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.

Parathyroid hormone-related protein and lung injury after pulmonary thromboendarterectomy.

Parathyroid hormone-related protein (PTHrP) is an autocrine growth and differentiation factor for alveolar type II epithelial cells. Type II cells secrete pulmonary surfactant and are pluripotent cells with a role in alveolar epithelial repair after lung injury. The goals of this study were to investigate whether the levels of PTHrP in bronchoalveolar lavage liquid (BAL) varied between patients who did and did not develop lung injury after pulmonary thromboendarterectomy (PTE). BAL was performed in 48 patients undergoing PTE for unresolved pulmonary emboli. Samples were obtained following induction of anesthesia, following separation from cardiopulmonary bypass, and 48 h postoperatively. PTHrP was measured by radioimmunoassay. Lung injury was diagnosed in 23 patients on the basis of hypoxemia (PaO(2)/FIO(2) < 300) and the presence of lung infiltrates in the absence of infection or atelectasis. Patients with lung injury had significantly lower preoperative BAL levels of PTHrP, 21 (21-30) pg/ml (median, interquartile gap), compared to patients without lung injury, 34 (21-41) pg/ml (P < 0.05). Preoperative BAL PTHrP levels < 32 pg/ml predicted lung injury with a positive predictive value of 60% and negative predictive value of 82%. The odds of developing lung injury for patients with preoperative PTHrP levels below this cutpoint were 6 times the odds for patients with higher levels.