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. 2000 Aug 17;83(6):775–781. doi: 10.1054/bjoc.2000.1357

Prognostic value of vascular endothelial growth factor (VEGF) in head and neck squamous cell carcinomas

H Mineta 1, K Miura 2, T Ogino 1, S Takebayashi 1, K Misawa 1, Y Ueda 1, I Suzuki 1, M Dictor 3, Å Borg 4, J Wennerberg 5
PMCID: PMC2363534  PMID: 10952783

Abstract

Vascular endothelial growth factor (VEGF) has been identified as the substance that increases the permeability and proliferation of vascular endothelial cells. We examined the clinical significance of VEGF expression in 60 head and neck squamous cell carcinomas using the methods of Western blot, immunohistochemistry, and reverse transcriptase-polymerase chain reaction (RT-PCR), comparatively, and analysed the relationship between VEGF status in Western blot and tumour size, lymph-node status, histologic grade and disease-free survival (DFS) rate. Western blot analysis revealed high VEGF expressors (tumour/normal tissue density ≥ 3-fold) in 26 patients (43%) and low VEGF expressors (< 3-fold) in 34 patients (57%). The results of the Western blot analysis correlated significantly with those of the RT-PCR (P= 0.00007) or immunohistochemistry (P= 0.00006). High VEGF expressors are associated with the progression of lymph-node spread (P= 0.0009), which are correlated with poor DFS. The 2-year DFS rate of high VEGF expressors (30%) was significantly lower than that of low VEGF expressors (78%) (P= 0.0008). Multivariate analysis showed VEGF expression and stage were independent predictors for the DFS (P= 0.045 and 0.041, respectively). VEGF expression may play an important role in progression of HNSCC. © 2000 Cancer Research Campaign

Keywords: vascular endothelial growth factor, Western blot, head and neck carcinomas, prognostic indicator

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Selected References

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  1. Abu-Jawdeh G. M., Faix J. D., Niloff J., Tognazzi K., Manseau E., Dvorak H. F., Brown L. F. Strong expression of vascular permeability factor (vascular endothelial growth factor) and its receptors in ovarian borderline and malignant neoplasms. Lab Invest. 1996 Jun;74(6):1105–1115. [PubMed] [Google Scholar]
  2. Boocock C. A., Charnock-Jones D. S., Sharkey A. M., McLaren J., Barker P. J., Wright K. A., Twentyman P. R., Smith S. K. Expression of vascular endothelial growth factor and its receptors flt and KDR in ovarian carcinoma. J Natl Cancer Inst. 1995 Apr 5;87(7):506–516. doi: 10.1093/jnci/87.7.506. [DOI] [PubMed] [Google Scholar]
  3. Bouck N., Stellmach V., Hsu S. C. How tumors become angiogenic. Adv Cancer Res. 1996;69:135–174. doi: 10.1016/s0065-230x(08)60862-3. [DOI] [PubMed] [Google Scholar]
  4. Brown L. F., Asch B., Harvey V. S., Buchinski B., Dvorak H. F. Fibrinogen influx and accumulation of cross-linked fibrin in mouse carcinomas. Cancer Res. 1988 Apr 1;48(7):1920–1925. [PubMed] [Google Scholar]
  5. Brown L. F., Berse B., Jackman R. W., Tognazzi K., Manseau E. J., Dvorak H. F., Senger D. R. Increased expression of vascular permeability factor (vascular endothelial growth factor) and its receptors in kidney and bladder carcinomas. Am J Pathol. 1993 Nov;143(5):1255–1262. [PMC free article] [PubMed] [Google Scholar]
  6. Burian M., Quint C., Neuchrist C. Angiogenic factors in laryngeal carcinomas: do they have prognostic relevance? Acta Otolaryngol. 1999 Mar;119(2):289–292. doi: 10.1080/00016489950181846. [DOI] [PubMed] [Google Scholar]
