Abstract
Cancer cells produce parathyroid hormone-related protein (PTHrP) in the early phase of malignancy development, before hypercalcemia occurs. The relationship between PTHrP and the clinicopathologic features of oral squamous cell carcinoma is poorly understood. We studied 60 patients (43 men, 17 women; mean age, 64.8 ± 11.2 years) with primary oral squamous cell carcinoma, from whom pretreatment biopsy specimens were obtained. We examined the relationship among immunohistochemical PTHrP expression, serum PTHrP levels, clinical characteristics of the tumor, and histopathologic aspects of the tumor. The mean calcium concentration for the 60 patients was 9.1 ± 0.4 mg/dl. No patients had laboratory evidence of hypercalcemia before treatment. Six patients had serum levels of C-terminal (C)-PTHrP higher than the normal level of 55.3 pmol/l. There were no significant differences in serum C-PTHrP levels according to TNM stages. Abundant positive immunoreactivity for anti-PTHrP (1-34) antibody was recognized diffusely in the whole cytoplasm of many tumor cells. Anti-PTHrP (38-64) antibody staining tended to localize as small granules in the cytoplasm, especially close to the nuclear periphery. There was no correlation between the serum C-PTHrP concentration and the intensity of either immunostain. The intensity of PTHrP was proportionally related to the degree of differentiation or extent of keratinization (P < 0.05) and the histologic malignancy grade of the tumor (P < 0.05), when using antibody against PTHrP (1-34), but not when using antibody against PTHrP (38-64). Serum C-PTHrP levels did not correlate with the intensity of cellular PTHrP expression and characteristics of the tumor at the initial patient visit. The fragment that includes PTHrP (1-34) may be involved in the differentiation of oral squamous cell carcinoma. The differences between immunoreactivities may have been due to differing tissue malignancies and the use of different antibodies. The results suggest the need for caution when interpreting immunoreactivities of PTHrP in malignancies.
Article PDF
Similar content being viewed by others
Avoid common mistakes on your manuscript.
References
WJ Burtis T Wu C Bunch (1987) ArticleTitleIdentification of a novel 17 000-dalton parathyroid hormone-like adenylate cyclase-stimulating protein from a tumor associated with humoral hypercalcemia of malignancy J Biol Chem 262 7151–6 Occurrence Handle3584110
JM Moseley M Kubota H Diefenbach Jagger (1987) ArticleTitleParathyroid hormone-related protein purified from a human lung cancer cell line Proc Natl Acad Sci U S A 84 5048–52 Occurrence Handle2885845
GJ Strewler PH Stern JW Jacobs (1987) ArticleTitleParathyroid hormonelike protein from human renal carcinoma cells. Structural and functional homology with parathyroid hormone J Clin Invest 80 1803–7 Occurrence Handle3680530
JJ Orloff AF Stewart (1992) Disorders of serum minerals caused by cancer FL Coe MJ Favus (Eds) Disorders of bone and mineral metabolism Raven New York 539–62
S Kimura (1986) Treatment for malignancy-associated hypercalcemia Annual report of the cancer research Ministry of Health and Welfare Tokyo 264
W Rankin V Grill TJ Martin (1997) ArticleTitleParathyroid hormone-related protein and hypercalcemia Cancer 80 IssueID8 Suppl 1564–71 Occurrence Handle10.1002/(SICI)1097-0142(19971015)80:8+<1564::AID-CNCR6>3.0.CO;2-K Occurrence Handle9362423
RE Coleman RD Rubens (1987) ArticleTitleThe clinical course of bone metastases from breast cancer Br J Cancer 55 61–6 Occurrence Handle3814476
GR Mundy (1990) ArticleTitleIncidence and pathophysiology of hypercalcemia Calcif Tissue Int 46 IssueIDSuppl S3–10 Occurrence Handle2105829
Goodwin WJ SuffixJr JR Chandler (1976) ArticleTitleHypercalcemia in epidermoid carcinoma of the head and neck Am J Surg 132 444–8 Occurrence Handle10.1016/0002-9610(76)90316-0 Occurrence Handle65132
