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Genetic analysis of invasion and metastasis
J G Collard1, E Roos, G La Rivière
1Division of Cell Biology, Netherlands Cancer Institute, Antoni van Leeuwenhoekhuis, Amsterdam.
Abstract:
Metastasis formation is a multistep process that probably requires a complex interplay of a large and heterogeneous group of genes, including genes involved in cellular resistance to immunorejection and genes controlling the invasive potential of cells. Transfection experiments have shown that oncogenes of the ras gene family as well as oncogenes of the kinase group are able to induce invasive and metastatic properties in non-transformed cells as well as in tumorigenic, but non-metastatic, cells. However, these findings are not in agreement with observations on spontaneous human tumours in which no correlation was found between activation or increased expression of ras genes and the invasive and metastatic properties of these cells. Further studies have indicated that in particular cell types nuclear oncogenes like N-myc and adenovirus derived E1A may influence metastasis formation by trans-regulation of other genes, including class I genes of the major histocompatibility complex and genes coding for proteolytic enzymes. The many efforts to identify additional invasion and metastasis associated genes by transfection of high molecular weight metastatic tumour DNA met with little success. Somatic cell fusion studies, however, indicate that such genes exist and that one or more of them are located on human chromosome 7.
Insights
Metastasis involves complex gene interactions. While some oncogenes promote invasion, human tumors show no ras gene correlation, suggesting other genes on chromosome 7 are key to metastasis.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Metastasis formation is a complex, multi-step process involving numerous genes.
- Genes influencing immunorejection resistance and cellular invasiveness are implicated.
- Oncogenes like ras and kinase group oncogenes can induce metastatic properties in cells.
Purpose of the Study:
- To investigate the genetic underpinnings of metastasis.
- To reconcile conflicting findings regarding ras gene involvement in human tumors.
- To identify novel genes associated with invasion and metastasis.
Main Methods:
- Transfection experiments with oncogenes.
- Analysis of spontaneous human tumors.
- Studies on nuclear oncogenes (N-myc, E1A) and their regulatory effects.
- Transfection of high molecular weight metastatic tumor DNA.
- Somatic cell fusion studies.
Main Results:
- Ras and kinase oncogenes induced invasive properties in experimental models.
- No correlation found between ras gene activation/expression and metastasis in human tumors.
- Nuclear oncogenes influence metastasis via trans-regulation of other genes.
- Efforts to identify metastasis genes via DNA transfection yielded limited success.
- Somatic cell fusion indicated the existence of metastasis-associated genes.
Conclusions:
- Metastasis involves a complex genetic interplay beyond simple oncogene activation.
- Human tumor data contradicts the direct role of ras genes in metastasis.
- Nuclear oncogenes and their regulatory targets are important in metastasis.
- Human chromosome 7 likely harbors genes crucial for invasion and metastasis.