In solid cancers, invasion and metastasis account for more than 90% of mortality. However, in the current armory of anticancer therapies, a specific category of anti-invasion and antimetastatic drugs is missing. Here, we coin the term 'migrastatics' for drugs interfering with all modes of cancer cell invasion and metastasis, to distinguish this class from conventional cytostatic drugs, which are mainly directed against cell proliferation. We define actin polymerization and contractility as target mechanisms for migrastatics, and review candidate migrastatic drugs. Critical assessment of these antimetastatic agents is warranted, because they may define new options for the treatment of solid cancers.

• Keywords
• contractility, invasion, metastasis, migrastatics, solid cancer, treatment,
• MeSH
• Drug Resistance, Neoplasm MeSH
• Molecular Targeted Therapy MeSH
• Humans MeSH
• Neoplasm Metastasis drug therapy   MeSH
• Biomarkers, Tumor MeSH
• Neoplasms drug therapy   etiology   metabolism   pathology   MeSH
• Drug Discovery * MeSH
• Cell Movement drug effects   MeSH
• Antineoplastic Agents chemistry   pharmacology   therapeutic use   MeSH
• Signal Transduction drug effects   MeSH
• Drug Synergism MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Review MeSH
• Names of Substances
• Biomarkers, Tumor MeSH
• Antineoplastic Agents MeSH

Crk-associated substrate (CAS) is a major tyrosine-phosphorylated protein in cells transformed by v-crk and v-src oncogenes and plays an important role in invasiveness of Src-transformed cells. A novel phosphorylation site on CAS, Tyr-12 (Y12) within the ligand-binding hydrophobic pocket of the CAS SH3 domain, was identified and found to be enriched in Src-transformed cells and invasive human carcinoma cells. To study the biological significance of CAS Y12 phosphorylation, phosphomimicking Y12E and nonphosphorylatable Y12F mutants of CAS were studied. The phosphomimicking mutation decreased interaction of the CAS SH3 domain with focal adhesion kinase (FAK) and PTP-PEST and reduced tyrosine phosphorylation of FAK. Live-cell imaging showed that green fluorescent protein-tagged CAS Y12E mutant is, in contrast to wild-type or Y12F CAS, excluded from focal adhesions but retains its localization to podosome-type adhesions. Expression of CAS-Y12F in cas-/- mouse embryonic fibroblasts resulted in hyperphosphorylation of the CAS substrate domain, and this was associated with slower turnover of focal adhesions and decreased cell migration. Moreover, expression of CAS Y12F in Src-transformed cells greatly decreased invasiveness when compared to wild-type CAS expression. These findings reveal an important role of CAS Y12 phosphorylation in the regulation of focal adhesion assembly, cell migration, and invasiveness of Src-transformed cells.

• MeSH
• Focal Adhesions metabolism   MeSH
• Focal Adhesion Protein-Tyrosine Kinases metabolism   MeSH
• Phosphorylation MeSH
• Neoplasm Invasiveness MeSH
• Humans MeSH
• Cell Adhesion Molecules metabolism   MeSH
• Mutation MeSH
• Mice MeSH
• Cell Transformation, Neoplastic MeSH
• Cell Line, Tumor MeSH
• Cell Movement MeSH
• Signal Transduction MeSH
• src Homology Domains MeSH
• Crk-Associated Substrate Protein chemistry   genetics   metabolism   MeSH
• Cell Line, Transformed MeSH
• Tyrosine metabolism   MeSH
• Protein Tyrosine Phosphatase, Non-Receptor Type 12 metabolism   MeSH
• Green Fluorescent Proteins metabolism   MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Mice MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• Focal Adhesion Protein-Tyrosine Kinases MeSH
• Cell Adhesion Molecules MeSH
• PTPN12 protein, human MeSH Browser
• Crk-Associated Substrate Protein MeSH
• Tyrosine MeSH
• Protein Tyrosine Phosphatase, Non-Receptor Type 12 MeSH
• Green Fluorescent Proteins MeSH