It was found that patients developing metastases during the first 2 years after diagnosis had significantly lower levels of tumor nm23 expression (56% of the mean value) compared to patients with less aggressive disease (164%) (P < 0.0004).
Tests with probe YNZ 22.1, near p53, showed no significant association with distant metastases. nm23-H1 may be, or may be located near, a late-acting suppressor gene in colorectal carcinoma, in which deletions may have prognostic value.
Our findings indicate that, in contrast to a proposed role for nm23-H1 as a tumor metastasis suppressor, increased p19/nm23 protein in neuroblastoma is correlated with features of the disease that are associated with aggressive tumors.
The product of the abnormal wing discs (awd) gene of Drosophila is 78% identical to the product of the nm23 gene of mammals, which is differentially expressed in certain metastatic tumors.
Short term (median follow-up of 16 months) clinical course data were consistent with nm23 RNA levels, in that 2 of 11 low nm23 RNA content patients (including one from the 0 involved lymph node group) developed metastases, while none of the high nm23 RNA patients have experienced recurrent disease.
Furthermore, nm23-H1 mRNA abundance may be a predictor of intrahepatic metastasis, the most important factor correlated with the metastatic potential of hepatocellular carcinoma.
One gene postulated to play a role in tumour metastasis suppression is NME1 (nm23-H1), and an inverse relationship between NME1 expression and metastatic potential has been observed for some solid tumours.
These findings indicated that two murine isotypes of nm23 but not those of humans are intimately related with the suppression of metastasis in the murine body.
Furthermore, carcinomas that had detectable metastasis at the time of surgery were negative fornm23-H1 protein more frequently than those that did not.
Twenty-eight cell lines derived from renal primary tumors and 8 cell lines derived from metastatic tumors expressed both the Nm23-H1 and Nm23-H2 proteins.
nm23 has properties of a metastasis suppressor gene and also has been implicated in the control of response to transforming growth factor beta 1 (TGF beta 1) by studies in melanoma cells.
For example, both the RB gene of retinoblastoma and the p53 gene, which is commonly mutated in breast and colon cancer among others, produce proteins involved in distinct steps of cell cycle control, while the nm23 product prevents metastasis.
In addition, we correlated the findings with other relevant molecular markers including the metastasis associated nm23-H1 gene and loss of heterozygosity (LOH) using multiple polymorphic markers for chromosome 17p and sequencing the entire open reading frame (ORF) of the p53 gene.
These results suggest that expression of the nm23 genes, especially nm23-H1, is activated, accompanied by c-erbB-2 and c-erbB-3 overexpressions, in early stages of the carcinogenic process of ovarian carcinoma and reduction of nm23-H1 expression occurs in association with lymph nodal and/or distant metastasis.
These results provide first evidence for novel mutation in the nm23 gene and demonstrate a correlation between the mutation in the nm23 gene and metastasis in colorectal oncogenesis which suggests that the nm23 gene plays a role in the causation of metastasis.
Additional studies demonstrated that the metastasis suppressor activity encoded by the chromosome 17 pter-q23 region is p53-independent and not due to enhanced expression of NM23 protein.
The time from biopsy of the primary MM to the appearance of the first lymph node metastasis also showed a positive correlation with the nm23 mRNA level in this metastasis.