  7. Dray T. G., Hardin N. J., Sofferman R. A. Angiogenesis as a prognostic marker in early head and neck cancer. Ann Otol Rhinol Laryngol. 1995 Sep;104(9 Pt 1):724–729. doi: 10.1177/000348949510400911. [DOI] [PubMed] [Google Scholar]
  8. Eisma R. J., Spiro J. D., Kreutzer D. L. Vascular endothelial growth factor expression in head and neck squamous cell carcinoma. Am J Surg. 1997 Nov;174(5):513–517. doi: 10.1016/s0002-9610(97)00166-9. [DOI] [PubMed] [Google Scholar]
  9. Ferrara N., Henzel W. J. Pituitary follicular cells secrete a novel heparin-binding growth factor specific for vascular endothelial cells. Biochem Biophys Res Commun. 1989 Jun 15;161(2):851–858. doi: 10.1016/0006-291x(89)92678-8. [DOI] [PubMed] [Google Scholar]
  10. Ferrara N., Houck K. A., Jakeman L. B., Winer J., Leung D. W. The vascular endothelial growth factor family of polypeptides. J Cell Biochem. 1991 Nov;47(3):211–218. doi: 10.1002/jcb.240470305. [DOI] [PubMed] [Google Scholar]
  11. Ferrara N., Houck K., Jakeman L., Leung D. W. Molecular and biological properties of the vascular endothelial growth factor family of proteins. Endocr Rev. 1992 Feb;13(1):18–32. doi: 10.1210/edrv-13-1-18. [DOI] [PubMed] [Google Scholar]
  12. Ferrara N., Leung D. W., Cachianes G., Winer J., Henzel W. J. Purification and cloning of vascular endothelial growth factor secreted by pituitary folliculostellate cells. Methods Enzymol. 1991;198:391–405. doi: 10.1016/0076-6879(91)98040-d. [DOI] [PubMed] [Google Scholar]
  13. Folkman J. Angiogenesis in cancer, vascular, rheumatoid and other disease. Nat Med. 1995 Jan;1(1):27–31. doi: 10.1038/nm0195-27. [DOI] [PubMed] [Google Scholar]
  14. Folkman J., Watson K., Ingber D., Hanahan D. Induction of angiogenesis during the transition from hyperplasia to neoplasia. Nature. 1989 May 4;339(6219):58–61. doi: 10.1038/339058a0. [DOI] [PubMed] [Google Scholar]
  15. Fontanini G., Boldrini L., Chinè S., Pisaturo F., Basolo F., Calcinai A., Lucchi M., Mussi A., Angeletti C. A., Bevilacqua G. Expression of vascular endothelial growth factor mRNA in non-small-cell lung carcinomas. Br J Cancer. 1999 Jan;79(2):363–369. doi: 10.1038/sj.bjc.6690058. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Fontanini G., Vignati S., Boldrini L., Chinè S., Silvestri V., Lucchi M., Mussi A., Angeletti C. A., Bevilacqua G. Vascular endothelial growth factor is associated with neovascularization and influences progression of non-small cell lung carcinoma. Clin Cancer Res. 1997 Jun;3(6):861–865. [PubMed] [Google Scholar]
  17. Gasparini G., Weidner N., Maluta S., Pozza F., Boracchi P., Mezzetti M., Testolin A., Bevilacqua P. Intratumoral microvessel density and p53 protein: correlation with metastasis in head-and-neck squamous-cell carcinoma. Int J Cancer. 1993 Nov 11;55(5):739–744. doi: 10.1002/ijc.2910550507. [DOI] [PubMed] [Google Scholar]
  18. Holmgren L., O'Reilly M. S., Folkman J. Dormancy of micrometastases: balanced proliferation and apoptosis in the presence of angiogenesis suppression. Nat Med. 1995 Feb;1(2):149–153. doi: 10.1038/nm0295-149. [DOI] [PubMed] [Google Scholar]
