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

  • Original Article – Cancer Research
  • Published:
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Abstract

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.

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Acknowledgements

Supported by Department of Veterans Affairs Merit Award (Hastings) and Career Development Award (Montgrain) grants.

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Authors and Affiliations

  1. Anesthesiology Service, VA Medical Center (125), VA San Diego Healthcare System, 3350 La Jolla Village Dr., San Diego, CA, 92161, USA

    Randolph H. Hastings

  2. Research Service, VA San Diego Healthcare System, San Diego, USA

    Randolph H. Hastings, Philippe R. Montgrain, Rick A. Quintana, Boris Chobrutskiy & Ashkhan Davani

  3. Medicine Service, VA San Diego Healthcare System, San Diego, USA

    Philippe R. Montgrain

  4. Department of Anesthesiology, UC San Diego, San Diego, USA

    Randolph H. Hastings

  5. Viral Vector Core, UC San Diego, San Diego, USA

    Atsushi Miyanohara

  6. Pathology Service, VA San Diego Healthcare System, San Diego, USA

    Sepi Mahooti

  7. Department of Medicine, UC San Diego, San Diego, USA

    Philippe R. Montgrain

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Correspondence to Randolph H. Hastings.

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Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institution research committee and with the 1964 Helsinki declaration and its later amendments. The local institution research board determined that the human study constituted a retrospective and satisfied all criteria for studies where formal consent is not required. All applicable international, national, and institutional guidelines for the care and use of animals were followed.

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Hastings, R.H., Montgrain, P.R., Quintana, R.A. et al. Lung carcinoma progression and survival versus amino- and carboxyl-parathyroid hormone-related protein expression. J Cancer Res Clin Oncol 143, 1395–1407 (2017). https://doi.org/10.1007/s00432-017-2396-4

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  • DOI: https://doi.org/10.1007/s00432-017-2396-4

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