April 2006
Volume 5
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April 2006
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Metastasis Susceptibility
One variable that may contribute to the complexity of this process is genetic background. Germline polymorphism has long been associated with human cancer risk. Much of human molecular epidemiology is based on the premise that certain constitutional polymorphisms are associated with different susceptibilities. Numerous examples of this type of cancer-associated variation also exist in experimental organisms, and hundreds of modifier or quantitative trait loci have been mapped in the mouse and rat that influence a wide variety of pathological conditions common in human populations, including disorders such as cancer, diabetes, and hypertension. These data suggest that many, probably most, phenotypes have a significant genetic contribution, even traits as complex as tumor dissemination. Evidence supporting the role of germline polymorphism in metastasis has come from the recent identification of a candidate for the metastasis efficiency modifier locus, Mtes1. Previous genetic studies demonstrated the presence of polymorphic genes in the mouse genome that suppressed the ability of a highly aggressive transgene-induced mammary tumor to metastasize to the lung. Genetic mapping studies revealed that one of these metastasis-suppressing genes, designated Mtes1, was located on proximal mouse chromosome 1, in a region orthologous to human chromosome 11q13. Genomic analysis of the region identified several interesting polymorphic genes, and subsequent in vitro and in vivo experiments identified a polymorphism in the negative regulator of Rap1 GTPase, Sipa1, which significantly influenced its protein-protein interactions and enzymatic function. In tumor cell lines, the rate of metastases was increased by Sipa1 overexpression and decreased by knocking down its expression in spontaneous metastasis assays in mice (Figure 1). The potential role of SIPA1 in human metastasis was investigated by examination of publicly available gene-expression profiles, which revealed higher expression of SIPA1 in metastatic prostate cancer compared with localized tumor, in agreement with the mouse data. In toto, the mouse results strongly support the concept of naturally occurring genetic variants playing an important role in the final, lethal stages of cancer, and the human data implicate SIPA1 in the metastatic process in human cancer. Figure 1. Modulation of Sipa1 levels significantly influences the metastatic capacity of a highly metastatic mouse mammary tumor cell line. Wild-type cells (center), cells overexpressing (right; FVB Sipa1), or cells silenced (left; siRNA) for the Sipa1 gene were implanted into the flanks of mice and allowed to develop into tumors. The metastatic capacity was then determined by counting lung surface nodules. Representative images of the lungs from each group are shown above the scatterplots. The black bars represent the median value for each experimental group. The existence of these polymorphic metastasis-susceptibility genes may have a significant impact on clinical prognosis. At present, evidence of lymph node metastasis is one of the most powerful prognostics for disease course in breast cancer. However, about 30% of women who are node negative at diagnosis develop metastatic disease, whereas 30% of women who are node positive are disease free a decade after local therapy. As a result, many women who do not benefit from aggressive systemic treatment may be receiving adjuvant therapy, with its associated side effects and morbidity. Conversely, there may be individuals who would benefit from systemic adjuvant therapy but are not treated due to the apparent localized nature of the tumor. Identification and screening of allelic variants of metastasis-susceptibility genes may therefore significantly improve patient stratification based on inherited risk assessment instead of lymph node status. This may ultimately enable more accurate tailoring of treatment, and thereby reduce the overall morbidity and mortality of cancer. |
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etastasis,
the final stage of cancer progression and the source of most cancer-related
mortality, is usually thought to be the result of oncogenic mutation and somatic
evolution of tumor cells, either within the primary tumor mass or at distant
sites. This hypothesis, while consistent with much of the data, does not entirely
explain all experimental and clinical observations. Additional variables that
contribute to metastatic progression therefore need to be identified and investigated
to develop a more comprehensive model of the terminal stages of cancer progression.