Abstract
Purpose
Osteosarcoma is the most common primary malignancy in orthopaedic surgery. Studies suggest that expression of VEGF and high vascularity within osteosarcoma may correlate with poor prognosis. The purpose of this study was to determine whether there was a correlation of VEGF expression with clinical tumour stage and metastasis.
Methods
This retrospective case series examined 54 cases of osteosarcoma patients who were treated during a ten-year period. Relevant clinical information included age, gender, tumour location, stage, adjuvant therapy, morbidity, mortality, and tumour subtypes. The clinical information was analysed for correlation of VEGF expression and tumour prognosis. Tumour sections were examined by routine H&E and by immunohistochemistry for VEGF, CD31, and the oncogenes c-myc and c-fos.
Results
There was a significantly positive correlation between VEGF expression and tumour stages among these cases (p < 0.01). The data also suggested a higher cancer recurrence and more frequent cases of remote metastasis in the high-VEGF group compared to the low-VEGF group. VEGF expression also positively associated with c-fos and c-myc expressions in the primary tumour sections.
Conclusion
The results of this study highlight the role of VEGF in angiogenesis and tumour burden. Data also suggest the influence of VEGF may associate with the elevations of c-fos and c-myc expression. The development of novel therapies to target the VEGF pathway in osteosarcoma may lead to improved survival.
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References
Messerschmitt PJ, Garcia RM, Abdul-Karim FW, Greenfield EM, Getty PJ (2009) Osteosarcoma. J Am Acad Orthop Surg 17(8):515–527
Rosen G, Suwansirikul S, Kwon C, Tan C, Wu SJ, Beattie EJ Jr, Murphy ML (1974) High-dose methotrexate with citrovorum factor rescue and adriamycin in childhood osteogenic sarcoma. Cancer 33(4):1151–1163
Coomber BL, Denton J, Sylvestre A, Kruth S (1998) Blood vessel density in canine osteosarcomas. Can J Vet Res 62(3):199–204
Keck PJ, Hauser SD, Krivi G, Sanzo K, Warren T, Feder J, Connolly DT (1989) Vascular permeability factor, an endothelial cell mitogen related to PDGF. Science 246(4935):1309–1312
Leung DW, Cachianes G, Kuang WJ, Goeddel DV, Ferrara N (1989) Vascular endothelial growth factor is a secreted angiogenic mitogen. Science 246(4935):1306–1309
Sallinen H, Anttila M, Narvainen J, Koponen J, Hamalainen K, Kholova I, Heikura T, Toivanen P, Kosma VM, Heinonen S, Alitalo K, Yla-Herttuala S (2009) Antiangiogenic gene therapy with soluble VEGFR-1, -2, and -3 reduces the growth of solid human ovarian carcinoma in mice. Mol Ther 17(2):278–284. doi:10.1038/mt.2008.258
Jia ZZ, Jiang GM, Feng YL (2011) Serum HIF-1alpha and VEGF levels pre- and post-TACE in patients with primary liver cancer. Chin Med Sci J (Chung-kuo i hsueh k'o hsueh tsa chih/Chinese Academy of Medical Sciences) 26(3):158–162
Roland CL, Dineen SP, Lynn KD, Sullivan LA, Dellinger MT, Sadegh L, Sullivan JP, Shames DS, Brekken RA (2009) Inhibition of vascular endothelial growth factor reduces angiogenesis and modulates immune cell infiltration of orthotopic breast cancer xenografts. Mol Cancer Ther 8(7):1761–1771. doi:10.1158/1535-7163.MCT-09-0280
Tokunaga T, Oshika Y, Abe Y, Ozeki Y, Sadahiro S, Kijima H, Tsuchida T, Yamazaki H, Ueyama Y, Tamaoki N, Nakamura M (1998) Vascular endothelial growth factor (VEGF) mRNA isoform expression pattern is correlated with liver metastasis and poor prognosis in colon cancer. Br J Cancer 77(6):998–1002
Yuan A, Yu CJ, Kuo SH, Chen WJ, Lin FY, Luh KT, Yang PC, Lee YC (2001) Vascular endothelial growth factor 189 mRNA isoform expression specifically correlates with tumor angiogenesis, patient survival, and postoperative relapse in non-small-cell lung cancer. J Clin Oncol 19(2):432–441
