Involvement of c-Src in carcinoma cell motility and metastasis.
Carcinoma cells exhibit dysfunction / dysregulation of cell adhesion systems that correlates with their abilities to migrate, invade, and metastasize. Here we show that the tyrosine kinase c-Src is required for motility and metastasis of two carcinoma cell lines. Adherent KYN-2 cells having a high level of c-Src kinase activity become scattered, extend lamellipodia, and exhibit high motility. Expression of a dominant-negative mutant form of c-Src caused formation of stress fibers and focal adhesions, and markedly reduced motility. HCT15 cells extended lamellipodia and became scattered in response to lysophosphatidic acid stimulation in parallel with transient activation of c-Src, which was inhibited by expression of a dominant-negative mutant form of c-Src or treatment with a specific Src kinase inhibitor. Furthermore, implantation of dominant-negative c-Src transfectants into the peritoneal cavity of SCID mice resulted in reduced peritoneal dissemination compared with control transfectants. These findings indicate that c-Src activation is critically involved in carcinoma cell migration and metastasis.
Sakamoto
M
M
Pathology Division, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan.
Takamura
M
M
Ino
Y
Y
Miura
A
A
Genda
T
T
Hirohashi
S
S
D000230:Adenocarcinoma / Q000201:enzymology / Q000473:pathology*; D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000201:enzymology / Q000473:pathology*; D002465:Cell Movement / Q000187:drug effects; D003110:Colonic Neoplasms / Q000201:enzymology / Q000473:pathology*; D004789:Enzyme Activation / Q000187:drug effects; D022001:Focal Adhesions / Q000648:ultrastructure; D005799:Genes, Dominant; D016391:Genes, src; D006801:Humans; D008113:Liver Neoplasms / Q000201:enzymology / Q000473:pathology*; D008246:Lysophospholipids / Q000494:pharmacology; D051379:Mice; D016513:Mice, SCID; D009361:Neoplasm Invasiveness / Q000503:physiopathology*; D009362:Neoplasm Metastasis / Q000503:physiopathology*; D009363:Neoplasm Proteins / Q000235:genetics / Q000502:physiology*; D009368:Neoplasm Transplantation; D010534:Peritoneal Neoplasms / Q000473:pathology; D016392:Proto-Oncogene Proteins pp60(c-src) / Q000502:physiology*; D011554:Pseudopodia / Q000648:ultrastructure; D011993:Recombinant Fusion Proteins / Q000502:physiology; D013047:Specific Pathogen-Free Organisms; D022502:Stress Fibers / Q000648:ultrastructure; D014162:Transfection; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000201:enzymology / Q000648:ultrastructure
D008246:Lysophospholipids; D009363:Neoplasm Proteins; D011993:Recombinant Fusion Proteins; D016392:Proto-Oncogene Proteins pp60(c-src)