Clinical-translational approaches to the Nm23-H1 metastasis suppressor. 2008

Patricia S Steeg, and Christine E Horak, and Kathy D Miller
Women's Cancers Section, Laboratory of Molecular Pharmacology, Center for Cancer Research, National Cancer Institute, 37 Convent Drive, Bethesda, MD 20892, USA. steegp@mail.nih.gov

Nm23-H1 significantly reduces metastasis without effects on primary tumor size and was the first discovered metastasis suppressor gene. At least three mechanisms are thought to contribute to the metastasis-suppressive effect of Nm23-H1: (a) its histidine kinase activity toward ATP-citrate lyase, aldolase C, and the kinase suppressor of ras, with the last inactivating mitogen-activated protein kinase signaling; (b) binding proteins that titer out "free" Nm23-H1 and inhibit its ability to suppress metastasis; and (c) altered gene expression downstream of Nm23-H1, particularly an inverse association with the lysophosphatidic acid receptor endothelial differentiation gene-28 (EDG2). Most metastasis suppressor genes, including Nm23-H1, affect metastatic colonization, which is the outgrowth of tumor cells in distant locations; therefore, they are of high translational interest. A phase II trial is ongoing to test the hypothesis that a compound, high-dose medroxyprogesterone acetate (MPA), used as an unconventional gluocorticoid, will stimulate breast cancer cells to reexpress Nm23-H1 and limit subsequent metastatic colonization.

UI MeSH Term Description Entries
D009361 Neoplasm Invasiveness Ability of neoplasms to infiltrate and actively destroy surrounding tissue. Invasiveness, Neoplasm,Neoplasm Invasion,Invasion, Neoplasm
D009369 Neoplasms New abnormal growth of tissue. Malignant neoplasms show a greater degree of anaplasia and have the properties of invasion and metastasis, compared to benign neoplasms. Benign Neoplasm,Cancer,Malignant Neoplasm,Tumor,Tumors,Benign Neoplasms,Malignancy,Malignant Neoplasms,Neoplasia,Neoplasm,Neoplasms, Benign,Cancers,Malignancies,Neoplasias,Neoplasm, Benign,Neoplasm, Malignant,Neoplasms, Malignant
D006801 Humans Members of the species Homo sapiens. Homo sapiens,Man (Taxonomy),Human,Man, Modern,Modern Man
D000818 Animals Unicellular or multicellular, heterotrophic organisms, that have sensation and the power of voluntary movement. Under the older five kingdom paradigm, Animalia was one of the kingdoms. Under the modern three domain model, Animalia represents one of the many groups in the domain EUKARYOTA. Animal,Metazoa,Animalia
D000970 Antineoplastic Agents Substances that inhibit or prevent the proliferation of NEOPLASMS. Anticancer Agent,Antineoplastic,Antineoplastic Agent,Antineoplastic Drug,Antitumor Agent,Antitumor Drug,Cancer Chemotherapy Agent,Cancer Chemotherapy Drug,Anticancer Agents,Antineoplastic Drugs,Antineoplastics,Antitumor Agents,Antitumor Drugs,Cancer Chemotherapy Agents,Cancer Chemotherapy Drugs,Chemotherapeutic Anticancer Agents,Chemotherapeutic Anticancer Drug,Agent, Anticancer,Agent, Antineoplastic,Agent, Antitumor,Agent, Cancer Chemotherapy,Agents, Anticancer,Agents, Antineoplastic,Agents, Antitumor,Agents, Cancer Chemotherapy,Agents, Chemotherapeutic Anticancer,Chemotherapy Agent, Cancer,Chemotherapy Agents, Cancer,Chemotherapy Drug, Cancer,Chemotherapy Drugs, Cancer,Drug, Antineoplastic,Drug, Antitumor,Drug, Cancer Chemotherapy,Drug, Chemotherapeutic Anticancer,Drugs, Antineoplastic,Drugs, Antitumor,Drugs, Cancer Chemotherapy
D015398 Signal Transduction The intracellular transfer of information (biological activation/inhibition) through a signal pathway. In each signal transduction system, an activation/inhibition signal from a biologically active molecule (hormone, neurotransmitter) is mediated via the coupling of a receptor/enzyme to a second messenger system or to an ion channel. Signal transduction plays an important role in activating cellular functions, cell differentiation, and cell proliferation. Examples of signal transduction systems are the GAMMA-AMINOBUTYRIC ACID-postsynaptic receptor-calcium ion channel system, the receptor-mediated T-cell activation pathway, and the receptor-mediated activation of phospholipases. Those coupled to membrane depolarization or intracellular release of calcium include the receptor-mediated activation of cytotoxic functions in granulocytes and the synaptic potentiation of protein kinase activation. Some signal transduction pathways may be part of larger signal transduction pathways; for example, protein kinase activation is part of the platelet activation signal pathway. Cell Signaling,Receptor-Mediated Signal Transduction,Signal Pathways,Receptor Mediated Signal Transduction,Signal Transduction Pathways,Signal Transduction Systems,Pathway, Signal,Pathway, Signal Transduction,Pathways, Signal,Pathways, Signal Transduction,Receptor-Mediated Signal Transductions,Signal Pathway,Signal Transduction Pathway,Signal Transduction System,Signal Transduction, Receptor-Mediated,Signal Transductions,Signal Transductions, Receptor-Mediated,System, Signal Transduction,Systems, Signal Transduction,Transduction, Signal,Transductions, Signal
D017322 Clinical Trials, Phase II as Topic Works about studies that are usually controlled to assess the effectiveness and dosage (if appropriate) of diagnostic, therapeutic, or prophylactic drugs, devices, or techniques. These studies are performed on several hundred volunteers, including a limited number of patients with the target disease or disorder, and last about two years. This concept includes phase II studies conducted in both the U.S. and in other countries. Drug Evaluation, FDA Phase 2 as Topic,Drug Evaluation, FDA Phase II as Topic,Evaluation Studies, FDA Phase 2 as Topic,Evaluation Studies, FDA Phase II as Topic
D054778 NM23 Nucleoside Diphosphate Kinases A family of nucleotide diphosphate kinases that play a role in a variety of cellular signaling pathways that effect CELL DIFFERENTIATION; CELL PROLIFERATION; and APOPTOSIS. They are considered multifunctional proteins that interact with a variety of cellular proteins and have functions that are unrelated to their enzyme activity. Nucleoside Diphosphate Kinase A,DR-NM23 Nucleoside Diphosphate Kinase,Expressed in Non-Metastatic Cells 2 Protein,Granzyme A-activated DNase,NDP Kinase A,NM23-H2 Nucleoside Diphosphate Kinase,NM23-H3 Nucleoside Diphosphate Kinase,NM23A Nucleoside Diphosphate Kinases,NM23B Nucleoside Diphosphate Kinase,NME1 Nucleoside Diphosphate Kinase,Nm23-H1 Nucleoside Diphosphate Kinase,Non-Metastatic Cells 1 Protein,Nucleoside Diphosphate Kinase 3,Nucleoside Diphosphate Kinase B,Nucleoside Diphosphate Kinase C,Tumor Metastatic Process-Associated Protein,DR NM23 Nucleoside Diphosphate Kinase,Expressed in Non Metastatic Cells 2 Protein,Granzyme A activated DNase,NM23 H2 Nucleoside Diphosphate Kinase,NM23 H3 Nucleoside Diphosphate Kinase,Nm23 H1 Nucleoside Diphosphate Kinase,Non Metastatic Cells 1 Protein,Tumor Metastatic Process Associated Protein

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