Angiogenesis in Mammary Tumors: Quantitation and Relation to Prognosis

  • Stephen B. Fox
Part of the Cardiovascular Molecular Morphogenesis book series (CARDMM)


Angiogenesis is the generation of new vessels from the existing vasculature and is essential for tumor growth and metastasis. This requisite increase in tumor vascularity has been recognized for many centuries. Indeed the tumor vasculature was described posthumously by John Hunter in 1794 who noted, “In a disease in which there is an increase in the part, as in tumors, the increase in the vessels is conspicuous.” However, it is only since Folkman’s (1971) hypothesis on antiangiogenesis that a quantitative method for measuring angiogenesis has been pursued.


Breast Cancer Vascular Endothelial Growth Factor Breast Carcinoma Mammary Tumor Tumor Angiogenesis 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Acenero, M. J., Gallego, M. G., et al. 1998. Vascular density as a prognostic indicator for invasive ductal breast carcinoma. Virchows Arch. 432(2):113–117. PubMedGoogle Scholar
  2. Axelsson, K., Ljung, B. M., Moore, D. H., Thor, A. D., Chew, K. L., Edgerton, S. M., Smith, H. S., and Mayall, B. H. 1995. Tumor angiogenesis as a prognostic assay for invasive ductal breast carcinoma. J. Natl. Cancer Inst. 87:997–1008. PubMedGoogle Scholar
  3. Barbareschi, M., Weidner, N., Gasparini, G., Morelli, L., Forti, S., Eccher, C., Fina, P., Caffo, O., Leonardi, E., Mauri, F., Bevilacqua, P., and Dalla Palma, P. 1995. Microvessel quantitation in breast carcinomas. Appl. Immunochem. 3:75–84.Google Scholar
  4. Barnhill, R. L., K. Fandrey, K., Levy, M. A., Mihm, M. C., and Hyman, B. 1992a. Angiogenesis and tumor progression of melanoma. Quantification of vascularity in melanocytic nevi and cutaneous malignant melanoma. Lab. Invest. 67:331–337.PubMedGoogle Scholar
  5. Barnhill, R. L., Mihm, M. J., and Ceballos, P. I. 1992b. Angiogenesis and regressing cutaneous malignant melanoma. Lancet 339:991–992.PubMedGoogle Scholar
  6. Belien, J. A., Somi, S., de Jong, J. S., van Diest, P. J., and Baak, J. P. 1999. Fully automated microvessel counting and hot spot selection by image processing of whole tumour sections in invasive breast cancer. J. Clin. Pathol. 52:184–192.PubMedGoogle Scholar
  7. Bevilacqua, P., Barbareschi, M., et al. 1995. Prognostic value of intratumoral microvessel density, a measure of tumor angiogenesis, in node-negative breast carcinoma-results of a multiparametric study. Breast Cancer Res. Treat. 36(2):205–217.PubMedGoogle Scholar
  8. Bigler, S., Deering, R., and Brawer, M. 1993. Comparisons of microscopic vascularity in benign and malignant prostate tissue. Hum. Pathol. 24:220–226.PubMedGoogle Scholar
  9. Bischoff, J. 1997. Cell adhesion and angiogenesis. J. Clin. Invest. 100:37–39.Google Scholar
  10. Bosari, S., Lee, A. K., DeLellis, R. A., Wiley, B. D., Heatley, G. J., and Silverman, M. L. 1992. Microvessel quantitation and prognosis in invasive breast carcinoma. Hum. Pathol. 23:755–761.PubMedGoogle Scholar
  11. Brawer, M. K., Deering, R. E., Brown, M., Preston, S. D., and Bigler, S. A. 1994. Predictors of pathologic stage in prostatic carcinoma. The role of neovascularity. Cancer 73:678–687.PubMedGoogle Scholar
  12. Brem, S., Cotran, R., and Folkman, J. 1972. Tumor angiogenesis: a quantitative method for histological grading. J. Natl. Cancer Inst. 48:347–356.PubMedGoogle Scholar
