Expression of human transforming growth factor alpha by Chinese hamster ovarian tumors in nude mice causes hypercalcemia and increased osteoclastic bone resorption.
Transforming growth factor alpha (TGF-alpha) is a polypeptide regulator of cell growth produced by many malignant tumors. It stimulates osteoclastic resorption in bone organ culture and osteoclast-like cell formation in marrow culture. To determine whether tumor production of TGF-alpha can cause hypercalcemia in vivo, we used Chinese hamster ovarian (CHO) cells transfected with the human TGF-alpha gene (TCHO), which stably express and secrete TGF-alpha. We used nontransfected CHO cells as controls (CCHO). TCHO and CCHO were inoculated intramuscularly into one hindlimb of nude mice and grew as local solid tumors. After 4 weeks of TCHO tumor growth, plasma ionized calcium (Ca2+) increased to reach 1.48 +/- 0.03 mM (mean +/- SEM), whereas mice bearing similarly sized CCHO tumors and non-tumor-bearing mice (NTB) remained normocalcemic (normal range for Ca2+, 1.15-1.30 mM). Plasma TGF-alpha was undetectable by an ELIFA assay in all NTB mice, was markedly increased in all TCHO mice (5.75 +/- 0.78 ng/ml), and was slightly increased in CCHO mice (0.50 +/- 0.22 ng/ml). Quantitative bone histomorphometry showed a prominent increase in osteoclastic bone resorption in TCHO mice. These data suggest that TGF-alpha is a mediator of hypercalcemia and increased osteoclastic bone resorption in tumors that produce it in sufficient quantity.
Yates
A J
AJ
Department of Medicine, University of Texas Health Science Center, San Antonio.
Boyce
B F
BF
Favarato
G
G
Aufdemorte
T B
TB
Marcelli
C
C
Kester
M B
MB
Walker
R
R
Langton
B C
BC
Bonewald
L F
LF
Mundy
G R
GR
D000818:Animals; D001862:Bone Resorption / Q000209:etiology* / Q000378:metabolism; D001842:Bone and Bones / Q000473:pathology; D016466:CHO Cells; D002455:Cell Division; D006224:Cricetinae; D003412:Cricetulus; D005260:Female; D006934:Hypercalcemia / Q000209:etiology* / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D010051:Ovarian Neoplasms / Q000150:complications / Q000378:metabolism* / Q000473:pathology; D014162:Transfection; D016211:Transforming Growth Factor alpha / Q000096:biosynthesis / Q000502:physiology*
D016211:Transforming Growth Factor alpha