Conditional overexpression of active transforming growth factor beta1 in vivo accelerates metastases of transgenic mammary tumors.
To address the role of transforming growth factor (TGF) beta in the progression of established tumors while avoiding the confounding inhibitory effects of TGF-beta on early transformation, we generated doxycycline (DOX)-inducible triple transgenic mice in which active TGF-beta1 expression could be conditionally regulated in mouse mammary tumor cells transformed by the polyomavirus middle T antigen. DOX-mediated induction of TGF-beta1 for as little as 2 weeks increased lung metastases >10-fold without a detectable effect on primary tumor cell proliferation or tumor size. DOX-induced active TGF-beta1 protein and nuclear Smad2 were restricted to cancer cells, suggesting a causal association between autocrine TGF-beta and increased metastases. Antisense-mediated inhibition of TGF-beta1 in polyomavirus middle T antigen-expressing tumor cells also reduced basal cell motility, survival, anchorage-independent growth, tumorigenicity, and metastases. Therefore, induction and/or activation of TGF-beta in hosts with established TGF-beta-responsive cancers can rapidly accelerate metastatic progression.
Muraoka-Cook
Rebecca S
RS
Department of Cancer Biology, Vanderbilt-Ingram Comprehensive Cancer Center, Vanderbilt University School of Medicine, Nashville, Tennessee, USA.
Kurokawa
Hirokazu
H
Koh
Yasuhiro
Y
Forbes
James T
JT
Roebuck
L Renee
LR
Barcellos-Hoff
Mary Helen
MH
Moody
Susan E
SE
Chodosh
Lewis A
LA
Arteaga
Carlos L
CL
D000818:Animals; D002465:Cell Movement / Q000502:physiology; D016373:DNA, Antisense / Q000235:genetics; D004268:DNA-Binding Proteins / Q000502:physiology; D005260:Female; D008325:Mammary Neoplasms, Experimental / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D051379:Mice; D008822:Mice, Transgenic; D009362:Neoplasm Metastasis; D009857:Oncogenes; D051785:Smad Proteins; D015534:Trans-Activators / Q000502:physiology; D016212:Transforming Growth Factor beta / Q000096:biosynthesis* / Q000235:genetics / Q000494:pharmacology; D053773:Transforming Growth Factor beta1
D016373:DNA, Antisense; D004268:DNA-Binding Proteins; D051785:Smad Proteins; C508961:Tgfb1 protein, mouse; D015534:Trans-Activators; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1