C Won DA Decker A Drelichman M Al-Sarraf ML Reed (1983) ArticleTitleHypercalcemia in head and neck carcinoma. Incidence and prognosis Cancer 52 2261–3 Occurrence Handle6640497
M Iwase Y Kurachi S Kakuta H Sakamaki M Nakamura-Mitsuhashi M Nagumo (2001) ArticleTitleHypercalcemia in patients with oral squamous cell carcinoma Clin Oral Invest 5 194–8 Occurrence Handle10.1007/s007840100123
EB Dorman H Yang CW Vaughan WK Hong MS Strong (1984) ArticleTitleThe incidence of hypercalcemia in squamous cell carcinoma of the head and neck Head Neck Surg 7 95–8 Occurrence Handle6511440
T Yoneda R Nishimura I Kato M Ohmae M Takita M Sakuda (1991) ArticleTitleFrequency of the hypercalcemia-leukocytosis syndrome in oral malignancies Cancer 68 617–22 Occurrence Handle2065282
K Rikimaru F Matsumoto E Hayashi H Bando M Nagayama (1995) ArticleTitleEvaluation of serum concentration of parathyroid hormone-related protein and its implication in hypercalcemia in squamous cell carcinoma of the head and neck Int J Oral Maxillofac Surg 24 365–8 Occurrence Handle8627105
S Ariyan LR Farber BP Hamilton RJ Papac (1974) ArticleTitlePseudohyperparathyroidism in head and neck tumors Cancer 33 159–66 Occurrence Handle4810091
RL Stephens HH Hansen FM Muggia (1973) ArticleTitleHypercalcemia in epidermoid tumors of the head and neck and esophagus Cancer 31 1487–91 Occurrence Handle4709963
DR Bajorunas (1990) ArticleTitleClinical manifestations of cancer-related hypercalcemia Semin Oncol 17 IssueID2 Suppl 5 16–25
A Hiraki H Ueoka A Bessho (2002) ArticleTitleParathyroid hormone-related protein measured at the time of first visit is an indicator of bone metastases and survival in lung carcinoma patients with hypercalcemia Cancer 95 1706–13 Occurrence Handle10.1002/cncr.10828 Occurrence Handle12365018
Y Okada M Tsuchimochi T Ono S Toya A Okano K Shibasaki (1998) ArticleTitleHypercalcemia of oral squamous cell carcinoma: serum PTHrP levels Jpn J Oral Maxillofac Surg 44 466–76
GJ Powell J Southby JA Danks (1991) ArticleTitleLocalization of parathyroid hormone-related protein in breast cancer metastases: increased incidence in bone compared with other sites Cancer Res 51 3059–61 Occurrence Handle2032246
NJ Bundred RA Walker WA Ratcliffe J Warwick JM Morrison JG Ratcliffe (1992) ArticleTitleParathyroid hormone related protein and skeletal morbidity in breast cancer Eur J Cancer 28 690–2 Occurrence Handle1591095
SJ Vargas MT Gillespie GJ Powell (1992) ArticleTitleLocalization of parathyroid hormone-related protein mRNA expression in breast cancer and metastatic lesions by in situ hybridization J Bone Miner Res 7 971–9 Occurrence Handle1442211
WM Philbrick JJ Wysolmerski S Galbraith (1996) ArticleTitleDefining the roles of parathyroid hormone-related protein in normal physiology Physiol Rev 76 127–73 Occurrence Handle8592727
M Ito A Ohtsuru H Enomoto (1994) ArticleTitleExpression of parathyroid hormone-related peptide in relation to perturbations of gastric motility in the rat Endocrinology 134 1936–42 Occurrence Handle10.1210/en.134.4.1936 Occurrence Handle8137762
CP Rodda M Kubota JA Heath (1988) ArticleTitleEvidence for a novel parathyroid hormone-related protein in fetal lamb parathyroid glands and sheep placenta: comparisons with a similar protein implicated in humoral hypercalcaemia of malignancy J Endocrinol 117 261–71 Occurrence Handle3379358
MA Thiede GA Rodan (1988) ArticleTitleExpression of a calcium-mobilizing parathyroid hormone-like peptide in lactating mammary tissue Science 242 278–80 Occurrence Handle3175653
WM Philbrick BE Dreyer IA Nakchbandi AC Karaplis (1998) ArticleTitleParathyroid hormone-related protein is required for tooth eruption Proc Natl Acad Sci U S A 95 11846–51 Occurrence Handle10.1073/pnas.95.20.11846 Occurrence Handle9751753
JA Danks PR Ebeling J Hayman (1989) ArticleTitleParathyroid hormone-related protein: immunohistochemical localization in cancers and in normal skin J Bone Miner Res 4 273–8 Occurrence Handle2728930
