Top

Published in:

Open Access 01-12-2022 | Radiotherapy | Research

Parathyroid hormone-related peptide and parathyroid hormone-related peptide receptor type 1 in locally advanced laryngeal cancer as prognostic indicators of relapse and survival

Authors: Giovanni Almadori, Antonella Coli, Eugenio De Corso, Dario Antonio Mele, Stefano Settimi, Giovanni Di Cintio, Francesca Brigato, Domenico Scannone, Libero Lauriola, Franco Oreste Ranelletti

Published in: BMC Cancer | Issue 1/2022

Abstract

Background

Parathyroid hormone-related peptide (PTHrP) overexpression and poor patient outcome have been reported for many human tumors, but no studies are available in laryngeal cancer. Therefore, we studied the expression of PTHrP and its receptor, parathyroid hormone-related peptide receptor type 1 (PTH1R), in primary locally advanced laryngeal squamous cell carcinomas (LALSCC) also in relation to the clinical outcome of patients.

Methods

We conducted a retrospective exploratory study, using immunohistochemistry, on PTHrP, PTH1R and HER1 expressions in LALSCC of 66 patients treated with bio-radiotherapy with cetuximab.

Results

The expressions of PTHrP and PTH1R in LALSCC were associated with the degree of tumor differentiation (p = 0.01 and 0.04, respectively). Poorly differentiated tumors, with worse prognosis, expressed PTHrP at nuclear level and were PTH1R negative. PTHrP and PTH1R were expressed at cytoplasmic level in normal larynx epithelium and more differentiated laryngeal cancer cells, suggesting an autocrine/paracrine role of PTHrP in squamous cell differentiation of well differentiated tumors with good prognosis. Eighty-one percent HER1 positive tumors expressed PTHrP (p < 0.0001), mainly at nuclear level, consistent with the known up-regulation of PTHrP gene by HER1 signaling. In multivariable analyses, patients with PTHrP positive tumors had a higher relative risk of relapse (HR = 5.49; CI 95% = 1.62–22.24; p = 0.006) and survival (HR = 8.21; CI 95% = 1.19–105.00; p = 0.031) while those with PTH1R positive tumors showed a lower relative risk of relapse (HR = 0.18; CI 95% = 0.04–0.62; p = 0.002) and survival (HR = 0.18; CI 95% = 0.04–0.91; p = 0.029).

Conclusions

In LALSCC nuclear PTHrP and absence of PTH1R expressions could be useful in predicting response and/or resistance to cetuximab in combined therapies, contributing to an aggressive behavior of tumor cells downstream to HER1.

Available only for authorised users

Siegel RL, Miller KD, Jemal A. Cancer statistics, 2016. CA Cancer J Clin. 2016;66(1):7–30 https://doi.org/10.3322/caac.21332.PubMedCrossRef

Department of Veterans Affairs Laryngeal Cancer Study Group, Wolf GT, Fisher SG, Hong WK, Hillman R, Spaulding M, Laramore GE, et al. Induction chemotherapy plus radiation compared with surgery plus radiation in patients with advanced laryngeal cancer. N Engl J Med 1991;324(24):1685–1690. https://doi.org/10.1056/NEJM199106133242402.

Forastiere AA, Goepfert H, Maor M, Pajak TF, Weber R, Morrison W, et al. Concurrent chemotherapy and radiotherapy for organ preservation in advanced laryngeal cancer. N Engl J Med. 2003;349(22):2091–8 https://doi.org/10.1056/NEJMoa031317.PubMedCrossRef

Pignon JP, le Maître A, Maillard E, Bourhis J. MACH-NC collaborative group. Meta-analysis of chemotherapy in head and neck cancer (MACH-NC): an update on 93 randomised trials and 17,346 patients. Radiother Oncol. 2009;92(1):4–14 https://doi.org/10.1016/j.radonc.2009.04.014.PubMedCrossRef

Wysolmerski JJ, Stewart AF. The physiology of parathyroid hormone-related protein: an emerging role as a developmental factor. Annu Rev Physiol. 1998;60:431–60 https://doi.org/10.1146/annurev.physiol.60.1.431.PubMedCrossRef

