Lung carcinoma progression and survival versus amino- and carboxyl-parathyroid hormone-related protein expression

• Published in: Journal of cancer research and clinical oncology Vol. 143; no. 8; pp. 1395 - 1407
• Main Authors: Hastings, Randolph H., Montgrain, Philippe R., Quintana, Rick A., Chobrutskiy, Boris, Davani, Ashkhan, Miyanohara, Atsushi, Mahooti, Sepi
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer Berlin Heidelberg 01.08.2017; Springer Nature B.V
• Subjects: Adenocarcinoma; Adenocarcinoma - genetics; Adenocarcinoma - pathology; Adenocarcinoma of Lung; Adult; Aged; Animals; Biomarkers, Tumor - biosynthesis; Biomarkers, Tumor - genetics; Cancer Research; Carcinoma, Non-Small-Cell Lung - genetics; Carcinoma, Non-Small-Cell Lung - pathology; Disease Progression; Disease-Free Survival; Female; Gene Expression Regulation, Neoplastic; Hematology; Hormones; Humans; Internal Medicine; Lung cancer; Lung carcinoma; Lung Neoplasms - genetics; Lung Neoplasms - pathology; Male; Medical prognosis; Medicine; Medicine & Public Health; Mice; Middle Aged; Oncology; Original Article – Cancer Research; Parathyroid; Parathyroid hormone; Parathyroid hormone-related protein; Parathyroid Hormone-Related Protein - biosynthesis; Parathyroid Hormone-Related Protein - genetics; Protein Domains - genetics; Protein expression; Survival; Tissue Array Analysis; Tumors; Xenograft Model Antitumor Assays; Xenografts; Carcinoma, non-small cell lung; Molecular diagnosis and prognosis; Tumor suppressor proteins; Oncogenes; Neuroendocrine and other endocrine factors; Biochemical markers
• ISSN: 0171-5216; 1432-1335
• DOI: 10.1007/s00432-017-2396-4

Purpose Expression of the carboxyl PTHrP region of parathyroid hormone-related protein (PTHrP) is a positive prognostic indicator in women with lung cancer, but amino PTHrP is a negative indicator in other lung cancer patients. This project investigated whether PTHrP could be expressed as predominantly amino PTHrP or carboxyl PTHrP in individual lung carcinomas. It also assessed domain-specific effects on cancer progression and patient survival. Methods PTHrP immunoreactivities were analyzed versus survival in a human lung cancer tissue microarray (TMA). Growth was compared in athymic mice for isogenic lung carcinoma xenografts differing in expression of amino and carboxyl PTHrP domains. Results In the TMA, 33 of 99 patient tumors expressed only one PTHrP domain, while 54 expressed both. By Cox regression, the hazard ratio for cancer-specific mortality (95% confidence interval) was 2.6 (1.28–5.44) for amino PTHrP ( P  = 0.008) and 0.6 (0–2.58) for carboxyl PTHrP ( P  = 0.092). Xenografts of H358 lung adenocarcinoma cells that overexpressed amino PTHrP grew twice as fast as isogenic low PTHrP tumors in athymic mice, but growth of tumors expressing amino plus carboxyl PTHrP was not significantly different than growth of the control tumors. In summary, the presence of amino PTHrP signifies worse prognosis in lung cancer patients. In mouse xenografts, this effect was abrogated if carboxyl PTHrP was also present. Conclusion Amino PTHrP and carboxyl PTHrP can vary independently in different lung carcinomas. Carboxyl PTHrP may temper the stimulatory effect of amino PTHrP on cancer progression.