S Kapitanović, T Čaev, M Berković, M Popović-Hadžija, S Radošević, S Seiwerth, S Spaventi, K Pavelić, R Spaventi
J Clin Pathol 2004
Acascade of cellular, biochemical, and genetic events is known to occur in the development and progression of tumours, leading to malignancy and ultimately to metastasis.
Tumour metastasis, the process by which tumour cells leave the primary tumour to colonise other sites of the body, is a major cause of death for patients with cancer. The complexity of metastatic dissemination of tumour cells can be realised by considering the steps that they must perform before successfully colonising a distant site. Metastasising cells must first disseminate from the primary tumour, invade the surrounding tissue, intravasate and extravasate the circulatory system, arrest, initiate angiogenesis, and colonise distant sites, at the same time evading the immune system.
The discovery of genetic alterations in oncogenes and tumour suppressor genes, which accompany tumour formation in a wide variety of human tumour types, has encouraged the search for genes that may promote or suppress tumour spread and metastasis. Among these, nm23 seemed to be the most promising candidate for a gene with metastasis suppressing function.3 The nm23 gene was originally identified by differential hybridisation of K-1735 melanoma cell line clones of varying metastatic potential. A tumour metastasis suppressor function was implicated by the reduced expression of nm23 in highly metastatic sublines compared with non-metastatic sublines derived from the same K-1735 clone.4 Two human nm23 genes, nm23-H1 and nm23-H2, have been cloned.5 They are 88% homologous to each other and encode two polypeptide subunits of a nucleoside diphosphate (NDP) kinase. NDP kinase transfers the c phosphate of nucleoside triphosphate to NDP via a high energy phosphohistidine intermediate.
It has been shown, however, that the biological function of nm23 is not related to its NDP kinase activity.6 Rather, the motility suppressive function of nm23-H1 is probably associated with histidine dependent phosphotransferase activity of the molecule.7 The expression of nm23 has been shown to be raised in several different tumours of lower metastatic potential than in the corresponding tumours of higher metastatic potential, including breast, hepatocellular, ovarian, and gastric carcinomas, and melanoma.8 In other tumours, such as neuroblastoma, pancreatic carcinoma, and head and neck carcinomas, surprisingly, the opposite trend has been reported.