Anti-transforming growth factor (TGF)-beta antibodies inhibit breast cancer cell tumorigenicity and increase mouse spleen natural killer cell activity. Implications for a possible role of tumor cell/host TGF-beta interactions in human breast cancer progression.
TGF-beta effects on angiogenesis, stroma formation, and immune function suggest its possible involvement in tumor progression. This hypothesis was tested using the 2G7 IgG2b, which neutralizes TGF-beta 1, -beta 2, and -beta 3, and the MDA-231 human breast cancer cell line. Inoculation of these cells in athymic mice decreases mouse spleen natural killer (NK) cell activity. Intraperitoneal injections of 2G7 starting 1 d after intraperitoneal inoculation of tumor cells suppressed intraabdominal tumor and lung metastases, whereas the nonneutralizing anti-TGF-beta 12H5 IgG2a had no effect. 2G7 transiently inhibited growth of established MDA-231 subcutaneous tumors. Histologically, both 2G7-treated and control tumors were identical. Intraperitoneal administration of 2G7 resulted in a marked increase in mouse spleen NK cell activity. 2G7 did not inhibit MDA-231 primary tumor or metastases formation, nor did it stimulate NK cell-mediated cytotoxicity in beige NK-deficient nude mice. Finally, serum-free conditioned medium from MDA-231 cells inhibited the NK cell activity of human blood lymphocytes. This inhibition was blocked by the neutralizing anti-TGF-beta 2G7 antibody but not by a nonspecific IgG2. These data support a possible role for tumor cell TGF-beta in the progression of mammary carcinomas by suppressing host immune surveillance.
Arteaga
C L
CL
Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee 37232.
Hurd
S D
SD
Winnier
A R
AR
Johnson
M D
MD
Fendly
B M
BM
Forbes
J T
JT
D000818:Animals; D000906:Antibodies / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000098:blood supply / Q000276:immunology / Q000473:pathology*; D002455:Cell Division; D003094:Collagen / Q000032:analysis / Q000378:metabolism; D003602:Cytotoxicity, Immunologic; D005169:Factor VIII / Q000032:analysis / Q000378:metabolism; D005260:Female; D006801:Humans; D007074:Immunoglobulin G / Q000145:classification / Q000494:pharmacology; D007694:Killer Cells, Natural / Q000276:immunology*; D008175:Lung Neoplasms / Q000276:immunology / Q000517:prevention & control / Q000556:secondary*; D051379:Mice; D008819:Mice, Nude; D009362:Neoplasm Metastasis; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic / Q000517:prevention & control; D011994:Recombinant Proteins / Q000494:pharmacology; D013154:Spleen / Q000276:immunology; D016212:Transforming Growth Factor beta / Q000276:immunology* / Q000494:pharmacology / Q000502:physiology*; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured
D000906:Antibodies; D007074:Immunoglobulin G; D011994:Recombinant Proteins; D016212:Transforming Growth Factor beta; D005169:Factor VIII; D003094:Collagen