Spontaneous regression of late stage tumors

描述：(申请人提供)肿瘤的生长和存活情况 细胞受肿瘤细胞内的内部遗传控制和 由宿主因素决定。在极少数癌症患者中， 恶性肿瘤可以通过未知的宿主部分或完全逆转 这一机制被称为“自发回归”。缺乏用于治疗的动物模型 自发回归阻碍了确定这些因素的努力 参与了这种有效的肿瘤耐药机制。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 诱发晚期腹水自然消退的突变 移植攻击性很强的小鼠肉瘤180细胞。自发的 晚期腹水的消退在携带腹水的小鼠中是完全和永久性的 突变。这种突变还可以保护小鼠免受肿瘤的侵袭。 在小鼠白血病细胞移植后。这种突变分离为 与单个基因座一致的显性特征。初始基因分型分析 建立了该突变与两个相邻微卫星标记的连锁 在小鼠的4号染色体上。在这个建议中，崔博士组装了一组 来自基因组学、病理学、免疫学、癌症发生学和生物化学的专家 确定其遗传基础、细胞机制及抗肿瘤谱。 这种强大的抗癌特性。这项提议的长期目标是 是为了确定类似的机制是否也适用于人类癌症 治疗和预防。这项建议有5个具体目标：1)建立一个 基因突变临界区的高分辨率遗传连锁图谱 通过基因分型分析4号染色体；2)为此构建物理图谱 关键区域；3)对关键区域的候选基因进行评估 DNA；4)确定肿瘤进展的细胞机制 5)以确定该突变是否提供了对 致癌物诱导的内源性上皮性肿瘤。完成这些目标将 全面了解这一现象的生物学机制 对肿瘤具有独特的强大抵抗力。将开发必要的工具以 将这些研究扩展到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 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.