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 (1999) Cell-retained isoforms of vascular endothelial growth factor (VEGF) are correlated with poor prognosis in osteosarcoma. Eur J Cancer 35(7):1089–1093
Kaya M, Wada T, Akatsuka T, Kawaguchi S, Nagoya S, Shindoh M, Higashino F, Mezawa F, Okada F, Ishii S (2000) Vascular endothelial growth factor expression in untreated osteosarcoma is predictive of pulmonary metastasis and poor prognosis. Clin Cancer Res 6(2):572–577
Ben Josef E, Yang SY, Ji TH, Bidart JM, Garde SV, Chopra DP, Porter AT, Tang DG (1999) Hormone-refractory prostate cancer cells express functional follicle-stimulating hormone receptor (FSHR). J Urol 161(3):970–976
Folkman J (1995) Angiogenesis in cancer, vascular, rheumatoid and other disease. Nat Med 1(1):27–31
Weidner N, Carroll PR, Flax J, Blumenfeld W, Folkman J (1993) Tumor angiogenesis correlates with metastasis in invasive prostate carcinoma. Am J Pathol 143(2):401–409
Weidner N, Folkman J (1996) Tumoral vascularity as a prognostic factor in cancer. Important Adv Oncol 167–190
Hanahan D, Folkman J (1996) Patterns and emerging mechanisms of the angiogenic switch during tumorigenesis. Cell 86(3):353–364
McMahon G (2000) VEGF receptor signaling in tumor angiogenesis. Oncologist 5(Suppl 1):3–10
Folkman J (2002) Role of angiogenesis in tumor growth and metastasis. Semin Oncol 29(6 Suppl 16):15–18
Suzuki K, Hayashi N, Miyamoto Y, Yamamoto M, Ohkawa K, Ito Y, Sasaki Y, Yamaguchi Y, Nakase H, Noda K, Enomoto N, Arai K, Yamada Y, Yoshihara H, Tujimura T, Kawano K, Yoshikawa K, Kamada T (1996) Expression of vascular permeability factor/vascular endothelial growth factor in human hepatocellular carcinoma. Cancer Res 56(13):3004–3009
Cole MD, McMahon SB (1999) The Myc oncoprotein: a critical evaluation of transactivation and target gene regulation. Oncogene 18(19):2916–2924
van den Berg S, Rahmsdorf HJ, Herrlich P, Kaina B (1993) Overexpression of c-fos increases recombination frequency in human osteosarcoma cells. Carcinogenesis 14(5):925–928
Wu JX, Carpenter PM, Gresens C, Keh R, Niman H, Morris JW, Mercola D (1990) The proto-oncogene c-fos is over-expressed in the majority of human osteosarcomas. Oncogene 5(7):989–1000
Gamberi G, Benassi MS, Bohling T, Ragazzini P, Molendini L, Sollazzo MR, Pompetti F, Merli M, Magagnoli G, Balladelli A, Picci P (1998) C-myc and c-fos in human osteosarcoma: prognostic value of mRNA and protein expression. Oncology 55(6):556–563
Pompetti F, Rizzo P, Simon RM, Freidlin B, Mew DJ, Pass HI, Picci P, Levine AS, Carbone M (1996) Oncogene alterations in primary, recurrent, and metastatic human bone tumors. J Cell Biochem 63(1):37–50
Takayama K, Ueno H, Nakanishi Y, Sakamoto T, Inoue K, Shimizu K, Oohashi H, Hara N (2000) Suppression of tumor angiogenesis and growth by gene transfer of a soluble form of vascular endothelial growth factor receptor into a remote organ. Cancer Res 60(8):2169–2177
Yang SY, Yu H, Krygier JE, Wooley PH, Mott MP (2007) High VEGF with rapid growth and early metastasis in a mouse osteosarcoma model. Sarcoma 2007:95628
Yin D, Jia T, Gong W, Yu H, Wooley PH, Mott MP, Yang SY (2008) VEGF blockade decelerates the growth of a murine experimental osteosarcoma. Int J Oncol 33(2):253–259
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Meghan Patni and Elizabeth Rinehart contributed equally in this study
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Lammli, J., Fan, M., Rosenthal, H.G. et al. Expression of Vascular Endothelial Growth Factor correlates with the advance of clinical osteosarcoma. International Orthopaedics (SICOT) 36, 2307–2313 (2012). https://doi.org/10.1007/s00264-012-1629-z
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DOI: https://doi.org/10.1007/s00264-012-1629-z