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.
Nm23 is a putative metastasis suppressor gene and alterations in this gene have been reported in colorectal carcinomas suggestive of a role for nm23 in the dissemination of these tumours.
Given the fact that not all NME-encoded proteins are catalytically active NDPKs and that NM23 generally refers to clinical studies on metastasis, we use here NME/NDPK to denote the 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.
Pilot in vivo metastasis assays indicate 1205Lu cells are highly responsive to the metastasis suppressor effects of NM23-H1, thus providing a valuable model for measuring the extent to which the nuclease function opposes metastasis and metastatic progression.
Evidence for a metastasis suppressor function of NME1 in vivo comes from crossing NME1 (-/-) mice with mice prone to develop hepatocellular carcinoma; the double transgenic mice present a higher incidence of lung metastases.
Upon mammary fat pad or subcutaneous injection into nude mice, both the nm23-H1 and control transfected lines produced primary tumors; however, the nm23-H1-transfected lines produced metastases in significantly fewer mice than did control transfected lines.
Our results are consistent with other studies reporting that NME1 down-regulation induces CIN in human cell lines and suggest that Drosophila model could be successfully used to study in vivo the impact of NME/Awd - induced genomic instability on tumour development and metastasis formation.
Six metastasis suppressor genes (nm23-H1, TIMP-4, BRMS-1, TXNIP, CRSP-3 and E-Cad) were downregulated significantly in malignant compared to benign pheochromocytoma (p < 0.05, Mann-Whitney U-test).
We developed a competitive permeable peptide (CPP) to impair the formation of the Nm23-H1/h-Prune complex and demonstrated that CPP causes impairment of cell motility, substantial impairment of tumor growth and metastases formation.
The h-prune PDE activity, suppressed by dipyridamole and enhanced by the interaction with nm23-H1, stimulates cellular motility and metastasis processes.
Apart from a housekeeping function, NM23 proteins are involved in the regulation of many cellular processes as well as in tumor metastasis, but their functions in epidermal homeostasis and repair are largely unknown.
There was no inverse correlation between the nm23 protein and melanoma metastasis which suggested that the nm23 protein does not appear to be lost during melanoma metastasis.
In sharp contrast, the low frequency of loss at NME1 and its equal distribution in nodal metastasis-positive and -negative patients suggests that inactivation of this gene by allelic loss probably does not play a role in the development of regional metastases from these tumors.