Spontaneous regression of late stage tumors

描述：（由申请人提供）肿瘤的生长和存活 肿瘤细胞受肿瘤细胞内的内部遗传控制和 的主机因素。在一个非常小的癌症患者群体中， 恶性肿瘤可以通过未知宿主部分或完全逆转 这一机制被称为“自发回归”。“缺乏动物模型 自发的退化阻碍了确定因素的努力， 参与了这种有效的肿瘤抵抗机制。崔博士和他的 同事们通过意想不到的观察发现了一种独特的老鼠 突变赋予自发消退的晚期腹水诱导 移植非常具有攻击性的小鼠肉瘤180细胞。自发 晚期腹水的消退是完全和永久的小鼠携带 突变这种突变还可以保护小鼠免受肿瘤的发展 移植小鼠白血病细胞后。这种突变分离为 与单一基因座一致的显性特征。初始基因型分析 建立了该突变与两个相邻微卫星标记的连锁 在小鼠4号染色体上。在这份提案中，崔博士召集了一群 来自基因组学、病理学、免疫学、致癌作用和生物化学的专家 以确定其遗传基础、细胞机制和抗肿瘤谱， 这种强大的抗肿瘤特性。本提案的长期目标 是确定类似的机制是否也能在人类癌症中有效 治疗和预防。该提案有五个具体目标：1）建立一个 突变关键区域的高分辨率遗传连锁图， 通过基因分型分析4号染色体; 2）构建此物理图谱 关键区域; 3）通过以下步骤评估关键区域中的候选基因： DNA; 4）确定肿瘤进展的细胞机制 5）确定突变是否提供保护， 致癌物诱导的内源性上皮肿瘤。实现这些目标将 提供了一个全面的了解这一生物学机制， 对肿瘤有独特的强大抵抗力将开发必要的工具， 将这些研究扩展到寻找人类的相似基因， 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 by both internal genetic control within the tumor cells and by host factors. In a very small population of cancer patients, progression of malignant tumors can be partially or completely reversed via 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 efficient mechanism of tumor resistance. Dr. Cui and his colleagues have identified, through unexpected observations, a unique mouse mutation conferring the spontaneous regression of late-stage ascites induced by the transplantation of very aggressive mouse sarcoma 180 cells. The spontaneous regression of late-stage ascites is complete and permanent in the mice carrying the mutation. This mutation also protects the mice against tumor development following transplantation of mouse leukemia cells. This mutation segregates as a dominant trait consistent with a single locus. 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 5 specific aims: 1) to establish a high-resolution genetic linkage map for the critical region of the mutation on chromosome 4 by genotyping analysis; 2) to construct a physical map for this critical region; 3) to evaluate the candidate genes in the critical region by DNA; 4) to determine the cellular mechanism by which the progression of tumors is reversed and 5) to determine if the mutation offers protection against carcinogen-induced endogenous epithelial tumors. 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.