Hypoxia Markers in Human Osteosarcoma: An Exploratory Study
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Neoplastic cells growing under hypoxic conditions exhibit a more aggressive phenotype by activating a cascade of molecular events partly mediated by hypoxia-inducible transcription factor (HIF-1α) and vascular endothelial growth factor (VEGF). The roles of these markers have been studied previously in several cancer lines. We ascertained the frequency of HIF-1α expression, VEGF expression, the degree of neovascularization, and cell proliferation in osteosarcoma samples. Samples from osteosarcoma patients were assessed for HIF-1α and VEGF protein expression using immunohistochemistry, neovascularization using antibodies for Factor VIII, and cell proliferation using the Ki-67 labeling index. Associations between these parameters and clinical features were examined. HIF-1α staining was positive in 35% of patients and metastases were present in 61% of these HIF-1α-positive patients. VEGF protein expression was detected in 69% of patients, 92% of whom were female. We observed an insignificant trend for a higher frequency of VEGF expression in the high-grade as compared to low-grade osteosarcoma. We observed no association between vascular density and proliferation index and any clinical parameters. We found an association between HIF-1α expression and metastatic disease and between VEGF expression and female gender.
- Bolger BS, Symonds RP, Stanton PD, MacLean AB, Burnett R, Kelly P, Cooke TG. Prediction of radiotherapy response of cervical carcinoma through measurement of proliferation rate. Br J Cancer. 1996;74:1223–1226.
- Bos R, van Diest PJ, van der Groep P, Shvarts A, Greijer AE, van der Wall E. Expression of hypoxia-inducible factor-1alpha and cell cycle proteins in invasive breast cancer are estrogen receptor related. Breast Cancer Res. 2004;6:R450–R459. CrossRef
- Chau NM, Rogers P, Aherne W, Carroll V, Collins I, McDonald E, Workman P, Ashcroft M. Identification of novel small molecule inhibitors of hypoxia-inducible factor-1 that differentially block hypoxia-inducible factor-1 activity and hypoxia-inducible factor-1α induction in response to hypoxic stress and growth factors. Cancer Res. 2005;65:4918–4928. CrossRef
- Chen WT, Huang CJ, Wu MT, Yang SF, Su YC, Chai CY. Hypoxia-inducible factor-1alpha is associated with risk of aggressive behavior and tumor angiogenesis in gastrointestinal stromal tumor. Jpn J Clin Oncol. 2005;35:207–213. CrossRef
- Cole DJ, Brown DC, Crossley E, Alcock CJ, Gatter KC. Carcinoma of the cervix uteri: an assessment of the relationship of tumour proliferation to prognosis. Br J Cancer. 1992;65:783–785.
- Eggert A, Ikegaki N, Kwiatkowski J, Zhao H, Brodeur GM, Himelstein BP. High-level expression of angiogenic factors is associated with advanced tumor stage in human neuroblastomas. Clin Cancer Res. 2000;6:1900–1908.
- Ferrandina G, Ranelletti FO, Gallotta V, Martinelli E, Zannoni GF, Gessi M, Scambia G. Expression of cyclooxygenase-2 (COX-2), receptors for estrogen (ER), and progesterone (PR), p53, ki67, and neu protein in endometrial cancer. Gynecol Oncol. 2005;98:383–389. CrossRef
- Ferrara N. VEGF and the quest for tumour angiogenesis factors. Nat Rev Cancer. 2002;2:795–803. CrossRef
- Fyles AW, Milosevic M, Wong R, Kavanagh MC, Pintilie M, Sun A, Chapman W, Levin W, Manchul L, Keane TJ, Hill RP. Oxygenation predicts radiation response and survival in patients with cervix cancer. Radiother Oncol. 1998;48:149–156. CrossRef
- Giatromanolaki A, Koukourakis MI, Kakolyris S, Turley H, O’Byrne K, Scott PA, Pezzella F, Georgoulias V, Harris AL, Gatter KC. Vascular endothelial growth factor, wild-type p53, and angiogenesis in early operable non-small lung cancer. Clin Cancer Res. 1997;3:2485–2492.
- Graeber TG, Osmanian C, Jacks T, Housman DE, Kock CJ, Lowe SW, Giaccia AJ. Hypoxia-mediated selection of cells with diminished apoptotic potential in solid tumours. Nature. 1996;379:88–91. CrossRef
- Grau C, Overgaard J. Effect of etoposide, carmustine, vincristine, 5–fluorouracil, or methotrexate on radiobiologically oxic and hypoxic cells in a C3H mouse mammary carcinoma in situ. Cancer Chemother Pharmacol. 1992;30:277–280. CrossRef
- Hockel M, Knoop C, Schlenger K, Vorndran B, Baussmann E, Mitze M, Knapstein PG, Vaupel P. Intratumoral pO2 predicts survival in advanced cancer of the uterine cervix. Radiother Oncol. 1993;26:45–50. CrossRef
- Hockel M, Schlenger K, Aral B, Mitze M, Schaffer U, Vaupel P. Association between tumor hypoxia and malignant progression in advanced cancer of the uterine cervix. Cancer Res. 1996;56:4509–4515.
