Genetic Modifiers of Intitiation and Progression of Mamm

肿瘤播散或转移过程是肿瘤临床治疗的一个重要方面。在大多数情况下，局部肿瘤患者的预后明显好于弥散性肿瘤患者。大多数癌症死亡率与转移性疾病而非原发肿瘤有关。据估计，60-70%的患者在诊断时已发展为转移性疾病，因此更好地了解导致肿瘤扩散的因素至关重要。已经进行了大量的研究，阐明了这一过程的各个组成部分。因此，对于与转移进展相关的不同分子和途径，包括癌基因的激活、金属蛋白酶的募集和运动因子，我们已经有了大量的了解。转移相关的杂合性缺失也被用作鉴定一类被称为转移抑制因子的基因成员的工具。迄今为止，这类基因的8个成员已被描述：NM23、KISS1、KAI1、E-cadherin、MKK4、TIMPs、Maspin、BRMS1、RhoGDI2。

The process of tumor dissemination or metastasis is an important aspect of clinical management of cancer. In most cases cancer patients with localized tumors have significantly better prognoses than those with disseminated tumors. The majority of cancer mortality has been associated with metastatic disease rather than the primary tumor. Since it has been estimated that 60-70% of patients have progressed to metastatic disease by the time of diagnosis better understanding of the factors leading to tumor dissemination is of vital importance. An enormous amount of research has been performed elucidating various components of this process. As a result a great deal is known about different molecules and pathways that are associated with metastatic progression, including activation of oncogenes, recruitment of metalloproteases, and motility factors. Metastasis-associated loss of heterozygosity has also been used as a tool to identify members of a class of genes known as the metastasis suppressors . To date eight members of this class of genes have been described: NM23, KISS1, KAI1, E-cadherin , MKK4, TIMPs, Maspin , BRMS1, RhoGDI2. Despite this wealth of information, the critical initiating events or molecular pathways for tumor dissemination remain unclear. Part of the difficulty unraveling the complexity of metastasis may be due to multiple converging pathways associated with malignant potential. Another confounding factor is likely to be genetic modulation of the efficiency of tumor dissemination. Identification of key regulatory components of the metastatic process would serve two functions. First, they might provide more accurate prognostic markers of potential metastatic progression in patients than the current standards. Second, they may provide insights into the critical events in tumor dissemination, potentially leading to additional avenues of research or the development of novel therapies. My laboratory uses animal models for gene discovery and/or test hypotheses that are difficult or impossible to do in human populations, including direct experimental testing of epidemiological correlations. The focus of my laboratory is a combined genetics and genomics approach to determine how constitutional genetic composition influences susceptibility to malignant progression. The model studied is the highly aggressive, metastatic transgenic mammary tumor FVB/N-TgN(MMTV-PyVT)634Mul mouse, which develops pulmonary metastatic lesions in ~85% of the animals by 100 days of age. By performing a breeding based strain survey, my laboratory demonstrated the first in vivo evidence that genetic background of the host is a major determinant of metastatic potential. Using quantitative trait genetic analysis of backcross or recombinant inbred mouse populations we subsequently mapped the location of at least two significant modifier genes and identified three other suggestive modifier genes. Currently my laboratory is applying both conventional mouse genetic and population-based strategies to attempt to identify and characterize the genes, pathways and polymorphisms that underlie the metastatic efficiency observed in the different genotypes. A two-prong strategy is being pursued. The first arm of the strategy is based on the conventional approach of developing interval specific congenic and subcongenic animals to generate a high-resolution mapping of the modifier genes followed by standard positional candidate strategies. While the conventional strategy has a high probability of success, it is a slow and laborious process that requires extensive animal breeding and manipulation. Therefore, in parallel with the conventional congenic based strategy, we are exploring alternative strategies for modifier candidate gene selection. For example, using latency as a phenotype in one of the backcrosses, we demonstrated that it is possible in some instances to select promising candidate genes based on known genetic interactions and bioinformatics based searches. The utility of this method was subsequently demonstrated by the identification of functional polymorphisms in both genes of interest, and by the in vivo replication of the latency phenotype in a transgenic experiment. We are currently pursuing this and other strategies to attempt to identify likely candidates for the metastasis efficiency genes, starting with the locus on chromosome 19. Finally, we plan to take advantage of the unique resources of mouse genetics to develop an integrated "trans-ome", genome, transcriptome and proteome, characterization of mammary tumor metastasis. By exploring the expression patterns and protein levels and post-translational modification in the AKXD recombinant inbred mouse-mapping panel used for genetic mapping of the metastasis modifier genes, we should be able to explore the interface of genetic susceptibility to tumor dissemination with the intricate and interwoven biochemical pathways of the cell. We believe that this global approach to interrogating the metastatic process may yield novel insights into the complex and multiple pathways involved in this process, and potentially lead to exciting new strategies and targets for clinical intervention.