  19. Ikeda N., Adachi M., Taki T., Huang C., Hashida H., Takabayashi A., Sho M., Nakajima Y., Kanehiro H., Hisanaga M. Prognostic significance of angiogenesis in human pancreatic cancer. Br J Cancer. 1999 Mar;79(9-10):1553–1563. doi: 10.1038/sj.bjc.6690248. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Inoue K., Ozeki Y., Suganuma T., Sugiura Y., Tanaka S. Vascular endothelial growth factor expression in primary esophageal squamous cell carcinoma. Association with angiogenesis and tumor progression. Cancer. 1997 Jan 15;79(2):206–213. doi: 10.1002/(sici)1097-0142(19970115)79:2<206::aid-cncr2>3.0.co;2-i. [DOI] [PubMed] [Google Scholar]
  21. Ishigami S. I., Arii S., Furutani M., Niwano M., Harada T., Mizumoto M., Mori A., Onodera H., Imamura M. Predictive value of vascular endothelial growth factor (VEGF) in metastasis and prognosis of human colorectal cancer. Br J Cancer. 1998 Nov;78(10):1379–1384. doi: 10.1038/bjc.1998.688. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Itakura J., Ishiwata T., Friess H., Fujii H., Matsumoto Y., Büchler M. W., Korc M. Enhanced expression of vascular endothelial growth factor in human pancreatic cancer correlates with local disease progression. Clin Cancer Res. 1997 Aug;3(8):1309–1316. [PubMed] [Google Scholar]
  23. Keck P. J., Hauser S. D., Krivi G., Sanzo K., Warren T., Feder J., Connolly D. T. Vascular permeability factor, an endothelial cell mitogen related to PDGF. Science. 1989 Dec 8;246(4935):1309–1312. doi: 10.1126/science.2479987. [DOI] [PubMed] [Google Scholar]
  24. Kumar H., Heer K., Lee P. W., Duthie G. S., MacDonald A. W., Greenman J., Kerin M. J., Monson J. R. Preoperative serum vascular endothelial growth factor can predict stage in colorectal cancer. Clin Cancer Res. 1998 May;4(5):1279–1285. [PubMed] [Google Scholar]
  25. Leung D. W., Cachianes G., Kuang W. J., Goeddel D. V., Ferrara N. Vascular endothelial growth factor is a secreted angiogenic mitogen. Science. 1989 Dec 8;246(4935):1306–1309. doi: 10.1126/science.2479986. [DOI] [PubMed] [Google Scholar]
  26. Linderholm B., Tavelin B., Grankvist K., Henriksson R. Does vascular endothelial growth factor (VEGF) predict local relapse and survival in radiotherapy-treated node-negative breast cancer? Br J Cancer. 1999 Oct;81(4):727–732. doi: 10.1038/sj.bjc.6690755. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Macchiarini P., Fontanini G., Hardin M. J., Squartini F., Angeletti C. A. Relation of neovascularisation to metastasis of non-small-cell lung cancer. Lancet. 1992 Jul 18;340(8812):145–146. doi: 10.1016/0140-6736(92)93217-b. [DOI] [PubMed] [Google Scholar]
  28. Maeda K., Chung Y. S., Ogawa Y., Takatsuka S., Kang S. M., Ogawa M., Sawada T., Sowa M. Prognostic value of vascular endothelial growth factor expression in gastric carcinoma. Cancer. 1996 Mar 1;77(5):858–863. doi: 10.1002/(sici)1097-0142(19960301)77:5<858::aid-cncr8>3.0.co;2-a. [DOI] [PubMed] [Google Scholar]
  29. Maeda K., Kang S. M., Onoda N., Ogawa M., Kato Y., Sawada T., Chung K. H. Vascular endothelial growth factor expression in preoperative biopsy specimens correlates with disease recurrence in patients with early gastric carcinoma. Cancer. 1999 Aug 15;86(4):566–571. doi: 10.1002/(sici)1097-0142(19990815)86:4<566::aid-cncr4>3.0.co;2-1. [DOI] [PubMed] [Google Scholar]
  30. Maeda T., Matsumura S., Hiranuma H., Jikko A., Furukawa S., Ishida T., Fuchihata H. Expression of vascular endothelial growth factor in human oral squamous cell carcinoma: its association with tumour progression and p53 gene status. J Clin Pathol. 1998 Oct;51(10):771–775. doi: 10.1136/jcp.51.10.771. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Moriyama M., Kumagai S., Kawashiri S., Kojima K., Kakihara K., Yamamoto E. Immunohistochemical study of tumour angiogenesis in oral squamous cell carcinoma. Oral Oncol. 1997 Sep;33(5):369–374. doi: 10.1016/s1368-8375(97)00025-0. [DOI] [PubMed] [Google Scholar]