Burtis WJ. Parathyroid hormone-related protein: structure, function, and measurement. Clin Chem. 1992;38(11):2171–83.PubMedCrossRef

Luparello C, Burtis WJ, Raue F, Birch MA, Gallagher JA. Parathyroid hormone-related peptide and 8701-BC breast cancer cell growth and invasion in vitro: evidence for growth-inhibiting and invasion-promoting effects. Mol Cell Endocrinol. 1995;111(2):225–32 https://doi.org/10.1016/0303-7207(95)03577-t.PubMedCrossRef

Massfelder T, Dann P, Wu TL, Vasavada R, Helwig JJ, Stewart AF. Opposing mitogenic and anti-mitogenic actions of parathyroid hormone-related protein in vascular smooth muscle cells: a critical role for nuclear targeting. Proc Natl Acad Sci U S A. 1997;94(25):13630–5 https://doi.org/10.1073/pnas.94.25.13630.PubMedPubMedCentralCrossRef

Tovar Sepulveda VA, Falzon M. Parathyroid hormone-related protein enhances PC-3 prostate cancer cell growth via both autocrine/paracrine and intracrine pathways. Regul Pept. 2002;105(2):109–20 https://doi.org/10.1016/s0167-0115(02)00007-1.PubMedCrossRef

10.

Hastings RH, Asirvatham A, Quintana R, Sandoval R, Dutta R, Burton DW, et al. Parathyroid hormone-related protein-(38-64) regulates lung cell proliferation after silica injury. Am J Physiol Lung Cell Mol Physiol 2002;283(1):L12–21.https://doi.org/10.1152/ajplung.00308.2001.

11.

Watson PH, Pickard BW. Nuclear trafficking of the G-protein-coupled parathyroid hormone receptor. Crit Rev Eukaryot Gene Expr. 2008;18(2):151–61 https://doi.org/10.1615/critreveukargeneexpr.v18.i2.40.PubMedCrossRef

12.

Nishihara M, Kanematsu T, Taguchi T, Razzaque MS. PTHrP and tumorigenesis: is there a role in prognosis? Ann N Y Acad Sci. 2007;1117:385–92 https://doi.org/10.1196/annals.1402.046.PubMedCrossRef

13.

Park SI, Lee C, Sadler WD, Koh AJ, Jones J, Seo JW, et al. Parathyroid hormone-related protein drives a CD11b+Gr1+ cell-mediated positive feedback loop to support prostate cancer growth. Cancer Res. 2013;73(22):6574–83 https://doi.org/10.1158/0008-5472.CAN-12-4692.PubMedCrossRef

14.

García M, Rodríguez-Hernández CJ, Mateo-Lozano S, Pérez-Jaume S, Gonçalves-Alves E, Lavarino C, et al. Parathyroid hormone-like hormone plays a dual role in neuroblastoma depending on PTH1R expression. Mol Oncol. 2019;13(9):1959–75 https://doi.org/10.1002/1878-0261.12542.PubMedPubMedCentralCrossRef

15.

Lv Z, Wu X, Cao W, Shen Z, Wang L, Xie F, et al. Parathyroid hormone-related protein serves as a prognostic indicator in oral squamous cell carcinoma. J Exp Clin Cancer Res. 2014;33(1):100 https://doi.org/10.1186/s13046-014-0100-y.PubMedPubMedCentralCrossRef

16.

Maurizi M, Almadori G, Ferrandina G, Distefano M, Romanini ME, Cadoni G, et al. Prognostic significance of epidermal growth factor receptor in laryngeal squamous cell carcinoma. Br J Cancer. 1996;74(8):1253–7.PubMedPubMedCentralCrossRef

17.

Kalyankrishna S, Grandis JR. Epidermal growth factor receptor biology in head and neck cancer. J Clin Oncol. 2006;24(17):2666–72 https://doi.org/10.1200/JCO.2005.04.8306.PubMedCrossRef

18.

Ang KK, Andratschke NH, Milas L. Epidermal growth factor receptor and response of head-and-neck carcinoma to therapy. Int J Radiat Oncol Biol Phys. 2004;58(3):959–65 https://doi.org/10.1016/j.ijrobp.2003.07.010.PubMedCrossRef

19.