  13. Brem, S. S., Jensen, H. M., and Gullino, P. M. 1978. Angiogenesis as a marker of preneoplastic lesions of the human breast. Cancer 41:239–244.PubMedGoogle Scholar
  14. Brooks, P. C. 1996. Role of integrins in angiogenesis. Eur. J. Cancer 32A:2423–2429.PubMedGoogle Scholar
  15. Brown, L. F., Guidi, A. J., Schnitt, S. J., Van De Water, L., Iruela-Arispe, M. L., Yeo, T. K., Tognazzi, K., and Dvorak, H. F. 1999. Vascular stroma formation in carcinoma in situ, invasive carcinoma, and metastatic carcinoma of the breast. Clin. Cancer Res. 5:1041–1056.PubMedGoogle Scholar
  16. Buadu, L., Murakami, J., Murayama, S., Hashiguchi, N., Sakai, S., Masuda, K., Toyoshima, S., Kuroki, S., and Ohno, S. 1996. Breast lesions: correlation of contrast medium enhancement patterns on MR images with histopathological findings and tumor angiogenesis. Radiology 200:639–649.PubMedGoogle Scholar
  17. Buckley, D. L., Drew, P. J., Mussurakis, S., Monson, J. R., and Horsman, A. 1997. Microvessel density of invasive breast cancer assessed by dynamic Gd-DTPA enhanced MRI. J. Magn. Reson. Imaging 7:461–464.PubMedGoogle Scholar
  18. Bundred, N., Bowcott, M., Walls, J., Faragher, E., and Knox, F. 1994. Angiogenesis in breast cancer predicts node metastasis and survival. Br. J. Surg. 81:768.Google Scholar
  19. Burrows, F. J., and Thorpe, P. E. 1994. Vascular targeting-a new approach to the therapy of solid tumors. Pharmacol. Ther. 64:155–174.PubMedGoogle Scholar
  20. Carnochan, P., Briggs, J. C., Westbury, G., and Davies, A. J. 1991. The vascularity of cutaneous melanoma: a quantitative histological study of lesions 0.85–1.25 mm in thickness. Br. J. Cancer 64:102–107.PubMedGoogle Scholar
  21. Chalkley, H. 1943. Method for the quantative morphological analysis of tissues. J. Natl. Cancer Inst. 4:47–53.Google Scholar
  22. Charpin, C., Devictor, B., Bergeret, D., Andrac, L., Boulat, J., Horschowski, N., Lavaut, M. N., and Piana, L. 1995. CD31 quantitative immunocytochemical assays in breast carcinomas. Am. J. Clin. Pathol. 103:443–448.PubMedGoogle Scholar
  23. Chaudhury, T. K., Lerner, M. P., and Nordquist, R. E. 1980. Angiogenesis by human melanoma and breast cancer cells. Cancer Lett. 11:43–49.PubMedGoogle Scholar
  24. Cheng, W. F., Lee, C. N., Chu, J. S., Chen, C. A., Chen, T. M., Shau, W. Y., Hsieh, C. Y., and Hsieh, F. J. 1999. Vascularity index as a novel parameter for the in vivo assessment of angiogenesis in patients with cervical carcinoma. Cancer 85:651–657.PubMedGoogle Scholar
  25. Chu, J. S., Huang, C. S., et al. 1998. The prognostic significance of tumor angiogenesis in Taiwanese patients with invasive ductal breast carcinomas. Cancer Lett. 134(1):7–14.PubMedGoogle Scholar
  26. Clahsen, P. C., van de Velde, C. J., Duval, C., Pallud, C., Mandard, A. M., DelobelleDeroide, A., van den Broek, L., Sahmoud, T. M., and van de Vijver, M. J. 1998. p53 protein accumulation and response to adjuvant chemotherapy in premenopausal women with node-negative early breast cancer. J. Clin. Oncol. 16:470–479.Google Scholar
  27. Colomer, R., Aparicio, J., Montero, S., Guzman, C., Larrodera, L., and Cortes-Funes, H. 1997. Low levels of basic fibroblast growth factor (bFGF) are associated with a poor prognosis in human breast carcinoma. Br. J. Cancer 76:1215–1220.PubMedGoogle Scholar