  32. Murray J. D., Carlson G. W., McLaughlin K., Pennington M., Lynn M., DeRose P. B., Williams J. K., Cohen C. Tumor angiogenesis as a prognostic factor in laryngeal cancer. Am J Surg. 1997 Nov;174(5):523–526. doi: 10.1016/s0002-9610(97)00168-2. [DOI] [PubMed] [Google Scholar]
  33. Neuchrist C., Quint C., Pammer A., Burian M. Vascular endothelial growth factor (VEGF) and microvessel density in squamous cell carcinomas of the larynx: an immunohistochemical study. Acta Otolaryngol. 1999;119(6):732–738. doi: 10.1080/00016489950180711. [DOI] [PubMed] [Google Scholar]
  34. O'Brien T., Cranston D., Fuggle S., Bicknell R., Harris A. L. Different angiogenic pathways characterize superficial and invasive bladder cancer. Cancer Res. 1995 Feb 1;55(3):510–513. [PubMed] [Google Scholar]
  35. O'Byrne K. J., Dobbs N., Propper D., Smith K., Harris A. L. Vascular endothelial growth factor platelet counts, and prognosis in renal cancer. Lancet. 1999 May 1;353(9163):1494–1495. doi: 10.1016/S0140-6736(99)00471-7. [DOI] [PubMed] [Google Scholar]
  36. Olson T. A., Mohanraj D., Carson L. F., Ramakrishnan S. Vascular permeability factor gene expression in normal and neoplastic human ovaries. Cancer Res. 1994 Jan 1;54(1):276–280. [PubMed] [Google Scholar]
  37. Paley P. J., Staskus K. A., Gebhard K., Mohanraj D., Twiggs L. B., Carson L. F., Ramakrishnan S. Vascular endothelial growth factor expression in early stage ovarian carcinoma. Cancer. 1997 Jul 1;80(1):98–106. doi: 10.1002/(sici)1097-0142(19970701)80:1<98::aid-cncr13>3.0.co;2-a. [DOI] [PubMed] [Google Scholar]
  38. Saito H., Tsujitani S., Kondo A., Ikeguchi M., Maeta M., Kaibara N. Expression of vascular endothelial growth factor correlates with hematogenous recurrence in gastric carcinoma. Surgery. 1999 Feb;125(2):195–201. [PubMed] [Google Scholar]
  39. Salven P., Heikkilä P., Anttonen A., Kajanti M., Joensuu H. Vascular endothelial growth factor in squamous cell head and neck carcinoma: expression and prognostic significance. Mod Pathol. 1997 Nov;10(11):1128–1133. [PubMed] [Google Scholar]
  40. Sauter E. R., Nesbit M., Watson J. C., Klein-Szanto A., Litwin S., Herlyn M. Vascular endothelial growth factor is a marker of tumor invasion and metastasis in squamous cell carcinomas of the head and neck. Clin Cancer Res. 1999 Apr;5(4):775–782. [PubMed] [Google Scholar]
  41. Scott P. A., Smith K., Poulsom R., De Benedetti A., Bicknell R., Harris A. L. Differential expression of vascular endothelial growth factor mRNA vs protein isoform expression in human breast cancer and relationship to eIF-4E. Br J Cancer. 1998 Jun;77(12):2120–2128. doi: 10.1038/bjc.1998.356. [DOI] [PMC free article] [PubMed] [Google Scholar]
  42. Senger D. R., Galli S. J., Dvorak A. M., Perruzzi C. A., Harvey V. S., Dvorak H. F. Tumor cells secrete a vascular permeability factor that promotes accumulation of ascites fluid. Science. 1983 Feb 25;219(4587):983–985. doi: 10.1126/science.6823562. [DOI] [PubMed] [Google Scholar]
  43. Shibusa T., Shijubo N., Abe S. Tumor angiogenesis and vascular endothelial growth factor expression in stage I lung adenocarcinoma. Clin Cancer Res. 1998 Jun;4(6):1483–1487. [PubMed] [Google Scholar]
