Inhibition of transforming growth factor alpha stimulation of human squamous cell carcinoma of the head and neck with anti-TGF-alpha antibodies and tyrphostin.
BACKGROUND
Transforming growth factor alpha (TGF-alpha) and its receptor (EGF-R) may regulate normal and malignant epithelial cell growth by an autocrine mechanism. We investigated the role of TGF-alpha in regulating head and neck SCC tumor growth.


METHODS
TGF-alpha and EGF-R levels were measured in 7 SCC cell lines and 14 SCC biopsies by RIA, Scatchard, and Western analysis. TGF-alpha autocrine stimulation of DNA synthesis in SCC cell lines was assessed by incubation with TGF-alpha neutralizing antibodies and tyrphostin AG 1478, a selective and potent inhibitor of EGF-R kinase.


RESULTS
All SCC cell lines synthesized TGF-alpha and expressed elevated EGF-R levels compared to normal keratinocytes. Twelve of the 14 SCC biopsies contained TGF-alpha protein and 8 had specific EGF-R. Exogenous TGF-alpha or EGF significantly increased DNA synthesis in 4 of 5 SCC cell lines. TGF-alpha neutralizing antibodies or tyrphostin AG 1478 reduced DNA synthesis in the two SCC cell lines (FaDu and SCC9) tested.


CONCLUSIONS
These results indicate that SCC cell lines and tumors usually synthesize TGF-alpha, have elevated levels of EGF-R, and are mitogenically stimulated by a TGF-alpha autocrine system. Selective inhibition of the TGF-alpha system by EGF-R kinase inhibitors or TGF-alpha neutralizing antibodies may be useful strategies for treating SCC that overexpress TGF-alpha and its receptor.
Solorzano
C C
CC
Department of Biochemistry, University of Louisville, Kentucky, USA.
Jones
S C
SC
Pettitjean
M
M
O'Daniel
T G
TG
Auffenberg
T
T
Woost
P G
PG
Copeland
E M
EM
Moldawer
L L
LL
Schultz
G S
GS
MacKay
S L
SL
D019898:Autocrine Communication / Q000502:physiology; D002294:Carcinoma, Squamous Cell / Q000503:physiopathology*; D004273:DNA, Neoplasm / Q000096:biosynthesis; D066246:ErbB Receptors / Q000502:physiology*; D006258:Head and Neck Neoplasms / Q000503:physiopathology*; D006801:Humans; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D012044:Regression Analysis; D016211:Transforming Growth Factor alpha / Q000037:antagonists & inhibitors*; D014407:Tumor Cells, Cultured
D004273:DNA, Neoplasm; D016211:Transforming Growth Factor alpha; D066246:ErbB Receptors; D011505:Protein-Tyrosine Kinases