  28. Cosgrove, D. O., Kedar, R. P., Bamber, J. C., al-Murrani, B., Davey, J. B., Fisher, C., McKinna, J. A., Svensson, W. E., Tohno, E., and Vagios, E. 1993. Breast diseases: color Doppler US in differential diagnosis. Radiology 189:99–104.PubMedGoogle Scholar
  29. Costello, P., McCann, A., Carney, D. N., and Dervan, P. A. 1995. Prognostic significance of microvessel density in lymph node negative breast carcinoma. Hum. Pathol. 26:1181–1184.PubMedGoogle Scholar
  30. DeLisser, H. M., Christofidou-Solomidou, M., Strieter, R. M., Burdick, M. D., Robinson, C. S., Wexler, R. S., Kerr, J. S., Garlanda, C., Merwin, J. R., Madri, J. A., and Albelda, S. M. 1997. Involvement of endothelial PECAM-1/CD31 in angiogenesis. Am. J. Pathol. 151:671–677.PubMedGoogle Scholar
  31. Dickinson, A. J., Fox, S. B., Persad, R. A., Hollyer, J., Sibley, G. N., and Harris, A. L. 1994. Quantification of angiogenesis as an independent predictor of prognosis in invasive bladder carcinomas. Br. J. Urol. 74:762–766.PubMedGoogle Scholar
  32. Dixon, J. M., Walsh, J., Paterson, D., and Chetty, U. 1992. Colour Doppler ultrasonography studies of benign and malignant breast lesions. Br. J. Surg. 79:259–260.PubMedGoogle Scholar
  33. Dvorak, H. F., Nagy, J. A., Dvorak, J. T., and Dvorak, A. M. 1988. Identification and characterisation of the blood vessels of solid tumours that are leaky to circulating macromolecules. Am. J. Pathol. 133:95–109.PubMedGoogle Scholar
  34. Engels, K., Fox, S. B., Whitehouse, R. M., Gatter, K. C., and Harris, A. L. 1997a. Distinct angiogenic patterns are associated with high-grade in situ ductal carcinomas of the breast. J. Pathol. 181:207–212.PubMedGoogle Scholar
  35. Engels, K., Fox, S. B., Whitehouse, R. M., Gatter, K. C., and Harris, A. L. 1997b. Up-regulation of thymidine phosphorylase expression is associated with a discrete pattern of angiogenesis in ductal carcinomas in situ of the breast. J. Pathol. 182:414–420.PubMedGoogle Scholar
  36. Evans, S. M., Laughlin, K. M., Pugh, C. R., Sehgal, C. M., and Saunders, H. M. 1997. Use of power Doppler ultrasound-guided biopsies to locate regions of tumour hypoxia. Br. J. Cancer 76:1308–1314.PubMedGoogle Scholar
  37. Fisher, C., Gilbertson, B. S., Powers, E. A., Petzold, G., Poorman, R., and Mitchell, M. A. 1994. Interstitial collagenase is required for angiogenesis in vitro. Dev. Biol. 162:499–510.PubMedGoogle Scholar
  38. Folkman, J. 1971. Tumor angiogenesis: therapeutic implications. N. Engl. J. Med. 285:82–86.Google Scholar
  39. Fox, S. B., Engels, K., Comley, M., Whitehouse, R., Turley, H., Gatter, K., and Harris, A. 1997a. Relationship of elevated tumour thymidine phosphorylase in node positive breast carcinomas to the effects of adjuvant CMF. Ann. Oncol. 8:271–275.PubMedGoogle Scholar
  40. Fox, S. B., Gatter, K., Bicknell, R., Going, J., Stanton, P., Cooke, T., and Harris, A. 1993a. Relationship of endothelial cell proliferation to tumor vascularity in human breast cancer. Cancer Res. 53:9161–9163.Google Scholar
  41. Fox, S. B., Gatter, K. C., Leek, R. D., Harris, A. L., Chew, K., Mayall, B., and Moore, D. H. 2nd. 2000b. Tumor angiogenesis as a prognostic assay for invasive ductal breast carcinoma. J. Natl. Cancer Inst. 92: 151–152.Google Scholar
