Ewing's Sarcoma Resistance to Immunity and Radiation

尤文氏肉瘤对免疫和辐射的抵抗力

• 批准号: 8620629
• 负责人: Joyce C Solheim
• 金额: $ 7.3万
• 依托单位: UNIVERSITY OF NEBRASKA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-04-01 至 2016-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8620629
• 关键词: Address; Adolescent; Adverse effects; Affect; Amyloid; Amyloid beta-Protein Precursor; Antigens; Apoptosis; Apoptotic; BCL2 gene; Binding; Binding Proteins; C-terminal; Cell Cycle Arrest; Cell Line; Cell Survival; Cell surface; Cells; Child; Cytotoxic T-Lymphocytes; Data; Development; Down-Regulation; Employee Strikes; Ewings sarcoma; Exhibits; Family member; HLA Antigens; Hela Cells; Immune; Immune system; Immunity; Immunotherapy; Link; Lysosomes; Major Histocompatibility Complex; Malignant Bone Neoplasm; Malignant Neoplasms; Molecular; Natural Killer Cells; Neoplasm Metastasis; Nervous system structure; Operative Surgical Procedures; Pain; Pathway interactions; Patients; Pharmaceutical Preparations; Ploidies; Population; Predisposition; Process; Production; Protein Family; Proteins; Radiation; Radiation therapy; Recurrence; Reporting; Resistance; Role; Surface; T-Lymphocyte; Testing; Therapeutic; Transcript; base; beta secretase; cell killing; chemotherapy; cytotoxic; cytotoxicity; fighting; inhibitor/antagonist; irradiation; killings; member; novel; protein function; public health relevance; radiation resistance; receptor; research study; response; soft tissue; trafficking; tumor

DESCRIPTION (provided by applicant): Ewing's sarcoma is a very painful cancer of the bone (and, more rarely, soft tissue) that strikes children and adolescents. Despite treatment with surgery, chemotherapy, and radiation, many patients with Ewing's sarcoma do not survive, particularly if the cancer has metastasized. Recurrent Ewing's sarcoma tends to exhibit resistance to chemo- and radiotherapies, motivating the development of novel therapies, including immunotherapies. However, some Ewing's sarcoma cells can escape elimination by the immune system and the mechanisms underlying evasion by this cancer are poorly understood, although there have been reports of down-regulated expression of major histocompatibility complex (MHC) class I molecules, and correlation of decreased MHC class I expression and poor survival. Since the function of MHC class I molecules is to present antigens (including cancer-associated antigens) to cytotoxic T lymphocytes, reduction of their surface expression could cause immune evasion. We have sought to characterize cellular changes associated with Ewing's sarcoma cells that avoid immune recognition, investigating the roles of MHC molecules and amyloid precursor-like protein 2 (APLP2) in this process. APLP2 is a ubiquitously expressed member of a protein family that also includes amyloid precursor protein (APP) and the nervous system-restricted amyloid precursor-like protein 1 (APLP1). APLP2 is found in transmembrane form at the cell surface, and its cleavage by beta-secretases leads to the production of ~12 kDa C-terminal fragments. Our new data suggests that elevated expression of APLP2 in Ewing's sarcoma cell lines reduces surface expression of MHC class I molecules. Following treatment with radiation, the Ewing's sarcoma cells that had relatively low APLP2 expression had increased MHC class I expression at the cell surface, but APLP2- high Ewing's sarcoma sub-populations did not. In our preliminary experiments, we have also demonstrated that following irradiation of Ewing's sarcoma cells APLP2 reduces cell cycle arrest at G2/M and lowers the proportion of cells with sub-G1 DNA content (indicating apoptosis). On the basis of our preliminary data, our central hypothesis is that APLP2 facilitates the survival of Ewing's sarcoma cells. To test our central hypothesis, the Specific Aims of this proposed project are (1) to determine the role of APLP2 in resistance of Ewing's sarcoma cells, pre- and post-irradiation, to cytotoxicity, and (2) to determine the contribution of APLP2 to radiation resistanc by Ewing's sarcoma cells. Overall, the studies proposed in this application are expected to provide a new perspective on molecular pathways regulating Ewing's sarcoma cell survival, involving evasion of both immunity and radiotherapy.

描述（由申请人提供）：尤文氏肉瘤是一种非常痛苦的骨癌（更罕见的是软组织癌），会侵袭儿童和青少年。尽管接受了手术、化疗和放疗治疗，许多尤文氏肉瘤患者还是无法存活，特别是当癌症已经转移时。复发性尤文氏肉瘤往往表现出对化疗和放疗的耐药性，这推动了包括免疫疗法在内的新型疗法的开发。然而，一些尤文氏肉瘤细胞可以逃避免疫系统的消除，并且这种癌症逃避的机制知之甚少，尽管有报道称主要组织相容性复合物（MHC）I类分子的表达下调，并且与免疫系统的相关性降低有关。 MHC I 类表达和生存率低。由于 MHC I 类分子的功能是将抗原（包括癌症相关抗原）呈递给细胞毒性 T 淋巴细胞，因此其表面表达的减少可能会导致免疫逃避。我们试图描述与避免免疫识别的尤文肉瘤细胞相关的细胞变化，研究 MHC 分子和淀粉样前体样蛋白 2 (APLP2) 在此过程中的作用。 APLP2 是蛋白质家族中普遍表达的成员，该蛋白质家族还包括淀粉样前体蛋白 (APP) 和神经系统限制性淀粉样前体样蛋白 1 (APLP1)。 APLP2 在细胞表面以跨膜形式存在，其被 β 分泌酶裂解导致产生约 12 kDa C 末端片段。我们的新数据表明，尤文氏肉瘤细胞系中 APLP2 的表达升高会降低 MHC I 类分子的表面表达。放射治疗后，APLP2表达相对较低的尤文氏肉瘤细胞表面的MHC I类表达增加，但APLP2高的尤文氏肉瘤亚群却没有。在我们的初步实验中，我们还证明，尤文氏肉瘤细胞照射后，APLP2 减少了 G2/M 期的细胞周期停滞，并降低了具有亚 G1 DNA 含量（表明细胞凋亡）的细胞比例。根据我们的初步数据，我们的中心假设是 APLP2 促进 尤因氏肉瘤细胞。为了检验我们的中心假设，该项目的具体目标是 (1) 确定 APLP2 在尤文氏肉瘤细胞照射前和照射后对细胞毒性的抵抗中的作用，以及 (2) 确定 APLP2 的贡献尤文氏肉瘤细胞对辐射的抵抗力。总体而言，本申请中提出的研究预计将为调节尤文氏肉瘤细胞存活的分子途径提供新的视角，包括逃避免疫和放射治疗。