Bonner JA, Harari PM, Giralt J, Cohen RB, Jones CU, Sur RK, et al. Radiotherapy plus cetuximab for locoregionally advanced head and neck cancer: 5-year survival data from a phase 3 randomised trial, and relation between cetuximab-induced rash and survival. Lancet Oncol. 2010;11(1):21–8 https://doi.org/10.1016/S1470-2045(09)70311-0.PubMedCrossRef

20.

Depenni R, Cossu Rocca M, Ferrari D, Azzarello G, Baldessari C, Alù M, et al. Clinical outcomes and prognostic factors in recurrent and/or metastatic head and neck cancer patients treated with chemotherapy plus cetuximab as first-line therapy in a real-world setting. Eur J Cancer. 2019;115:4–12 https://doi.org/10.1016/j.ejca.2019.03.022.PubMedCrossRef

21.

Nadler E, Joo S, Boyd M, Black-Shinn J, Chirovsky D. Treatment patterns and outcomes among patients with recurrent/metastatic squamous cell carcinoma of the head and neck. Future Oncol. 2019;15(7):739–51.PubMedCrossRef

22.

Picon H, Guddati AK. Mechanisms of resistance in head and neck cancer. Am J Cancer Res. 2020;10(9):2742–51.PubMedPubMedCentral

23.

Cramer SD, Peehl DM, Edgar MG, Wong ST, Deftos LJ, Feldman D. Parathyroid hormone--related protein (PTHrP) is an epidermal growth factor-regulated secretory product of human prostatic epithelial cells. Prostate. 1996;29(1):20–29. https://doi.org/10.1002/(SICI)1097-0045(199607)29:1<20::AID-PROS3>3.0.CO;2-M.

24.

Cho YM, Lewis DA, Koltz PF, Richard V, Gocken TA, Rosol TJ, et al. Regulation of parathyroid hormone-related protein gene expression by epidermal growth factor-family ligands in primary human keratinocytes. J Endocrinol. 2004;181(1):179–90 https://doi.org/10.1677/joe.0.1810179.PubMedCrossRef

25.

Gilmore JL, Scott JA, Bouizar Z, Robling A, Pitfield SE, Riese DJ 2nd, et al. Amphiregulin-EGFR signaling regulates PTHrP gene expression in breast cancer cells. Breast Cancer Res Treat. 2008;110(3):493–505 https://doi.org/10.1007/s10549-007-9748-8.PubMedCrossRef

26.

Gilmore JL, Gonterman RM, Menon K, Lorch G, Riese DJ 2nd, Robling A, et al. Reconstitution of amphiregulin-epidermal growth factor receptor signaling in lung squamous cell carcinomas activates PTHrP gene expression and contributes to cancer-mediated diseases of the bone. Mol Cancer Res. 2009;7(10):1714–28 https://doi.org/10.1158/1541-7786.MCR-09-0131.PubMedPubMedCentralCrossRef

27.

Chang WM, Lin YF, Su CY, Peng HY, Chang YC, Hsiao JR, et al. Parathyroid hormone-like hormone is a poor prognosis marker of head and neck Cancer and promotes cell growth via RUNX2 regulation. Sci Rep. 2017;7:41131 https://doi.org/10.1038/srep41131.PubMedPubMedCentralCrossRef

28.

Yamada T, Tsuda M, Ohba Y, Kawaguchi H, Totsuka Y, Shindoh M. PTHrP promotes malignancy of human oral cancer cell downstream of the EGFR signaling. Biochem Biophys Res Commun. 2008;368(3):575–81 https://doi.org/10.1016/j.bbrc.2008.01.121.PubMedCrossRef

29.

Schweitzer DH, Boxman IL, Löwik CW, van Krieken JH, Weissglas MG, Baatenburg de Jong RJ, et al. Parathyroid hormone related protein and interleukin-6 mRNA expression in larynx and renal cell carcinomas from normocalcaemic and hypercalcaemic patients. J Clin Pathol. 1995;48(10):896–900 https://doi.org/10.1136/jcp.48.10.896.PubMedPubMedCentralCrossRef

30.