  44. Shimada Y., Imamura M., Watanabe G., Uchida S., Harada H., Makino T., Kano M. Prognostic factors of oesophageal squamous cell carcinoma from the perspective of molecular biology. Br J Cancer. 1999 Jun;80(8):1281–1288. doi: 10.1038/sj.bjc.6990499. [DOI] [PMC free article] [PubMed] [Google Scholar]
  45. Suzuki K., Hayashi N., Miyamoto Y., Yamamoto M., Ohkawa K., Ito Y., Sasaki Y., Yamaguchi Y., Nakase H., Noda K. Expression of vascular permeability factor/vascular endothelial growth factor in human hepatocellular carcinoma. Cancer Res. 1996 Jul 1;56(13):3004–3009. [PubMed] [Google Scholar]
  46. Takahashi A., Sasaki H., Kim S. J., Tobisu K., Kakizoe T., Tsukamoto T., Kumamoto Y., Sugimura T., Terada M. Markedly increased amounts of messenger RNAs for vascular endothelial growth factor and placenta growth factor in renal cell carcinoma associated with angiogenesis. Cancer Res. 1994 Aug 1;54(15):4233–4237. [PubMed] [Google Scholar]
  47. Takahashi Y., Kitadai Y., Bucana C. D., Cleary K. R., Ellis L. M. Expression of vascular endothelial growth factor and its receptor, KDR, correlates with vascularity, metastasis, and proliferation of human colon cancer. Cancer Res. 1995 Sep 15;55(18):3964–3968. [PubMed] [Google Scholar]
  48. Takahashi Y., Tucker S. L., Kitadai Y., Koura A. N., Bucana C. D., Cleary K. R., Ellis L. M. Vessel counts and expression of vascular endothelial growth factor as prognostic factors in node-negative colon cancer. Arch Surg. 1997 May;132(5):541–546. doi: 10.1001/archsurg.1997.01430290087018. [DOI] [PubMed] [Google Scholar]
  49. Takano S., Yoshii Y., Kondo S., Suzuki H., Maruno T., Shirai S., Nose T. Concentration of vascular endothelial growth factor in the serum and tumor tissue of brain tumor patients. Cancer Res. 1996 May 1;56(9):2185–2190. [PubMed] [Google Scholar]
  50. Toi M., Hoshina S., Takayanagi T., Tominaga T. Association of vascular endothelial growth factor expression with tumor angiogenesis and with early relapse in primary breast cancer. Jpn J Cancer Res. 1994 Oct;85(10):1045–1049. doi: 10.1111/j.1349-7006.1994.tb02904.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  51. Weidner N., Semple J. P., Welch W. R., Folkman J. Tumor angiogenesis and metastasis--correlation in invasive breast carcinoma. N Engl J Med. 1991 Jan 3;324(1):1–8. doi: 10.1056/NEJM199101033240101. [DOI] [PubMed] [Google Scholar]
  52. Weindel K., Marmé D., Weich H. A. AIDS-associated Kaposi's sarcoma cells in culture express vascular endothelial growth factor. Biochem Biophys Res Commun. 1992 Mar 31;183(3):1167–1174. doi: 10.1016/s0006-291x(05)80313-4. [DOI] [PubMed] [Google Scholar]
  53. Williams J. K., Carlson G. W., Cohen C., Derose P. B., Hunter S., Jurkiewicz M. J. Tumor angiogenesis as a prognostic factor in oral cavity tumors. Am J Surg. 1994 Nov;168(5):373–380. doi: 10.1016/s0002-9610(05)80079-0. [DOI] [PubMed] [Google Scholar]
  54. Yoshiji H., Gomez D. E., Shibuya M., Thorgeirsson U. P. Expression of vascular endothelial growth factor, its receptor, and other angiogenic factors in human breast cancer. Cancer Res. 1996 May 1;56(9):2013–2016. [PubMed] [Google Scholar]
  55. Zätterström U. K., Brun E., Willén R., Kjellén E., Wennerberg J. Tumor angiogenesis and prognosis in squamous cell carcinoma of the head and neck. Head Neck. 1995 Jul-Aug;17(4):312–318. doi: 10.1002/hed.2880170407. [DOI] [PubMed] [Google Scholar]

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