- Hockel M, Vaupel P. Tumor hypoxia: definitions and current clinical, biologic, and molecular aspects. J Natl Cancer Inst. 2001;93:266–276. CrossRef
- Iyer NV, Leung SW, Semenza GL. The human hypoxia-inducible factor 1α gene: HIF1A structure and evolutionary conservation. Genomics. 1998;52:159–165. CrossRef
- Junior AT, de Abreu Alves F, Pinto CA, Carvalho AL, Kowalski LP, Lopes MA. Clinicopathological and immunohistochemical analysis of twenty-five head and neck osteosarcomas. Oral Oncol. 2003;39:521–530. CrossRef
- Kaya M, Wada T, Akatsuka T, Kawaguchi S, Nagoya S, Shindoh M, Higashino F, Mezawa F, Okada F, Ishii S. Vascular endothelial growth factor expression in untreated osteosarcoma is predictive of pulmonary metastasis and poor prognosis. Clin Cancer Res. 2000;6:572–577.
- Keck PJ, Hauser SD, Krivi G, Sanzo K, Warren T, Feder J, Connolly DT. Vascular permeability factor, an endothelial cell mitogen related to PDGF. Science. 1989;246:1309–1312. CrossRef
- Koong AC, Denko NC, Hudson KM, Schindler C, Swiersz L, Koch C, Evans S, Ibrahim H, Le QT, Terris DJ, Giaccia AJ. Candidate genes for the hypoxic tumor phenotype. Cancer Res. 2000;60:883–887.
- Koos RD, Kazi AA, Roberson MS, Jones JM. New insight into the transcriptional regulation of vascular endothelial growth factor expression in the endometrium by estrogen and relaxin. Ann N Y Acad Sci. 2005;1041:233–247. CrossRef
- Lagrange JL, Courdi A, Chauvel P, Gioanni J, Ettore F, Bongain A, Duforestel T, Gillet JY. The labelling index in carcinoma of the uterine cervix: its correlation with tumour sterilization. Br J Radiol. 1992;65:63–65. CrossRef
- Lee AH, Dublin EA, Bobrow LG, Poulsom R. Invasive lobular and invasive ductal carcinoma of the breast show distinct patterns of vascular endothelial growth factor expression and angiogenesis. J Pathol. 1998;185:394–401. CrossRef
- Lee YH, Tokunaga T, Oshika Y, Suto R, Yanagisawa K, Tomisawa M, Fukuda H, Nakano H, Abe S, Tateishi A, Kijima H, Yamazaki H, Tamaoki N, Ueyama Y, Nakamura M. Cell-retained isoforms of vascular endothelial growth factor (VEGF) are correlated with poor prognosis in osteosarcoma. Eur J Cancer. 1999;35:1089–1093. CrossRef
- Manolagas SC. Birth and death of bone cells: basic regulatory mechanisms and implications for the pathogenesis and treatment of osteoporosis. Endocr Rev. 2000;21:115–137. CrossRef
- Manolagas SC, Kousteni S, Jilka RL. Sex steroids and bone. Recent Prog Horm Res. 2002;57:385–409. CrossRef
- Mueller MD, Vigne JL, Minchenko A, Lebovic DI, Leitman DC, Taylor RN. Regulation of vascular endothelial growth factor (VEGF) gene transcription by estrogen receptors alpha and beta. Proc Natl Acad Sci USA. 2000;97:10972–10977. CrossRef
- Nakano T, Oka K, Arai T. Histological and immunohistochemical prediction for local control of cervical squamous cell carcinoma treated with radiotherapy alone. Int J Radiation Oncology Biol Phys. 1990;19:1011–1019.
- Pan KM, Baldwin M, Nguyen J, Gasset M, Serban A, Groth D, Mehlhorn I, Huang Z, Fletterick RJ, Cohen FE, Prusiner SB. Conversion of alpha-helices beta-sheets features in the formation of the scrapie prion proteins. Proc Natl Acad Sci USA. 1993;90:10962–10966. CrossRef
- Peng TS, Qiu JS, Wu HX, Liang HZ, Luo CQ. Expressions of CD44s, MMP-9, and Ki-67: possible association with invasion, metastasis, and recurrence of osteosarcoma. Ai Zheng. 2002;21:745–750.
- Perrone G, Santini D, Vincenzi B, Zagami M, La Cesa A, Bianchi A, Altomare V, Primavera A, Battista C, Vetrani A, Tonini G, Rabitti C. COX-2 expression in DCIS: correlation with VEGF, HER-2/neu, prognostic molecular markers and clinicopathological features. Histopathology. 2005;46:561–568. CrossRef
- Poon RT, Fan ST, Wong J. Clinical implications of circulating angiogenic factors in cancer patients. J Clin Oncol. 2001;19:1207–1225.
