Abstract
Angiogenesis of tumours might develop as a result of environmental conditions, such as hypoxia, and/or as a result of genetic alterations specific for tumour cells. The relative contributions of these mechanisms were investigated by comparing the in vivo expression of vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) to the hypoxic fraction, the angiogenic potential and the vascular density of four human melanoma lines (A-07, D-12, R-18, U-25) grown intradermally in Balb/c nu/nu mice. VEGF expression, bFGF expression and expression of pimonidazole, a marker of hypoxic cells, were investigated by immunohistochemistry. An association between high VEGF and bFGF expression and high angiogenic potential was detected, suggesting an important role for VEGF/bFGF in the angiogenesis of melanomas. High VEGF/bFGF expression was also related to low hypoxic fraction and high vascular density. Thus, the constitutive, genetically determined level of VEGF was probably more important than hypoxia-induced upregulation in the angiogenesis of the melanoma xenografts. © 2000 Cancer Research Campaign
Keywords: angiogenesis, hypoxia, immunohistochemistry, VEGF
Full Text
The Full Text of this article is available as a PDF (1.2 MB).
Selected References
These references are in PubMed. This may not be the complete list of references from this article.
- Chiarotto J. A., Hill R. P. A quantitative analysis of the reduction in oxygen levels required to induce up-regulation of vascular endothelial growth factor (VEGF) mRNA in cervical cancer cell lines. Br J Cancer. 1999 Jul;80(10):1518–1524. doi: 10.1038/sj.bjc.6690555. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Claffey K. P., Brown L. F., del Aguila L. F., Tognazzi K., Yeo K. T., Manseau E. J., Dvorak H. F. Expression of vascular permeability factor/vascular endothelial growth factor by melanoma cells increases tumor growth, angiogenesis, and experimental metastasis. Cancer Res. 1996 Jan 1;56(1):172–181. [PubMed] [Google Scholar]
- Cordon-Cardo C., Vlodavsky I., Haimovitz-Friedman A., Hicklin D., Fuks Z. Expression of basic fibroblast growth factor in normal human tissues. Lab Invest. 1990 Dec;63(6):832–840. [PubMed] [Google Scholar]
- D'Amore P. A., Shima D. T. Tumor angiogenesis: a physiological process or genetically determined? Cancer Metastasis Rev. 1996 Jun;15(2):205–212. doi: 10.1007/BF00437473. [DOI] [PubMed] [Google Scholar]
- Danielsen T., Rofstad E. K. VEGF, bFGF and EGF in the angiogenesis of human melanoma xenografts. Int J Cancer. 1998 Jun 10;76(6):836–841. doi: 10.1002/(sici)1097-0215(19980610)76:6<836::aid-ijc12>3.0.co;2-0. [DOI] [PubMed] [Google Scholar]
- Danielsen T., Smith-Sørensen B., Grønlund H. A., Hvidsten M., Børresen-Dale A. L., Rofstad E. K. No association between radiosensitivity and TP53 status, G1 arrest or protein levels of p53, myc, ras or raf in human melanoma lines. Int J Radiat Biol. 1999 Sep;75(9):1149–1160. doi: 10.1080/095530099139629. [DOI] [PubMed] [Google Scholar]
- Fontanini G., Vignati S., Lucchi M., Mussi A., Calcinai A., Boldrini L., Chiné S., Silvestri V., Angeletti C. A., Basolo F. Neoangiogenesis and p53 protein in lung cancer: their prognostic role and their relation with vascular endothelial growth factor (VEGF) expression. Br J Cancer. 1997;75(9):1295–1301. doi: 10.1038/bjc.1997.220. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Goto F., Goto K., Weindel K., Folkman J. Synergistic effects of vascular endothelial growth factor and basic fibroblast growth factor on the proliferation and cord formation of bovine capillary endothelial cells within collagen gels. Lab Invest. 1993 Nov;69(5):508–517. [PubMed] [Google Scholar]
- Guidi A. J., Abu-Jawdeh G., Berse B., Jackman R. W., Tognazzi K., Dvorak H. F., Brown L. F. Vascular permeability factor (vascular endothelial growth factor) expression and angiogenesis in cervical neoplasia. J Natl Cancer Inst. 1995 Aug 16;87(16):1237–1245. doi: 10.1093/jnci/87.16.1237. [DOI] [PubMed] [Google Scholar]
- Hlatky L., Tsionou C., Hahnfeldt P., Coleman C. N. Mammary fibroblasts may influence breast tumor angiogenesis via hypoxia-induced vascular endothelial growth factor up-regulation and protein expression. Cancer Res. 1994 Dec 1;54(23):6083–6086. [PubMed] [Google Scholar]
- Kim K. J., Li B., Winer J., Armanini M., Gillett N., Phillips H. S., Ferrara N. Inhibition of vascular endothelial growth factor-induced angiogenesis suppresses tumour growth in vivo. Nature. 1993 Apr 29;362(6423):841–844. doi: 10.1038/362841a0. [DOI] [PubMed] [Google Scholar]
- Lyng H., Sundfør K., Rofstad E. K. Oxygen tension in human tumours measured with polarographic needle electrodes and its relationship to vascular density, necrosis and hypoxia. Radiother Oncol. 1997 Aug;44(2):163–169. doi: 10.1016/s0167-8140(97)01920-8. [DOI] [PubMed] [Google Scholar]