JA Hayman JA Danks PR Ebeling JM Moseley BE Kemp TJ Martin (1989) ArticleTitleExpression of parathyroid hormone related protein in normal skin and in tumours of skin and skin appendages J Pathol 158 293–6 Occurrence Handle10.1002/path.1711580405 Occurrence Handle2769487
S Kitazawa M Fukase R Kitazawa (1991) ArticleTitleImmunohistologic evaluation of parathyroid hormone-related protein in human lung cancer and normal tissue with newly developed monoclonal antibody Cancer 67 984–9 Occurrence Handle1991268
EJ Atillasoy WJ Burtis LM Milstone (1991) ArticleTitleImmunohistochemical localization of parathyroid hormone-related protein (PTHRP) in normal human skin J Invest Dermatol 96 277–80 Occurrence Handle10.1111/1523-1747.ep12464480 Occurrence Handle1991989
SM Kaiser P Laneuville SM Bernier JS Rhim R Kremer D Goltzman (1992) ArticleTitleEnhanced growth of a human keratinocyte cell line induced by antisense RNA for parathyroid hormone-related peptide J Biol Chem 267 13623–8 Occurrence Handle1618864
SM Kaiser D Goltzman (1993) ArticleTitleParathyroid hormone-related peptide Clin Invest Med 16 395–406 Occurrence Handle8261693
SM Kaiser M Sebag JS Rhim R Kremer D Goltzman (1994) ArticleTitleAntisense-mediated inhibition of parathyroid hormone-related peptide production in a keratinocyte cell line impedes differentiation Mol Endocrinol 8 139–47 Occurrence Handle10.1210/me.8.2.139 Occurrence Handle8170470
LH Sobin Ch Wittekind (Eds) (1997) UICC, TNM classification of malignant tumours EditionNumber5th ed. John Wiley and Sons New York 11
M Fukunaga S Eto S Saito (1992) ArticleTitleMulticentric clinical studies on measurement of carboxyl-terminal parathyroid hormone-related protein in normal subjects (the first report) Horumon to Rinsho (Clinical endocrinology) 40 977–86
RB Payne ME Carver DB Morgan (1979) ArticleTitleInterpretation of serum total calcium: effects of adjustment for albumin concentration on frequency of abnormal values and on detection of change in the individual J Clin Pathol 32 56–60 Occurrence Handle429580
K Watanabe S Ohnami Y Nakano (1991) ArticleTitleFundamental and clinical evaluation of serum C-PTHrP levels by “C-PTHrP RIA kit” Horumon to Rinsho (Clinical endocrinology) 39 873–81
G Anneroth J Batsakis M Luna (1987) ArticleTitleReview of the literature and a recommended system of malignancy grading in oral squamous cell carcinomas Scand J Dent Res 95 229–49 Occurrence Handle3299675
JJ Pindborg CJ Reichart I Smith I van der Waal LH Sobin World Health (1997) Organization international histological classification of tumors, histological typing of cancer and precancer of the oral mucosa EditionNumber2nd ed. Springer Berlin Tokyo Heidelberg New York 11–12
WJ Burtis TG Brady JJ Orloff (1990) ArticleTitleImmunochemical characterization of circulating parathyroid hormone-related protein in patients with humoral hypercalcemia of cancer N Engl J Med 322 1106–12 Occurrence Handle2320080
WA Ratcliffe S Norbury DA Heath JG Ratcliffe (1991) ArticleTitleDevelopment and validation of an immunoradiometric assay of parathyrin-related protein in unextracted plasma Clin Chem 37 678–85 Occurrence Handle2032320
MR Pandian CH Morgan E Carlton GV Segre (1992) ArticleTitleModified immunoradiometric assay of parathyroid hormone-related protein: clinical application in the differential diagnosis of hypercalcemia Clin Chem 38 282–8 Occurrence Handle1371724
WA Ratcliffe S Norbury RA Stott DA Heath JG Ratcliffe (1991) ArticleTitleImmunoreactivity of plasma parathyrin-related peptide: three region-specific radioimmunoassays and a two-site immunoradiometric assay compared Clin Chem 37 1781–7 Occurrence Handle1845254
JJ Orloff D Reddy AE de Papp KH Yang NE Soifer AF Stewart (1994) ArticleTitleParathyroid hormone-related protein as a prohormone: posttranslational processing and receptor interactions Endocr Rev 15 40–60 Occurrence Handle10.1210/er.15.1.40 Occurrence Handle8156938
