Parathyroid hormone-related protein regulates the growth of orthotopic human lung tumors in athymic mice.
BACKGROUND
Parathyroid hormone-related protein (PTHrP) has growth regulatory effects for many malignant cells and may influence the progression of carcinomas of the breast, prostate, and lung. In the current study, the authors investigated the in vivo and in vitro effects of PTHrP neutralizing antibody and PTHrP treatment on the growth of BEN cells, a human lung squamous cell carcinoma line that expresses PTHrP and its receptor.


METHODS
Orthotopic lung tumors were produced in 20 athymic mice with BEN-GFP cells (a clonal line that stably expresses green fluorescent protein [GFP]) by instilling suspensions of 3 x 10(6) cells per mouse into the lungs of anesthetized animals. The mice were divided into 2 groups receiving either subcutaneous mouse antihuman PTHrP antibodies or irrelevant mouse immunoglobulin (Ig) G (150 microg) twice weekly.


RESULTS
After 30 days, 6 of 10 mice receiving anti-PTHrP antibodies had lung tumors visible on macroscopic inspection, but only 1 of the 10 mice treated with irrelevant IgG had a lung tumor that was of that size (P < 0.01). GFP fluorescence was significantly greater in lung homogenates of the PTHrP antibody-treated mice than in the mice treated with IgG (6006 +/- 411 vs. 2907 +/- 282 relative fluorescent units, respectively; P < 0.001). Although neutralizing antibodies stimulated BEN cell lung tumor growth, exogenous PTHrP 1-34 treatment (0.01-1 nM) inhibited the growth of cultured BEN cells by approximately 40%.


CONCLUSIONS
Although PTHrP expression has been reported to be associated with more aggressive malignancies, the data from the current study suggest that PTHrP 1-34 was a paracrine growth inhibitor in BEN human lung carcinoma cells. The growth-related effects of PTHrP are complex, and can be both stimulatory and inhibitory.
Hastings
R H
RH
Anesthesiology and Medicine Services, VA San Diego Healthcare System and the University of California, San Diego, California 92161-5085, USA. rhhastings@ucsd.edu
Burton
D W
DW
Quintana
R A
RA
Biederman
E
E
Gujral
A
A
Deftos
L J
LJ
D000818:Animals; D000906:Antibodies / Q000276:immunology; D002118:Calcium / Q000097:blood; D002294:Carcinoma, Squamous Cell / Q000276:immunology / Q000473:pathology*; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D008175:Lung Neoplasms / Q000276:immunology / Q000473:pathology*; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D044162:Parathyroid Hormone-Related Protein; D011506:Proteins / Q000276:immunology / Q000502:physiology*; D014407:Tumor Cells, Cultured
D000906:Antibodies; C470121:PTHLH protein, human; D044162:Parathyroid Hormone-Related Protein; D011506:Proteins; D002118:Calcium