The Expression Pattern of the Urokinase Plasminogen Activation System in Human Colon Cancer Is Recapitulated in Liver Metastases with Desmoplastic Encapsulation
Metastatic growth and invasion by colon cancer cells in the liver requires the ability of the cancer cells to interact with the new tissue environment. This interaction does not lead to one consistent histological invasion pattern but in two distinct patterns: those with desmoplastic encapsulation and those with solid growth. The potent matrix degrading protease, plasmin(ogen), is activated on cell surfaces by urokinase plasminogen activator (uPA), which activity is regulated by uPA-receptor (uPAR) and type-1 plasminogen activator inhibitor (PAI-1). To compare the expression patterns of uPA, uPAR and PAI-1 in primary colon adenocarcinomas with that in colon cancer liver metastases, we have analysed matched samples from 14 patients of which 6 had liver metastasis with desmoplastic growth pattern and 8 had metastasis with solid growth. In the primary tumours, we found focal upregulation of uPAR-immunoreactivity and uPA mRNA-expression in stromal cells at the invasive front. Similarly we found focal upregulation of uPAR at the metastasis periphery in all 6 liver metastases with desmoplastic encapsulation, whereas only one of the 8 liver metastases with solid growth pattern had focal upregulation of uPAR in the metastasis/liver parenchyma interface. uPA mRNA was also found upregulated in 5 of the 6 liver metastases with desmoplastic growth in the desmoplastic periphery and was not found upregulated in the metastases periphery in any of the 9 remaining metastases. In addition, we found invasive budding cancer cells, which are positive for Laminin-5γ2, expressing both uPAR and uPA mRNA in all primary tumours and in the liver metastases with desmoplastic growth pattern. PAI-1 was found in myofibroblasts located within the desmoplastic capsule of liver metastases in a comparable pattern as found in the primary tumours. Interestingly, PAI-1 was also found in some hepatocytes located close to the metastases independent of the metastasis growth pattern. We conclude that metastasis-induced desmoplasia with recruitment of macrophages and myofibroblasts upregulates the expression of uPAR, uPA and PAI-1 in a pattern similar to that in the primary tumours. Our findings suggest that the molecular expression patterns can be partly recapitulated in metastases and that alternative invasion mechanisms in metastases remains to be characterised.
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