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


CONCLUSIONS
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.
Anesthesiology Service, VA Medical Center (125), VA San Diego Healthcare System, 3350 La Jolla Village Dr., San Diego, CA, 92161, USA. rhhastings@ucsd.edu.|Research Service, VA San Diego Healthcare System, San Diego, USA. rhhastings@ucsd.edu.|Department of Anesthesiology, UC San Diego, San Diego, USA. rhhastings@ucsd.edu.
Randolph H
http://orcid.org/0000-0003-4870-101X
RH
Hastings
Research Service, VA San Diego Healthcare System, San Diego, USA.|Medicine Service, VA San Diego Healthcare System, San Diego, USA.|Department of Medicine, UC San Diego, San Diego, USA.
Philippe R
PR
Montgrain
Research Service, VA San Diego Healthcare System, San Diego, USA.
Rick A
RA
Quintana
Research Service, VA San Diego Healthcare System, San Diego, USA.
Boris
B
Chobrutskiy
Research Service, VA San Diego Healthcare System, San Diego, USA.
Ashkhan
A
Davani
Viral Vector Core, UC San Diego, San Diego, USA.
Atsushi
A
Miyanohara
Pathology Service, VA San Diego Healthcare System, San Diego, USA.
Sepi
S
Mahooti
D000230:Adenocarcinoma / Q000235:genetics* / Q000473:pathology; D000077192:Adenocarcinoma of Lung; D000328:Adult; D000368:Aged; D000818:Animals; D014408:Biomarkers, Tumor / Q000096:biosynthesis / Q000235:genetics*; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics* / Q000473:pathology; D018450:Disease Progression; D018572:Disease-Free Survival; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics* / Q000473:pathology; D008297:Male; D051379:Mice; D008875:Middle Aged; D044162:Parathyroid Hormone-Related Protein / Q000096:biosynthesis / Q000235:genetics*; D000072417:Protein Domains / Q000235:genetics; D046888:Tissue Array Analysis; D023041:Xenograft Model Antitumor Assays
D014408:Biomarkers, Tumor; C470121:PTHLH protein, human; D044162:Parathyroid Hormone-Related Protein
Biochemical markers; Carcinoma, non-small cell lung; Molecular diagnosis and prognosis; Neuroendocrine and other endocrine factors; Oncogenes; Tumor suppressor proteins