  42. Fox, S. B., and Harris, A. L. 2001. Diagnostic and prognostic significance of tumour angiogenesis. In: Fan, T., and Auerbach, R. eds. New Angiotherapy. Humana Press, Cambridge, MA.Google Scholar
  43. Fox, S. B., and Harris, A. L. 1997. Markers of tumor angiogenesis: clinical applications in prognosis and anti-angiogenic therapy. Invest. New Drugs 15:15–28.PubMedGoogle Scholar
  44. Fox, S. B., Kakolyris, S., Taylor, M., Gatter, K. C., and Harris, A. L. 2000a. Vascular remodelling in breast cancer angiogenesis assessed by LH39 basement membrane antigen and CD31. Br. J. Cancer 82:844–851.PubMedGoogle Scholar
  45. Fox, S. B., Leek, R. D., Bliss, J., Mansi, J. L., Gusterson, B., Gatter, K. C., and Harris, A. L. 1997b. Association of tumor angiogenesis with bone marrow micrometastases in breast cancer patients. J. Natl. Cancer Inst. 89:1044–1049.PubMedGoogle Scholar
  46. Fox, S. B., Leek, R., Smith, K., Hollyer, J., Greenall, M., and Harris, A. 1994. Tumor angiogenesis in node negative breast carcinomas-relationship to epidermal growth factor receptor and survival. Breast Cancer Res. Treat. 29:109–116.PubMedGoogle Scholar
  47. Fox, S. B., Leek, R. D., Weekes, M. P., Whitehouse, R. M., Gatter, K. C., and Harris, A. L. 1995b. Quantitation and prognostic value of breast cancer angiogenesis: comparison of microvessel density, Chalkley count, and computer image analysis. J. Pathol. 177:275–283.PubMedGoogle Scholar
  48. Fox, S. B., Stuart, N., Smith, K., Brunner, N., and Harris, A. L. 1993b. High levels of uPA and PAI-1 are associated with highly angiogenic breast carcinomas. J. Pathol. 170:388–398.Google Scholar
  49. Fox, S. B., Turner, G., Gatter, K., and Harris, A. 1995a. The increased expression of adhesion molecules ICAM-3, E and P selectin on breast cancer endothelium. J. Pathol. 177:369–376.Google Scholar
  50. Fox, S. B., Westwood, M., Moghaddam, A., Comley, M., Turley, H., Whitehouse, R. M., Bicknell, R., Gatter, K. C., and Harris, A. L. 1996. The angiogenic factor platelet-derived endothelial cell growth factor/thymidine phosphorylase is up-regulated in breast cancer epithelium and endothelium. Br. J. Cancer 73:275–280.PubMedGoogle Scholar
  51. Fregene, T. A., Kellog, C., and Pienta, K. J. 1994. Microvessel quantitation as a measure of angiogenic activity in benign breast tissues lesions: a marker for precancerous disease? Int. J. Oncol. 4:1199–1202.PubMedGoogle Scholar
  52. Frouge, C., Guinbretiere, J., Contesso, G., di Paola, R., and Blery, M. 1994. Correlation between contrast enhancement in dynamic magnetic resonance imaging of the breast and tumor angiogenesis. Invest. Radio!. 29:1043–1049.Google Scholar
  53. Furusato, M., Wakui, S., Sasaki, H., Ito, K., and Ushigome, S. 1994. Tumour angiogenesis in latent prostatic carcinoma. Br. J. Cancer 70:1244–1246.PubMedGoogle Scholar
  54. Gasparini, G., Fox, S. B., Verderio, P., Bonoldi, E., Bevilacqua, P., Borrachi, P., Dante, S., Marubini, E., and Harris, A. 1996. Determination of angiogenesis adds information to estrogen receptor status in predicting the efficacy of adjuvant tamoxifen in node-positive breast cancer patients. Clin. Cancer Res. 2:1191–1198.PubMedGoogle Scholar
  55. Gasparini, G., Toi, M., Gion, M., Verderio, P., Dittadi, R., Hanatani, M., Matsubara, I., Vinante, O., Bonold, E., Boracchi, P., Gatti, C., Suzuki, H., and Tominaga, T. 1997. Prognostic-significance of vascular endothelial growth-factor protein in node-negative breast-carcinoma. J. Natl. Cancer Inst. 89:139–147.PubMedGoogle Scholar
