Metastasis is a major cause of death in cancer patients and involves a multistep process including detachment of cancer cells from a primary cancer, invasion of surrounding tissue, spread through circulation, re-invasion and proliferation in distant organs. KiSS-1 is a human metastasis suppressor gene, that suppresses metastases of human melanomas and breast carcinomas without affecting tumorigenicity. However, its gene product and functional mechanisms have not been elucidated. Here we show that KiSS-1 (refs 1, 4) encodes a carboxy-terminally amidated peptide with 54 amino-acid residues, which we have isolated from human placenta as the endogenous ligand of an orphan G-protein-coupled receptor (hOT7T175) and have named 'metastin'. Metastin inhibits chemotaxis and invasion of hOT7T175-transfected CHO cells in vitro and attenuates pulmonary metastasis of hOT7T175-transfected B16-BL6 melanomas in vivo. The results suggest possible mechanisms of action for KiSS-1 and a potential new therapeutic approach.

A chemokine receptor, CXCR4, and its endogenous ligand, stromal cell-derived factor-1 (SDF-1), have been recognized to be involved in the metastasis of several types of cancers. T140 analogs are peptidic CXCR4 antagonists composed of 14 amino acid residues that were previously developed as anti-HIV agents having inhibitory activity against HIV-entry through its co-receptor, CXCR4. Herein, we report that these compounds e¡ectively inhibited SDF-1-induced migration of human breast cancer cells (MDA-MB-231), human leukemia T cells (Sup-T1) and human umbilical vein endothelial cells at concentrations of 10^100 nM in vitro. Furthermore, slow release administration by subcutaneous injection using an Alzet osmotic pump of a potent and bio-stable T140 analog, 4F-benzoyl-TN14003, gave a partial, but statistically signi¢cant (P 9 9 0.05 (t-test)) reduction in pulmonary metastasis of MDA-MB-231 in SCID mice, even though no attempt was made to inhibit other important targets such as CCR7. These results suggest that T140 analogs have potential use for cancer therapy, and that small molecular CXCR4 antagonists could potentially replace neutralizing antibodies as anti-metastatic agents for breast cancer. ß

The pathomechanism of amyotrophic lateral sclerosis (ALS) remains unclear. There is some evidence that excitotoxic cell death is involved in the degeneration of the motor nervous system, and that ligand-gated receptor channels play a role in the pathogenesis of the disease. Several electrophysiological and anatomical studies support the pathophysiological concept of an impaired inhibitory, namely GABAergic, control of the motoneurons in the cerebral cortex of ALS patients. The aim of our study was to investigate the expression of GABAA-receptor subunit mRNAs and the GABA synthesizing enzyme glutamic acid decarboxylase (GAD) in the motor cortex of ALS patients compared to tissue of control persons. We performed in situ hybridization histochemistry (ISH) on human postmortem motor cortex sections of ALS patients (n = 5) and age matched controls with no history of neurological disease (n = 5). The most intriguing finding was a significantly reduced mRNA expression of the alpha1-subunit in ALS patients while the level of beta1-subunit mRNA was elevated in the patients group. This may indicate specific alterations of the GABAA receptor subunit composition and result in distinct physiological and pharmacological properties of these receptors in ALS patients.

An autopsy case of unclassifiable presenil dementia is reported. The outstanding pathological findings were as follows; 1. presence of senile plaques, neurofibrillary changes, Pick bodies, Hirano bodies, granulovacuolar degeneration of neurons, etc. 2. numerous Lewy bodies in the brain stem and diencephalon, 3. peculiar swollen neurons with intracytoplasmic, eosinophilic and argentophilic inclusions ("Lewy-like-bodies") in the cerebral cortices. Detailed study of the last mentioned inclusions indicates that they are almost identical to Lewy bodies, though there are some minor differences, in histochemical and electronmicroscopic findings. Nosologically, this case may represent either a combination of Alzheimer's disease, Pick's disease and idiopathic Parkinsonism with "Lewy-like-bodies" in the cerebral cortices, or a single disease. As far as we know, no similar case been reported.

BackgroundNectin-2 is a Ca2+-independent cell-cell adhesion molecule that is one of the plasma membrane components of adherens junctions. However, little has been reported about the involvement of Nectin-2 in cancer.MethodsTo determine the expression of Nectin-2 in cancer tissues and cancer cell lines, we performed gene expression profile analysis, immunohistochemistry studies, and flow cytometry analysis. We also investigated the potential of this molecule as a target for antibody therapeutics to treat cancers by generating and characterizing an anti-Nectin-2 rabbit polyclonal antibody (poAb) and 256 fully human anti-Nectin-2 monoclonal antibodies (mAbs). In addition, we tested anti-Nectin-2 mAbs in several in vivo tumor growth inhibition models to investigate the primary mechanisms of action of the mAbs.ResultsIn the present study, we found that Nectin-2 was over-expressed in clinical breast and ovarian cancer tissues by using gene expression profile analysis and immunohistochemistry studies. Nectin-2 was over-expressed in various cancer cell lines as well. Furthermore, the polyclonal antibody specific to Nectin-2 suppressed the in vitro proliferation of OV-90 ovarian cancer cells, which express endogenous Nectin-2 on the cell surface. The anti-Nectin-2 mAbs we generated were classified into 7 epitope bins. The anti-Nectin-2 mAbs demonstrated antibody-dependent cellular cytotoxicity (ADCC) and epitope bin-dependent features such as the inhibition of Nectin-2-Nectin-2 interaction, Nectin-2-Nectin-3 interaction, and in vitro cancer cell proliferation. A representative anti-Nectin-2 mAb in epitope bin VII, Y-443, showed anti-tumor effects against OV-90 cells and MDA-MB-231 breast cancer cells in mouse therapeutic models, and its main mechanism of action appeared to be ADCC.ConclusionsWe observed the over-expression of Nectin-2 in breast and ovarian cancers and anti-tumor activity of anti-Nectin-2 mAbs via strong ADCC. These findings suggest that Nectin-2 is a potential target for antibody therapy against breast and ovarian cancers.