抗性，并研究CD31+细胞在诱导这种抗性表型中的作用。 这项工作将采用多方面的研究策略，对这些细胞在抗血管生成抵抗中的意义进行全面研究。我们将在体外研究单个CD31+细胞的特征，以更好地了解它们的细胞表型，同时也进行肿瘤的体内研究。 生长和血管发育以及耐药性研究。通过与哈佛大学放射肿瘤学系的Janiel Shields博士的合作，我们将检测人类黑色素瘤细胞系中CD31的表达。通过与外科肿瘤学部的大卫·奥利拉博士的另一项合作（见信），我们将鉴定原发性人黑色素瘤异种移植物中的这些CD 31+细胞，并在这些异种移植物中诱导抗血管生成抗性，以检查CD 31+黑色素瘤细胞在该表型的人类模型中所起的作用。总的来说，这项研究应该提供新的治疗靶点，可以与目前的抗血管生成治疗结合使用，以改善癌症的结果。