Lifetime exposure to a soluble TGF-beta antagonist protects mice against metastasis without adverse side effects.
TGF-betas play diverse and complex roles in many biological processes. In tumorigenesis, they can function either as tumor suppressors or as pro-oncogenic factors, depending on the stage of the disease. We have developed transgenic mice expressing a TGF-beta antagonist of the soluble type II TGF-beta receptor:Fc fusion protein class, under the regulation of the mammary-selective MMTV-LTR promoter/enhancer. Biologically significant levels of antagonist were detectable in the serum and most tissues of this mouse line. The mice were resistant to the development of metastases at multiple organ sites when compared with wild-type controls, both in a tail vein metastasis assay using isogenic melanoma cells and in crosses with the MMTV-neu transgenic mouse model of metastatic breast cancer. Importantly, metastasis from endogenous mammary tumors was suppressed without any enhancement of primary tumorigenesis. Furthermore, aged transgenic mice did not exhibit the severe pathology characteristic of TGF-beta null mice, despite lifetime exposure to the antagonist. The data suggest that in vivo the antagonist may selectively neutralize the undesirable TGF-beta associated with metastasis, while sparing the regulatory roles of TGF-betas in normal tissues. Thus this soluble TGF-beta antagonist has potential for long-term clinical use in the prevention of metastasis.
Yang
Yu-An
YA
Laboratory of Cell Regulation and Carcinogenesis, National Cancer Institute, Bethesda, Maryland 20892, USA.
Dukhanina
Oksana
O
Tang
Binwu
B
Mamura
Mizuko
M
Letterio
John J
JJ
MacGregor
Jennifer
J
Patel
Sejal C
SC
Khozin
Shahram
S
Liu
Zi-Yao
ZY
Green
Jeffrey
J
Anver
Miriam R
MR
Merlino
Glenn
G
Wakefield
Lalage M
LM
D000818:Animals; D005260:Female; D005822:Genetic Vectors; D006801:Humans; D007141:Immunoglobulin Fc Fragments / Q000235:genetics / Q000502:physiology*; D007074:Immunoglobulin G / Q000235:genetics / Q000502:physiology*; D008113:Liver Neoplasms / Q000556:secondary*; D015674:Mammary Neoplasms, Animal / Q000473:pathology / Q000517:prevention & control*; D008324:Mammary Tumor Virus, Mouse; D008546:Melanoma, Experimental / Q000517:prevention & control*; D051379:Mice; D008822:Mice, Transgenic; D009362:Neoplasm Metastasis / Q000517:prevention & control; D017346:Protein Serine-Threonine Kinases; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics / Q000276:immunology / Q000502:physiology*; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000502:physiology; D012995:Solubility; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors*; D014407:Tumor Cells, Cultured
D007141:Immunoglobulin Fc Fragments; D007074:Immunoglobulin G; D018125:Receptors, Transforming Growth Factor beta; D011993:Recombinant Fusion Proteins; D016212:Transforming Growth Factor beta; D017346:Protein Serine-Threonine Kinases; D000077294:Receptor, Transforming Growth Factor-beta Type II