TGF-beta during human colorectal carcinogenesis: the shift from epithelial to mesenchymal signaling.
Transforming growth factor-beta (TGF-beta) activates not only TGF-beta type I receptor (Tbeta RI) but also c-Jun N-terminal kinase (JNK), converting the mediator Smad3 to two distinct phosphoisoforms: C-terminally phosphorylated Smad3 (pSmad3C) and linker phosphorylated Smad3 (pSmad3L). While Tbeta RI/pSmad3C pathway inhibits growth of normal epithelial cells, the activated mesenchymal cells invade via JNK/pSmad3L pathway. During sporadic human colorectal carcinogenesis, TGF-beta signaling confers a selective advantage upon tumor cells by shifting from epithelial Tbeta RI/pSmad3C pathway to mesenchymal JNK/pSmad3L pathway. Loss of epithelial homeostasis and acquisition of a migratory, mesenchymal phenotype are essential for tumor invasion. In a future, specific inhibition of the JNK/pSmad3L pathway will become a therapy for human colorectal cancer that restores the lost tumor-suppressive function observed in normal colorectal epithelial cells at the expense of effects promoting the aggressive behavior.
Matsuzaki
K
K
Department of Gastroenterology and Hepatology, Kansai Medical University, 10-15 Fumizonocho, Moriguchi, Osaka, 570-8507, Japan. matsuzak@takii.kmu.ac.jp
Seki
T
T
Okazaki
K
K
D000818:Animals; D002454:Cell Differentiation; D015179:Colorectal Neoplasms / Q000378:metabolism* / Q000473:pathology; D004848:Epithelium / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D008648:Mesoderm / Q000378:metabolism / Q000473:pathology; D009361:Neoplasm Invasiveness; D015398:Signal Transduction; D016212:Transforming Growth Factor beta / Q000378:metabolism*
D016212:Transforming Growth Factor beta