Epithelial-mesenchymal transition induced by growth suppressor p12CDK2-AP1 promotes tumor cell local invasion but suppresses distant colony growth.
Epithelial-mesenchymal transition (EMT) has been considered essential for metastasis, a multistep process including local invasion, intravasation, extravasation, and proliferation at distant sites. However, controversy remains as to whether EMT truly happens and how important it is to metastasis. We studied the involvement of EMT in individual steps of metastasis and found that p12(CDK2-AP1), a down-stream effector of transforming growth factor beta, induced EMT of hamster cheek pouch carcinoma-1 cells by promoting the expression of Twist2. EMT cells have an increased invasive but decreased metastatic phenotype. When s.c. inoculated, both EMT and non-EMT cells established primary tumors, but only EMT cells invaded into the adjacent tissues and blood vessels; however, neither cells formed lung metastases. When i.v. inoculated, only non-EMT cells established lung metastases. Moreover, s.c. inoculation of a mixture of the two cell types resulted in intravasation of both cell types and formation of lung metastasis from non-EMT cells. Our results allowed us to propose a novel model for the role of EMT in cancer metastasis. We showed that EMT and non-EMT cells cooperate to complete the spontaneous metastasis process. We thus hypothesize that EMT cells are responsible for degrading the surrounding matrix to lead the way of invasion and intravasation. Non-EMT cells then enter the blood stream and reestablish colonies in the secondary sites.
Tsuji
Takanori
T
Department of Pathology, Harvard Medical School and Molecular Oncology Research Institute, Tufts Medical Center, Boston, Massachusetts 02115, USA.
Ibaragi
Soichiro
S
Shima
Kaori
K
Hu
Miaofen G
MG
Katsurano
Miki
M
Sasaki
Akira
A
Hu
Guo-fu
GF
D000818:Animals; D015820:Cadherins / Q000096:biosynthesis / Q000235:genetics; D006224:Cricetinae; D004847:Epithelial Cells / Q000473:pathology; D006801:Humans; D015603:Keratinocytes / Q000473:pathology / Q000502:physiology; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000556:secondary*; D008648:Mesoderm / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009062:Mouth Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D011494:Protein Kinases / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D014162:Transfection; D016212:Transforming Growth Factor beta / Q000494:pharmacology; D025521:Tumor Suppressor Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*
C096151:CDK2AP1 protein, human; D015820:Cadherins; D016212:Transforming Growth Factor beta; D025521:Tumor Suppressor Proteins; D011494:Protein Kinases; C496849:Cdk2ap1 protein, mouse