Bonner JA, Harari PM, Giralt J, Azarnia N, Shin DM, Cohen RB, et al. Radiotherapy plus cetuximab for squamous-cell carcinoma of the head and neck. N Engl J Med. 2006;354(6):567–78 https://doi.org/10.1056/NEJMoa053422.PubMedCrossRef

31.

El-Naggar AK, Chan JKC, Grandis JR, Takata T, Slootweg PJ, editors. WHO classification of head and neck Tumours. Lyon: IARC; 2017.

32.

Monego G, Lauriola L, Ramella S, D'Angelillo RM, Lanza P, Granone P, et al. Parathyroid hormone-related peptide and parathyroid hormone-related peptide receptor type 1 expression in human lung adenocarcinoma. Chest. 2010;137(4):898–908 https://doi.org/10.1378/chest.09-1358.PubMedCrossRef

33.

Almadori G, Lauriola L, Coli A, Bussu F, Gallus R, Scannone D, et al. Minichromosome maintenance protein 7 and geminin expression: prognostic value in laryngeal squamous cell carcinoma in patients treated with radiotherapy and cetuximab. Head Neck. 2017;39(4):684–93 https://doi.org/10.1002/hed.24670.PubMedCrossRef

34.

Lawless, J. F. and Singhal, K. Efficient screening of nonnormal regression models. Biometrics. 1978;34:318–327. https://doi.org/10.2307/2530022

35.

Harrell FE. Regression modeling strategies. With applications to linear models, logistic and ordinal regression, and survival analysis. 2nd edition, Springer Series in Statistics, Springer International Publishing, Springer Nature Switzerland AG, 2015. ISBN 978–3–319-19424-0. https://doi.org/10.1007/978-3-319-19425-7.

36.

Kooperberg C, Stone CJ, Truong YK. Hazard regression. J Am Stat Assoc. 1995;90:78–94 https://doi.org/10.1080/01621459.1995.10476491.CrossRef

37.

Edwards CM, Johnson RW. From good to bad: the opposing effects of PTHrP on tumor growth, dormancy, and metastasis throughout Cancer progression. Front Oncol. 2021;22(11):644303 https://doi.org/10.3389/fonc.2021.644303.CrossRef

38.

Kumari R, Robertson JF, Watson SA. Nuclear targeting of a midregion PTHrP fragment is necessary for stimulating growth in breast cancer cells. Int J Cancer. 2006;119(1):49–59 https://doi.org/10.1002/ijc.21802.PubMedCrossRef

39.

Park SI, McCauley LK. Nuclear localization of parathyroid hormone-related peptide confers resistance to anoikis in prostate cancer cells. Endocr Relat Cancer. 2012;19(3):243–54 https://doi.org/10.1530/ERC-11-0278.PubMedPubMedCentralCrossRef

40.

Bhatia V, Saini MK, Falzon M. Nuclear PTHrP targeting regulates PTHrP secretion and enhances LoVo cell growth and survival. Regul Pept. 2009;158(1–3):149–55 https://doi.org/10.1016/j.regpep.2009.07.008.PubMedPubMedCentralCrossRef

41.

Shen X, Qian L, Falzon M. PTH-related protein enhances MCF-7 breast cancer cell adhesion, migration, and invasion via an intracrine pathway. Exp Cell Res. 2004;294(2):420–33 https://doi.org/10.1016/j.yexcr.2003.11.028.PubMedCrossRef

42.

Luparello C. Parathyroid hormone-related protein (PTHrP): a key regulator of life/death decisions by tumor cells with potential clinical applications. Cancers (Basel). 2011;3(1):396–407 https://doi.org/10.3390/cancers3010396.CrossRef

43.

Asadi F, Farraj M, Sharifi R, Malakouti S, Antar S, Kukreja S. Enhanced expression of parathyroid hormone-related protein in prostate cancer as compared with benign prostatic hyperplasia. Hum Pathol. 1996;27(12):1319–23 https://doi.org/10.1016/s0046-8177(96)90344-5.PubMedCrossRef

44.