LJ Fraher K Klein R Marier (1995) ArticleTitleComparison of the pharmacokinetics of parenteral parathyroid hormone-(1-34) [PTH-(1-34)] and PTH-related peptide-(1-34) in healthy young humans J Clin Endocrinol Metab 80 60–4 Occurrence Handle10.1210/jc.80.1.60 Occurrence Handle7829640
JG Henry M Mitnick PR Dann AF Stewart (1997) ArticleTitleParathyroid hormone-related protein-(1-36) is biologically active when administered subcutaneously to humans J Clin Endocrinol Metab 82 900–6
WJ Burtis (1992) ArticleTitleParathyroid hormone-related protein: structure, function, and measurement Clin Chem 38 2171–83 Occurrence Handle1424107
NJ Bundred J Walls WA Ratcliffe (1996) ArticleTitleParathyroid hormone-related protein, bone metastases and hypercalcaemia of malignancy Ann R Coll Surg Engl 78 354–8 Occurrence Handle8712650
M Tsuchimochi A Kameta M Harada Y Okada M Katagiri (1999) ArticleTitleParathyroid hormone-related protein (PTHrP) expression and bone invasion by oral squamous cell carcinoma J Jpn Stomatol Soc 48 40–9
G Anneroth LS Hansen S Silverman SuffixJr (1986) ArticleTitleMalignancy grading in oral squamous cell carcinoma. I. Squamous cell carcinoma of the tongue and floor of mouth: histologic grading in the clinical evaluation J Oral Pathol 15 162–8 Occurrence Handle3084741
EW Odell P Jani M Sherriff (1994) ArticleTitleThe prognostic value of individual histologic grading parameters in small lingual squamous cell carcinomas. The importance of the pattern of invasion Cancer 74 789–94 Occurrence Handle8039106
M Mangin K Ikeda BE Dreyer L Milstone AE Broadus (1988) ArticleTitleTwo distinct tumor-derived, parathyroid hormone-like peptides result from alternative ribonucleic acid splicing Mol Endocrinol 2 1049–55 Occurrence Handle2464747
M Mangin K Ikeda BE Dreyer AE Broadus (1989) ArticleTitleIsolation and characterization of the human parathyroid hormone-like peptide gene Proc Natl Acad Sci U S A 86 2408–12 Occurrence Handle2928340
J Southby LM Murphy TJ Martin MT Gillespie (1996) ArticleTitleCell-specific and regulator-induced promoter usage and messenger ribonucleic acid splicing for parathyroid hormone-related protein Endocrinology 137 1349–57 Occurrence Handle10.1210/en.137.4.1349 Occurrence Handle8625910
MA Thiede GJ Strewler RA Nissenson M Rosenblatt GA Rodan (1988) ArticleTitleHuman renal carcinoma expresses two messages encoding a parathyroid hormone-like peptide: evidence for the alternative splicing of a single-copy gene Proc Natl Acad Sci U S A 85 4605–9 Occurrence Handle3290897
LS Ditmer DW Burton LJ Deftos (1996) ArticleTitleElimination of the carboxy-terminal sequences of parathyroid hormone-related protein 1–173 increases production and secretion of the truncated forms Endocrinology 137 1608–17 Occurrence Handle10.1210/en.137.5.1608 Occurrence Handle8612492
JJ Wysolmerski AF Stewart (1998) ArticleTitleThe physiology of parathyroid hormone-related protein: an emerging role as a developmental factor Annu Rev Physiol 60 431–60 Occurrence Handle10.1146/annurev.physiol.60.1.431 Occurrence Handle9558472
J Southby LM O’Keeffe TJ Martin MT Gillespie (1995) ArticleTitleAlternative promoter usage and mRNA splicing pathways for parathyroid hormone-related protein in normal tissues and tumours Br J Cancer 72 702–7 Occurrence Handle7669584
LL Plawner WM Philbrick WJ Burtis AE Broadus AF Stewart (1995) ArticleTitleCell type-specific secretion of parathyroid hormone-related protein via the regulated versus the constitutive secretory pathway J Biol Chem 270 14078–84 Occurrence Handle10.1074/jbc.270.23.14078 Occurrence Handle7775469
NE Soifer KE Dee KL Insogna (1992) ArticleTitleParathyroid hormone-related protein. Evidence for secretion of a novel mid-region fragment by three different cell types J Biol Chem 267 18236–43 Occurrence Handle1517251
N Amizuka JE Henderson K Hoshi (1996) ArticleTitleProgrammed cell death of chondrocytes and aberrant chondrogenesis in mice homozygous for parathyroid hormone-related peptide gene deletion Endocrinology 137 5055–67 Occurrence Handle10.1210/en.137.11.5055 Occurrence Handle8895380