  56. Gasparini, G., Toi, M., et al. 1998. Prognostic significance of p53, angiogenesis, and other conventional features in operable breast cancer: Subanalysis in node-positive and node-negative patients. Int. J. Oncol. 12(5):1117–1125.PubMedGoogle Scholar
  57. Gasparini, G., Toi, M., Miceli, R., Vermeulen, P. B., Dittadi, R., Biganzoli, E., Morabito, A., Fanelli, M., Gatti, C., Suzuki, H., Tominaga, T., Dirix, L. Y., and Gion, M. 1999. Clinical relevance of vascular endothelial growth factor and thymidine phosphorylase in patients with node-positive breast cancer treated with either adjuvant chemotherapy or hormone therapy. Cancer J. Sci. Am. 5:101–111.PubMedGoogle Scholar
  58. Gilles, R., Zafrani, B., Guinebretiere, J. M., Meunier, M., Lucidarme, O., Tardivon, A. A., Rochard, F., Vanel, D., Neuenschwander, S., and Arriagada, R. 1995. Ductal carcinoma in situ: MR imaging-histopathologic correlation. Radiology 196:415–419.PubMedGoogle Scholar
  59. Gimbrone, M. A., Jr., and Gullino, P. M. 1976a. Neovascularization induced by intraocular xenografts of normal, preneoplastic, and neoplastic mouse mammary tissues. J. Natl. Cancer Inst. 56:305–318.PubMedGoogle Scholar
  60. Gimbrone, M. A. J., and Gullino, P. M. 1976b. Angiogenic capacity of preneoplastic lesions of the murine mammary gland as a marker of neoplastic transformation. Cancer Res. 36:2611–2620.PubMedGoogle Scholar
  61. Goulding, H., Abdul, R. N., et al. 1995. Assessment of angiogenesis in breast carcinoma: an important factor in prognosis? Hum. Pathol. 26(11):1196–1200.PubMedGoogle Scholar
  62. Guidi, A., Fischer, L., Harris, J., and Schnitt, S. 1994. Microvessel density and distribution in ductal carcinoma in situ of the breast. J. Natl. Cancer Inst. 86:614–619.PubMedGoogle Scholar
  63. Guinebretiere, J. M., Le, M. G., Gavoille, A., Bahi, J., and Contesso, G. 1994. Angiogenesis and risk of breast cancer in women with fibrocystic disease. J. Natl. Cancer Inst. 86:635–636.PubMedGoogle Scholar
  64. Hall, N. R., Fish, D. E., Hunt, N., Goldin, R. D., Guillou, P. J., and Monson, J. R. 1992. Is the relationship between angiogenesis and metastasis in breast cancer real? Surg. Oncol. 1:223–229.PubMedGoogle Scholar
  65. Hanahan, D., and Folkman, J. 1996. Patterns and emerging mechanisms of the angiogenic switch during tumorigenesis. Cell 86:353–364.PubMedGoogle Scholar
  66. Hansen, S., Grabau, D. A., Rose, C., Bak, M., and Sorensen, F. B. 1998. Angiogenesis in breast cancer: a comparative study of the observer variability of methods for determining microvessel density. Lab. Invest. 78:1563–1573.PubMedGoogle Scholar
  67. Heffelfinger, S., Yassin, R., Miller, M., and Lower, E. 1996. Vascularity of proliferative breast disease and carcinoma in situ correlates with histological features. Clin. Cancer Res. 2:1873–1878.PubMedGoogle Scholar
  68. Heinmann, R., Ferguson, D., et al. 1996. Angiogenesis as a predictor of long term survival for patients with node-negative breast cancer. J. Natl. Cancer Inst. 88:1764–1769.Google Scholar
  69. Honkoop, A. H., van Diest, P. J., de Jong, J. S., Linn, S. C., Giaccone, G., Hoekman, K., Wagstaff, J., and Pinedo, H. M. 1998. Prognostic role of clinical, pathological and biological characteristics in patients with locally advanced breast cancer. Br. J. Cancer 77:621–626.PubMedGoogle Scholar