- Mattern J., Kallinowski F., Herfarth C., Volm M. Association of resistance-related protein expression with poor vascularization and low levels of oxygen in human rectal cancer. Int J Cancer. 1996 Jul 3;67(1):20–23. doi: 10.1002/(SICI)1097-0215(19960703)67:1<20::AID-IJC5>3.0.CO;2-1. [DOI] [PubMed] [Google Scholar]
- Mazure N. M., Chen E. Y., Yeh P., Laderoute K. R., Giaccia A. J. Oncogenic transformation and hypoxia synergistically act to modulate vascular endothelial growth factor expression. Cancer Res. 1996 Aug 1;56(15):3436–3440. [PubMed] [Google Scholar]
- Mukhopadhyay D., Tsiokas L., Sukhatme V. P. Wild-type p53 and v-Src exert opposing influences on human vascular endothelial growth factor gene expression. Cancer Res. 1995 Dec 15;55(24):6161–6165. [PubMed] [Google Scholar]
- Obermair A., Kucera E., Mayerhofer K., Speiser P., Seifert M., Czerwenka K., Kaider A., Leodolter S., Kainz C., Zeillinger R. Vascular endothelial growth factor (VEGF) in human breast cancer: correlation with disease-free survival. Int J Cancer. 1997 Aug 22;74(4):455–458. doi: 10.1002/(sici)1097-0215(19970822)74:4<455::aid-ijc17>3.0.co;2-8. [DOI] [PubMed] [Google Scholar]
- Pötgens A. J., Lubsen N. H., van Altena M. C., Schoenmakers J. G., Ruiter D. J., de Waal R. M. Vascular permeability factor expression influences tumor angiogenesis in human melanoma lines xenografted to nude mice. Am J Pathol. 1995 Jan;146(1):197–209. [PMC free article] [PubMed] [Google Scholar]
- Raleigh J. A., Calkins-Adams D. P., Rinker L. H., Ballenger C. A., Weissler M. C., Fowler W. C., Jr, Novotny D. B., Varia M. A. Hypoxia and vascular endothelial growth factor expression in human squamous cell carcinomas using pimonidazole as a hypoxia marker. Cancer Res. 1998 Sep 1;58(17):3765–3768. [PubMed] [Google Scholar]
- Rofstad E. K., Danielsen T. Hypoxia-induced angiogenesis and vascular endothelial growth factor secretion in human melanoma. Br J Cancer. 1998 Mar;77(6):897–902. doi: 10.1038/bjc.1998.148. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Rofstad E. K., Danielsen T. Hypoxia-induced metastasis of human melanoma cells: involvement of vascular endothelial growth factor-mediated angiogenesis. Br J Cancer. 1999 Aug;80(11):1697–1707. doi: 10.1038/sj.bjc.6690586. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Rofstad E. K., Måseide K. Fraction of radiobiologically hypoxic cells in human melanoma xenografts measured by using single-cell survival, tumour growth delay and local tumour control as end points. Br J Cancer. 1998 Oct;78(7):893–898. doi: 10.1038/bjc.1998.598. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Rofstad E. K. Orthotopic human melanoma xenograft model systems for studies of tumour angiogenesis, pathophysiology, treatment sensitivity and metastatic pattern. Br J Cancer. 1994 Nov;70(5):804–812. doi: 10.1038/bjc.1994.403. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Seghezzi G., Patel S., Ren C. J., Gualandris A., Pintucci G., Robbins E. S., Shapiro R. L., Galloway A. C., Rifkin D. B., Mignatti P. Fibroblast growth factor-2 (FGF-2) induces vascular endothelial growth factor (VEGF) expression in the endothelial cells of forming capillaries: an autocrine mechanism contributing to angiogenesis. J Cell Biol. 1998 Jun 29;141(7):1659–1673. doi: 10.1083/jcb.141.7.1659. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Shweiki D., Itin A., Soffer D., Keshet E. Vascular endothelial growth factor induced by hypoxia may mediate hypoxia-initiated angiogenesis. Nature. 1992 Oct 29;359(6398):843–845. doi: 10.1038/359843a0. [DOI] [PubMed] [Google Scholar]
- Shweiki D., Neeman M., Itin A., Keshet E. Induction of vascular endothelial growth factor expression by hypoxia and by glucose deficiency in multicell spheroids: implications for tumor angiogenesis. Proc Natl Acad Sci U S A. 1995 Jan 31;92(3):768–772. doi: 10.1073/pnas.92.3.768. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Takahashi Y., Bucana C. D., Cleary K. R., Ellis L. M. p53, vessel count, and vascular endothelial growth factor expression in human colon cancer. Int J Cancer. 1998 Feb 20;79(1):34–38. doi: 10.1002/(sici)1097-0215(19980220)79:1<34::aid-ijc7>3.0.co;2-x. [DOI] [PubMed] [Google Scholar]
- 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]
- Tufto I., Lyng H., Rofstad E. K. Vascular density in human melanoma xenografts: relationship to angiogenesis, perfusion and necrosis. Cancer Lett. 1998 Jan 30;123(2):159–165. doi: 10.1016/s0304-3835(97)00424-2. [DOI] [PubMed] [Google Scholar]
- Westphal J. R., van't Hullenaar R. G., van der Laak J. A., Cornelissen I. M., Schalkwijk L. J., van Muijen G. N., Wesseling P., de Wilde P. C., Ruiter D. J., de Waal R. M. Vascular density in melanoma xenografts correlates with vascular permeability factor expression but not with metastatic potential. Br J Cancer. 1997;76(5):561–570. doi: 10.1038/bjc.1997.427. [DOI] [PMC free article] [PubMed] [Google Scholar]