Alipov GK, Ito M, Nakashima M, Ikeda Y, Nakayama T, Ohtsuru A, et al. Expression of parathyroid hormone-related peptide (PTHrP) in gastric tumours. J Pathol. 1997;182(2):174–9. https://doi.org/10.1002/(SICI)1096-9896(199706)182:2<174::AID-PATH840>3.0.CO;2-4.

45.

Taguchi T, Kanematsu T. Clinicopathological implications of parathyroid hormone-related protein in human colorectal tumours. J Pathol. 1999;187(2):217–22. https://doi.org/10.1002/(SICI)1096-9896(199901)187:2<217::AID-PATH210>3.0.CO;2-0.

46.

Atillasoy EJ, Burtis WJ, Milstone LM. Immunohistochemical localization of parathyroid hormone-related protein (PTHRP) in normal human skin. J Invest Dermatol. 1991;96(2):277–80 https://doi.org/10.1111/1523-1747.ep12464480.PubMedCrossRef

47.

Kaiser SM, Sebag M, Rhim JS, Kremer R, Goltzman D. Antisense-mediated inhibition of parathyroid hormone-related peptide production in a keratinocyte cell line impedes differentiation. Mol Endocrinol. 1994;8(2):139–47 https://doi.org/10.1210/mend.8.2.8170470.PubMed

48.

Huang Q, Yu GP, McCormick SA, Mo J, Datta B, Mahimkar M, et al. Genetic differences detected by comparative genomic hybridization in head and neck squamous cell carcinomas from different tumor sites: construction of oncogenetic trees for tumor progression. Genes Chromosomes Cancer. 2002;34(2):224–33 https://doi.org/10.1002/gcc.10062.PubMedCrossRef

49.

Orloff JJ, Reddy D, de Papp AE, Yang KH, Soifer NE, Stewart AF. Parathyroid hormone-related protein as a prohormone: posttranslational processing and receptor interactions. Endocr Rev. 1994;15(1):40–60 https://doi.org/10.1210/edrv-15-1-40.PubMed

50.

Hastings RH, Montgrain PR, Quintana RA, Chobrutskiy B, Davani A, Miyanohara A, et al. Lung carcinoma progression and survival versus amino- and carboxyl-parathyroid hormone-related protein expression. J Cancer Res Clin Oncol. 2017;143(8):1395–407 https://doi.org/10.1007/s00432-017-2396-4.PubMedCrossRef

51.

Ho PW, Goradia A, Russell MR, Chalk AM, Milley KM, Baker EK, et al. Knockdown of PTHR1 in osteosarcoma cells decreases invasion and growth and increases tumor differentiation in vivo. Oncogene. 2015;34(22):2922–33 https://doi.org/10.1038/onc.2014.217.PubMedCrossRef

52.

Rabinowits G, Haddad RI. Overcoming resistance to EGFR inhibitor in head and neck cancer: a review of the literature. Oral Oncol. 2012;48(11):1085–9 https://doi.org/10.1016/j.oraloncology.2012.06.016.PubMedCrossRef

53.

Boeckx C, Baay M, Wouters A, Specenier P, Vermorken JB, Peeters M, et al. Anti-epidermal growth factor receptor therapy in head and neck squamous cell carcinoma: focus on potential molecular mechanisms of drug resistance. Oncologist. 2013;18(7):850–64 https://doi.org/10.1634/theoncologist.2013-0013.PubMedPubMedCentralCrossRef

54.

Licitra L, Störkel S, Kerr KM, Van Cutsem E, Pirker R, Hirsch FR, et al. Predictive value of epidermal growth factor receptor expression for first-line chemotherapy plus cetuximab in patients with head and neck and colorectal cancer: analysis of data from the EXTREME and CRYSTAL studies. Eur J Cancer. 2013;49(6):1161–8 https://doi.org/10.1016/j.ejca.2012.11.018.PubMedCrossRef

55.

Jung K, Kang H, Mehra R. Targeting phosphoinositide 3-kinase (PI3K) in head and neck squamous cell carcinoma (HNSCC). Cancers Head Neck. 2018;3:3 https://doi.org/10.1186/s41199-018-0030-z.PubMedPubMedCentralCrossRef

56.