JE Henderson N Amizuka H Warshawsky (1995) ArticleTitleNucleolar localization of parathyroid hormone-related peptide enhances survival of chondrocytes under conditions that promote apoptotic cell death Mol Cell Biol 15 4064–75 Occurrence Handle7623802
MH Lam SL Olsen WA Rankin (1997) ArticleTitlePTHrP and cell division: expression and localization of PTHrP in a keratinocyte cell line (HaCaT) during the cell cycle J Cell Physiol 173 433–46 Occurrence Handle10.1002/(SICI)1097-4652(199712)173:3<433::AID-JCP16>3.0.CO;2-C Occurrence Handle9369957
E Bucht H Rong Y Pernow (1998) ArticleTitleParathyroid hormone-related protein in patients with primary breast cancer and eucalcemia Cancer Res 58 4113–16 Occurrence Handle9751621
FP Dunne S Lee WA Ratcliffe AC Hutchesson NJ Bundred DA Heath (1993) ArticleTitleParathyroid hormone-related protein (PTHrP) gene expression in solid tumours associated with normocalcaemia and hypercalcaemia J Pathol 17 215–21 Occurrence Handle10.1002/path.1711710310
J Southby MW Kissin JA Danks (1990) ArticleTitleImmunohistochemical localization of parathyroid hormone-related protein in human breast cancer Cancer Res 50 7710–16 Occurrence Handle2253214
M Iwamura W Wu M Muramoto (1999) ArticleTitleParathyroid hormone-related protein is an independent prognostic factor for renal cell carcinoma Cancer 86 1028–34 Occurrence Handle10.1002/(SICI)1097-0142(19990915)86:6<1028::AID-CNCR19>3.0.CO;2-G Occurrence Handle10491530
Merendino JJ SuffixJr KL Insogna LM Milstone AE Broadus AF Stewart (1986) ArticleTitleA parathyroid hormone-like protein from cultured human keratinocytes Science 231 388–90 Occurrence Handle2417317
LJ Deftos AF Gazdar K Ikeda AE Broadus (1989) ArticleTitleThe parathyroid hormone-related protein associated with malignancy is secreted by neuroendocrine tumors Mol Endocrinol 3 503–8 Occurrence Handle2747656
J Foley BJ Longely JJ Wysolmerski BE Dreyer AE Broadus WM Philbrick (1998) ArticleTitlePTHrP regulates epidermal differentiation in adult mice J Invest Dermatol 111 1122–8 Occurrence Handle10.1046/j.1523-1747.1998.00428.x Occurrence Handle9856827
R Kremer CD Woodworth D Goltzman (1996) ArticleTitleExpression and action of parathyroid hormone-related peptide in human cervical epithelial cells Am J Physiol 271 C164–71 Occurrence Handle8760042
M Iwamura PA di Sant’Agnese G Wu (1993) ArticleTitleImmunohistochemical localization of parathyroid hormone-related protein in human prostate cancer Cancer Res 53 1724–6 Occurrence Handle8467485
F Asadi M Farraj R Sharifi S Malakouti S Antar S Kukreja (1996) ArticleTitleEnhanced expression of parathyroid hormone-related protein in prostate cancer as compared with benign prostatic hyperplasia Hum Pathol 27 1319–23 Occurrence Handle10.1016/S0046-8177(96)90344-5 Occurrence Handle8958305
GK Alipov M Ito M Nakashima (1997) ArticleTitleExpression of parathyroid hormone-related peptide (PTHrP) in gastric tumours J Pathol 182 174–9 Occurrence Handle10.1002/(SICI)1096-9896(199706)182:2<174::AID-PATH840>3.0.CO;2-4 Occurrence Handle9274527
M Nishihara M Ito T Tomioka A Ohtsuru T Taguchi T Kanematsu (1999) ArticleTitleClinicopathological implications of parathyroid hormone-related protein in human colorectal tumours J Pathol 187 217–22 Occurrence Handle10.1002/(SICI)1096-9896(199901)187:2<217::AID-PATH210>3.0.CO;2-0 Occurrence Handle10365097
S Kitazawa R Kitazawa M Fukase T Fujimori S Maeda (1992) ArticleTitleImmunohistochemical evaluation of parathyroid hormone-related protein (PTHrP) in the uterine cervix Int J Cancer 50 731–5 Occurrence Handle1544706
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Tsuchimochi, M., Kameta, A., Sue, M. et al. Immunohistochemical localization of parathyroid hormone-related protein (PTHrP) and serum PTHrP in normocalcemic patients with oral squamous cell carcinoma. Odontology 93, 61–71 (2005). https://doi.org/10.1007/s10266-005-0049-6
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1007/s10266-005-0049-6