Spontaneous regression of late-stage tumors in mice

描述（申请人提供）：肿瘤细胞的生长和存活受肿瘤细胞内部遗传控制和宿主因子的调控。在极少数癌症患者中，恶性肿瘤的进展可以通过一种未知的宿主机制部分或完全逆转，这种机制被称为“自发消退”。缺乏自发回归的动物模型阻碍了识别参与肿瘤抵抗机制的因素的努力。崔博士和他的同事们发现了一种独特的、由基因决定的小鼠特征，这种特征赋予了侵袭性小鼠肉瘤180细胞移植引起的晚期腹水的自发消退。在携带突变的小鼠中，晚期腹水的自发消退是完全和永久的。这一特性也保护小鼠在白血病细胞移植后不发生肿瘤。免疫学研究表明，肿瘤细胞引起免疫细胞向肿瘤部位迁移。浸润的免疫细胞形成细胞-细胞聚集体，诱导肿瘤细胞坏死破裂，在肿瘤移植后数小时内消除肿瘤细胞。遗传学研究表明，激活免疫细胞对肿瘤细胞的这种独特反应可能是由这些小鼠的显性突变引起的。初步基因型分析表明，该突变与小鼠4号染色体上相邻的两个微卫星标记有连锁关系。在该提案中，崔博士召集了一组来自基因组学，病理学，免疫学，癌变学和生物化学的专家来确定这种强大的肿瘤抗性性状的遗传基础，细胞机制和抗肿瘤谱。这项提议的长期目标是确定类似的机制是否也能有效地用于人类癌症的治疗和预防。本研究有三个具体目的：1)确定肿瘤排斥反应的免疫成分；2)确定肿瘤排斥反应的抗肿瘤谱；3)确定受突变影响的基因。这些目标的完成将提供对这种独特的、强大的肿瘤抗性的生物学机制的全面理解。将开发必要的工具来扩展这些研究，以在人类中寻找类似的基因，并设计更好、更有效的癌症治疗和预防策略。

DESCRIPTION (provided by applicant): The growth and survival of neoplastic cells is regulated both by internal genetic control within tumor cells and by host factors. In a very small population of cancer patients, progression of malignant tumors can be partially or completely reversed by an unknown host mechanism termed "spontaneous regression". Lack of animal models for spontaneous regression has hampered the efforts to identify the factors involved in this mechanism of tumor resistance. Dr. Cui and his colleagues have identified a unique, genetically-determined mouse trait conferring the spontaneous regression of late-stage ascites induced by the transplantation of aggressive mouse sarcoma 180 cells. The spontaneous regression of late-stage ascites is complete and permanent in the mice carrying the mutation. This trait also protects the mice against tumor development following transplantation of mouse leukemia cells. Immunological studies revealed that tumor cells elicited a migration of immune cells to the tumor site. The infiltrating immune cells form cell-cell aggregates and induced necrotic rupture of tumor cells, eliminating tumor cells in a few hours after tumor transplantation. Genetic studies suggest that this unique response of activated immune cells to tumor cells may be caused by a dominant mutation in these mice. Initial genotype analysis established a linkage of this mutation to two adjacent microsatellite markers on mouse chromosome 4. In this proposal Dr. Cui has assembled a group of experts from genomics, pathology, immunology, carcinogenesis and biochemistry to determine the genetic basis, cellular mechanism and anti-tumor spectrum of this powerful tumor resistance trait. The long-term objective of this proposal is to determine if a similar mechanism can be also effective in human cancer treatment and prevention. This proposal has 3 specific aims: 1) to identify the immunological components for tumor rejection; 2) to determine the anti-tumor spectrum of tumor rejection, 3) to identify the gene(s) affected by the mutation. Completion of these aims will provide a comprehensive understanding of the biological mechanism of this unique, powerful resistance to tumors. Necessary tools will be developed to extend these studies to search for similar genes in humans and to design better, more efficient strategies of cancer treatment and prevention.