  70. Horak, E. R., Leek, R., Klenk, N., LeJeune, S., Smith, K., Stuart, N., Greenall, M., Stepniewska, K., and Harris, A. L. 1992. Angiogenesis, assessed by platelet/endothelial cell adhesion molecule antibodies, as indicator of node metastases and survival in breast cancer. Lancet 340:1120–1124.PubMedGoogle Scholar
  71. Huber, S. 1998. Doppler ultrasound in the diagnosis of breast lesions. Anticancer Res. 18:2147–2150.PubMedGoogle Scholar
  72. Hulka, C. A., Edmister, W. B., Smith, B. L., Tan, L., Sgroi, D. C., Campbell, T., Kopans, D. B., and Weisskoff, R. M. 1997. Dynamic echo-planar imaging of the breast: experience in diagnosing breast carcinoma and correlation with tumor angiogenesis. Radiology 205:837–842.PubMedGoogle Scholar
  73. Hulka, C. A., Smith, B. L., Sgroi, D. C., Tan, L., Edmister, W. B., Semple, J. R, Campbell, T., Kopans, D. B., Brady, T. J., and Weisskoff, R. M. 1995. Benign and malignant breast lesions: differentiation with echo-planar MR imaging. Radiology 197:33–38.PubMedGoogle Scholar
  74. Jacquemier, J. D., Penault-Llorca, F. M., Bertucci, F., Sun, Z. Z., Houvenaeghel, G. F., Geneix, J. A., Puig, B. D., Bardou, V. J., Hassoun, J. A., Birnbaum, D., and Viens, R. J. 1998. Angiogenesis as a prognostic marker in breast carcinoma with conventional adjuvant chemotherapy: a multiparametric and immunohistochemical analysis. J. Pathol. 184:130–135.PubMedGoogle Scholar
  75. Jensen, H. M., Chen, I., De, V. M., and Lewis, A. E. 1982. Angiogenesis induced by normal human breast tissue: a probable marker for precancer. Science 218:293–295.PubMedGoogle Scholar
  76. Jitsuiki, Y., Hasebe, T., Tsuda, H., Imoto, S., Tsubono, Y., Sasaki, S., and Mukai, K. 1999. Optimizing microvessel counts according to tumor zone in invasive ductal carcinoma of the breast. Mod. Pathol. 12:492–498.PubMedGoogle Scholar
  77. Kaczmarek, J., Castellani, P., Nicolo, G., Spina, B., Allemanni, G., and Zardi, L. 1994. Distribution of oncofetal fibronectin isoforms in normal, hyperplastic and neoplastic human breast tissues. Int. J. Cancer 58:11–16.Google Scholar
  78. Karelia, N. H., Patel, D. D., et al. 1997. Prognostic significance of tumor angiogenesis in advanced breast carcinoma: An Indian experience. Neoplasma 44(3):163–166.PubMedGoogle Scholar
  79. Kato, T., Kimura, T., et al. 1997. Clinicopathologic study of angiogenesis in Japanese patients with breast cancer. World Journal of Surgery 21(1):49–56.PubMedGoogle Scholar
  80. Kato, T., Kimura, T., et al. 1999. The methodology of quantitation of microvessel density and prognostic value of neovascularization associated with long-term survival in Japanese patients with breast cancer. Breast Cancer Res. Treat. 53(1):19–31.PubMedGoogle Scholar
  81. Kedar, R. P., Cosgrove, D. O., Bamber, J. C., and Bell, D. S. 1995. Automated quantification of color Doppler signals: a preliminary study in breast tumors. Radiology 197:39–43.PubMedGoogle Scholar
  82. Kedar, R. P., Cosgrove, D. O., Smith, I. E., Mansi, J. L., and Bamber, J. C. 1994. Breast carcinoma: measurement of tumor response to primary medical therapy with color Doppler flow imaging. Radiology 190:825–830.PubMedGoogle Scholar
  83. Kohlberger, P., Obermair Sliutz, G., et al. 1996. Quantitative immunohistochemistry of factor VIII-related antigen in breast carcinoma. Am. J. Clin. Pathol. 105:705–710.PubMedGoogle Scholar
