Aberrant TGF-beta production and regulation in metastatic malignancy.
We have examined the possible role of transforming growth factor-beta (TGF-beta) in metastatic malignancy by analyzing the production and activation of TGF-beta 1 and -beta 2 and the regulation of TGF-beta-responsive genes in oncogene-transformed metastatic fibrosarcomas. All transformed lines derived from either 10T1/2 or NIH 3T3 by either H-ras or protein-kinase encoding oncogenes produced more TGF-beta than parental cells. However, only highly metastatic fibrosarcomas secreted activated TGF-beta at rates that were greater than parental fibroblasts. Immunohistochemical staining for TGF-beta 1 showed widespread intra- and extracellular distribution in metastatic lung nodules and adjacent tissue. Cells isolated from tumors successfully metastasizing to the lung had TGF-beta 1 mRNA levels which were increased 19-fold over in vitro controls. Despite the greatly enhanced rate of secretion of activated TGF-beta, metastatic cells exhibited markedly altered responses of TGF-beta 1 and TGF-beta 2, being unable to either increase collagen secretion or enhance collagen alpha 2(1) or TGF-beta 1 mRNA levels. This lack of response was not due to either altered TGF-beta receptor affinity or numbers. Metastatic progression was, therefore, associated with an increase in the secretion of activated TGF-beta 1 and a loss of the ability to deregulate TGF-beta-responsive genes.
Schwarz
L C
LC
Manitoba Institute of Cell Biology, Winnipeg, Canada.
Wright
J A
JA
Gingras
M C
MC
Kondaiah
P
P
Danielpour
D
D
Pimentel
M
M
Sporn
M B
MB
Greenberg
A H
AH
D000818:Animals; D002461:Cell Line, Transformed; D005354:Fibrosarcoma / Q000235:genetics / Q000378:metabolism* / Q000556:secondary; D015972:Gene Expression Regulation, Neoplastic; D007150:Immunohistochemistry; D008175:Lung Neoplasms / Q000378:metabolism / Q000556:secondary; D051379:Mice; D008809:Mice, Inbred C3H; D009857:Oncogenes; D011494:Protein Kinases / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000378:metabolism; D018125:Receptors, Transforming Growth Factor beta; D016212:Transforming Growth Factor beta / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D014407:Tumor Cells, Cultured
D012333:RNA, Messenger; D011956:Receptors, Cell Surface; D018125:Receptors, Transforming Growth Factor beta; D016212:Transforming Growth Factor beta; D011494:Protein Kinases