- Riggs BL, Khosla S, Melton LJ 3rd. A unitary model for involutional osteoporosis: estrogen deficiency causes both type I and type II osteoporosis in postmenopausal women and contributes to bone loss in aging men. J Bone Miner Res. 1998;13:763–773. CrossRef
- Riggs BL, Khosla S, Melton LJ 3rd. Sex steroids and the construction and conservation of the adult skeleton. Endocr Rev. 2002;23:279–302. CrossRef
- Rofstad EK, Danielsen T. Hypoxia-induced metastasis of human melanoma cells: involvement of vascular endothelial growth factor-mediated angiogenesis. Br J Cancer. 1999;80:169–707. CrossRef
- Rosen G, Caparros B, Huvos AG, et al. Preoperative chemotherapy for osteogenic sarcoma: Selection of postoperative adjuvant chemotherapy based on the response of the primary tumor to preoperative chemotherapy. Cancer 1982;49:1221–1230. CrossRef
- Semenza GL. Regulation of mammalian O2 homeostasis by hypoxia-inducible factor 1. Annu Rev Cell Dev Biol. 1999;15:551–578. CrossRef
- Subbaramaiah K, Dannenberg AJ. Cyclooxygenase 2: a molecular target for cancer prevention and treatment. Trends Pharmacol Sci. 2003;24:96–102. CrossRef
- Tan C, de Noronha RG, Roecker AJ, Pyrzynska B, Khwaja F, Zhang Z, Zhang H, Teng Q, Nicholson AC, Giannakakou P, Zhou W, Olson JJ, Pereira MM, Nicolaou KC, Van Meir EG. Identification of a novel small-molecule inhibitor of the hypoxia-inducible factor 1 pathway. Cancer Res. 2005; 65:605–612.
- Tsang RW, Fyles AW, Kirkbride P, Levin W, Manchul LA, Milosevic MF, Rawlings GA, Banerjee D, Pintilie M, Wilson GD. Proliferation measurements with flow cytometry Tpot in cancer of the uterine cervix: correlation between two laboratories and preliminary clinical results. Int J Radiat Oncol Biol Phys. 1995;32:1319–1329.
- Tsang RW, Fyles AW, Milosevic M, Syed A, Pintilie M, Levin W, Manchul LA. Interrelationship of proliferation and hypoxia in carcinoma of the cervix. Int J Radiation Oncology Biol Phys. 2000;46:95–99. CrossRef
- Tsang RW, Wong CS, Fyles AW, Levin W, Manchul LA, Milosevic M, Chapman W, Li YQ, Pintilie M. Tumour proliferation, apoptosis in human uterine cervix carcinoma II: correlations with clinical outcome. Radiother Oncol. 1999;50:93–101. CrossRef
- Vaupel P, Kallinowski F, Okuniell P. Blood flow, oxygen and nutrient supply, and metabolic microenvironment of human tumors: a review. Cancer Res. 1989;49:6449–6465.
- Vaupel P, Mayer A. Hypoxia in cancer: Significance and impact on clinical outcome. Cancer Metastasis Rev. 2007;26:225–239. CrossRef
- Willet CG, Warland G, Hagan MP, Daly WJ, Coen J, Shellito PC, Compton CC. Tumor proliferation in rectal cancer following preoperative irradiation. J Clin Oncol. 1995;13:1417–1424.
- Wouters BG, Brown JM. Cells at intermediate oxygen levels can be more important than the “hypoxic fraction” in determining tumor response to fractionated radiotherapy. Radiat Res. 1997;147:541–550. CrossRef
- Wu Q, Yang SH, Wang RY, Ye SN, Xia T, Ma DZ. Effect of silencing HIF-1alpha by RNA interference on expression of vascular endothelial growth factor in osteosarcoma cell line SaOS-2 under hypoxia. Ai Zheng. 2005;24:531–535.
- Wu Q, Yang SH, Ye SN, Wang RY. Therapeutic effects of RNA interference targeting HIF-1 alpha gene on human osteosarcoma. Zhonghua Yi Xue Za Zhi. 2005;85:409–413.
- Zheng MH, Xu J, Robbins P, Pavlos N, Wysocki S, Kumta SM, Wood DJ, Papadimitriou JM. Gene expression of vascular endothelial growth factor in giant cell tumors of bone. Hum Pathol 2000;31:804–812. CrossRef
- Zhong H, De Marzo AM, Laughner E, Lim M, Hilton DA, Zagzag D, Buechler P, Isaacs WB, Semenza GL, Simons JW. Overexpression of hypoxia-inducible factor 1alpha in common human cancers and their metastases. Cancer Res. 1999;59:5830–5835.
- Zhu ZH, Rong TH, Zeng CG, Wu QL, Ma Y, Huang XP, Li BJ, Zhang PY, Zhao JM, Hu W, Zhang SY, Yu H, Ma GW, Zhang LJ, Wen ZS, Fu JH, Long H. Vascular endothelial growth factor expression and microvessel density in Stage I–II non-small cell lung cancer and their prognostic significances. Ai Zheng. 2005;24:865–869.
- Hypoxia Markers in Human Osteosarcoma: An Exploratory Study
Clinical Orthopaedics and Related Research
Volume 466, Issue 9 , pp 2052-2059
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- 1. Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, NY, USA
- 2. Division of Hematology/Oncology, Department of Pediatrics, The Children’s Hospital at Montefiore, 3415 Bainbridge Avenue, Rosenthal 3rd Floor, Bronx, NY, 10467, USA