Saki M, Toulany M, Rodemann HP. Acquired resistance to cetuximab is associated with the overexpression of Ras family members and the loss of radiosensitization in head and neck cancer cells. Radiother Oncol. 2013;108(3):473–8 https://doi.org/10.1016/j.radonc.2013.06.023.PubMedCrossRef

57.

Shen X, Mula RV, Evers BM, Falzon M. Increased cell survival, migration, invasion, and Akt expression in PTHrP-overexpressing LoVo colon cancer cell lines. Regul Pept. 2007;141(1–3):61–72 https://doi.org/10.1016/j.regpep.2006.12.017.PubMedPubMedCentralCrossRef

58.

Bhatia V, Mula RV, Weigel NL, Falzon M. Parathyroid hormone-related protein regulates cell survival pathways via integrin alpha6beta4-mediated activation of phosphatidylinositol 3-kinase/Akt signaling. Mol Cancer Res. 2009;7(7):1119–31 https://doi.org/10.1158/1541-7786.MCR-08-0568.PubMedPubMedCentralCrossRef

59.

Sato K, Yamakawa Y, Shizume K, Satoh T, Nohtomi K, Demura H, et al. Passive immunization with anti-parathyroid hormone-related protein monoclonal antibody markedly prolongs survival time of hypercalcemic nude mice bearing transplanted human PTHrP-producing tumors. J Bone Miner Res. 1993;8(7):849–60 https://doi.org/10.1002/jbmr.5650080711.PubMedCrossRef

60.

Talon I, Lindner V, Sourbier C, Schordan E, Rothhut S, Barthelmebs M, et al. Antitumor effect of parathyroid hormone-related protein neutralizing antibody in human renal cell carcinoma in vitro and in vivo. Carcinogenesis. 2006;27(1):73–83 https://doi.org/10.1093/carcin/bgi203.PubMedCrossRef

61.

Gessi M, Monego G, Calviello G, Lanza P, Giangaspero F, Silvestrini A, et al. Human parathyroid hormone-related protein and human parathyroid hormone receptor type 1 are expressed in human medulloblastomas and regulate cell proliferation and apoptosis in medulloblastoma-derived cell lines. Acta Neuropathol. 2007;114(2):135–45 https://doi.org/10.1007/s00401-007-0212-y.PubMedCrossRef

Title: Parathyroid hormone-related peptide and parathyroid hormone-related peptide receptor type 1 in locally advanced laryngeal cancer as prognostic indicators of relapse and survival
Authors: Giovanni Almadori
Antonella Coli
Eugenio De Corso
Dario Antonio Mele
Stefano Settimi
Giovanni Di Cintio
Francesca Brigato
Domenico Scannone
Libero Lauriola
Franco Oreste Ranelletti
Publication date: 01-12-2022
Publisher: BioMed Central
Keywords: Radiotherapy
Laryngeal Cancer
Laryngeal Cancer
Cetuximab
Published in: BMC Cancer / Issue 1/2022
Electronic ISSN: 1471-2407
DOI: https://doi.org/10.1186/s12885-022-09748-1

Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras

Prof. Fabrice Barlesi

Developed by: Springer Medicine

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Background

Methods

Results

Conclusions

Please log in to get access to this content

Other articles of this Issue 1/2022

Serum-based measurements of stromal activation through ADAM12 associate with poor prognosis in colorectal cancer

Shikonin derivatives cause apoptosis and cell cycle arrest in human chondrosarcoma cells via death receptors and MAPK regulation

A cervical cancer biorepository for pharmacogenomics research in Zimbabwe

A new nomogram model for prognosis of hepatocellular carcinoma based on novel gene signature that regulates cross-talk between immune and tumor cells

Development of nomogram models of inflammatory markers based on clinical database to predict prognosis for hepatocellular carcinoma after surgical resection

A multicenter prospective cohort study to evaluate feasibility of radio-frequency identification surgical guidance for nonpalpable breast lesions: design and rationale of the RFID Localizer 1 Trial

Keynote webinar | Spotlight on antibody–drug conjugates in cancer