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It is interesting that MMP inhibitors are getting more attention again. MMPs are thought to play a role in metastasis. There were some failed trials with MMP inhibitors, but one theory is that they were given to late stage cancer patients. One researcher said that they may work better in early stage patients BEFORE the metastasis has occurred.

It seems unfortunate that most of the trials are for stage IV patients. I am not saying they shouldnt be in trials, just that maybe if trials were more readily available to stage I-III patients they would not become stage IV patients

appended research article ......

Cleavage of metastasis suppressor gene product KiSS-1 protein/metastin by matrix metalloproteinases

Takahisa Takino1, Naohiko Koshikawa2, Hisashi Miyamori1, Motohiro Tanaka3, Takuma Sasaki3,4, Yasunori Okada5, Motoharu Seiki2 and Hiroshi Sato1,4

1Department of Molecular Virology and Oncology, Cancer Research Institute, Kanazawa University, Kanazawa 920-0934, Japan

2Department of Cancer Cell Research, Institute of Medical Science, University of Tokyo, Tokyo 108-8639, Japan

3Department of Chemotherapy, Cancer Research Institute, Kanazawa University, Kanazawa 920-0934, Japan

4Center for the Development of Molecular Target Drugs, Cancer Research Institute, Kanazawa University, Kanazawa 920-0934, Japan

5Department of Pathology, Medical School, Keio University, Tokyo 160-8582, Japan

Correspondence to: H Sato, Department of Molecular Virology and Oncology, Cancer Research Institute, Kanazawa University, 13-1 Takara-machi, Kanazawa 920-0934, Japan. E-mail: vhsato@kenroku.kanazawa-u.ac.jp


A human placenta cDNA library was screened by the expression cloning method for gene products that interact with matrix metalloproteinases (MMPs), and we isolated a cDNA whose product formed a stable complex with pro-MMP-2 and pro-MMP-9. The cDNA encoded the metastasis suppressor gene KiSS-1. KiSS-1 protein was shown to form a complex with pro-MMP. KiSS-1 protein is known to be processed to peptide ligand of a G-protein-coupled receptor (hOT7T175) named metastin, and suppresses metastasis of tumors expressing the receptor. Active MMP-2, MMP-9, MT1-MMP, MT3-MMP and MT5-MMP cleaved the Gly118-Leu119 peptide bond of not only full-length KiSS-1 protein but also metastin decapeptide. Metastin decapeptide induced formation of focal adhesion and actin stress fibers in cells expressing the receptor, and digestion of metastin decapeptide by MMP abolished its ligand activity. Migration of HT1080 cells expressing hOT7T175 that harbor a high-level MMP activity was only slightly suppressed by either metastin decapeptide or MMP inhibitor BB-94 alone, but the combination of metastin decapeptide and BB-94 showed a synergistic effect in blocking cell migration. We propose that metastin could be used as an antimetastatic agent in combination with MMP inhibitor, or MMP-resistant forms of metastin could be developed and may also be efficacious.

Oncogene (2003) 22, 4617-4626. doi:10.1038/sj.onc.1206542


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