  84. Kondo, S., Asano, M., Matsuo, K., Ohmori, I., and Suzuki, H. 1994. Vascular endothelial growth factor/vascular permeability factor is detectable in the sera of tumor-bearing mice and cancer patients. Biochem. Biophys. Acta 1221:211–214.PubMedGoogle Scholar
  85. Kraft, A., Weindel, K., Ochs, A., Marth, C., Zmija, J., Schumacher, P., Unger, C., Marmé, D., and Gastl, G. 1999. Vascular endothelial growth factor in the sera and effusions of patients with malignant and nonmalignant disease. Cancer 85:178–187.PubMedGoogle Scholar
  86. Kumar, S., Ghellal, A., Li, C., Byrne, G., Haboubi, N., Wang, J. M., and Bundred, N. 1999. Breast carcinoma: vascular density determined using CD105 antibody correlates with tumor prognosis. Cancer Res. 59:856–861.PubMedGoogle Scholar
  87. Kuzu, I., Bicknell, R., Harris, A. L., Jones, M., Gatter, K. C., and Mason, D. Y. 1992. Heterogeneity of vascular endothelial cells with relevance to diagnosis of vascular tumours. J. Clin. Pathol. 45:143–148.PubMedGoogle Scholar
  88. Lakhani, S. R. 1999. The transition from hyperplasia to invasive carcinoma of the breast. J. Pathol. 187:272–278.PubMedGoogle Scholar
  89. Lee, A., Happerfield, L., and Bobrow, L. 1997a. Comparison of four endothelial markers for assessing angiogenesis in carcinoma of the breast. J. Cell Pathol. 2:67–73.Google Scholar
  90. Lee, A. H., Happerfield, L. C., Bobrow, L. G., and Millis, R. R. 1997b. Angiogenesis and inflammation in ductal carcinoma in situ of the breast. J. Pathol. 181:200–206.PubMedGoogle Scholar
  91. Lee, W. J., Chu, J. S., Houng, S. J., Chung, M. F., Wang, S. M., and Chen, K. M. 1995. Breast cancer angiogenesis: a quantitative morphologic and Doppler imaging study. Ann. Surg. Oncol. 2:246–251.PubMedGoogle Scholar
  92. Lin, G., Lunderquist, A., Hagerstrand, I., and Boijsen, E. 1984. Postmortem examination of the blood supply and vascular pattern of small liver metastases in man. Surgery 96:517–526.PubMedGoogle Scholar
  93. Linderholm, B., Tavelin, B., Grankvist, K., and Henriksson, R. 1998. Vascular endothelial growth factor is of high prognostic value in node-negative breast carcinoma. J. Clin. Oncol. 16:3121–3128.PubMedGoogle Scholar
  94. Lipponen, P., Ji, H., et al. 1994. Tumour vascularity and basement membrane structure in breast cancer as related to tumour histology and prognosis. J. Cancer Res. Clin. Oncol. 120(11):645–650.PubMedGoogle Scholar
  95. Ludwig, C. U., Aebersold, D. M., and Rothen, C. 1998. Perioperative angiogenesis and outcome in premenopausal women with breast cancer. Lancet 352:147.PubMedGoogle Scholar
  96. Macaulay, V. M., Fox, S. B., Zhang, H., Whitehouse, R. M., Leek, R. D., Gatter, K. C., and Harris, A. L. 1995. Breast cancer angiogenesis and tamoxifen resistence. Endocr. Rel. Cancer 2:1–8.Google Scholar
  97. Maiorana, A., and Gullino, P. M. 1978. Acquisition of angiogenic capacity and neoplastic transformation in the rat mammary gland. Cancer Res. 38:4409–4414.PubMedGoogle Scholar
  98. Makris, A., Powles, T. J., Kakolyris, S., Dowsett, M., Ashley, S. E., and Harris, A. L. 1999. Reduction in angiogenesis after neoadjuvant chemoendocrine therapy in patients with operable breast carcinoma. Cancer 85:1996–2000.PubMedGoogle Scholar
  99. Maniotis, A. J., Folberg, R., Hess, A., Seftor, E. A., Gardner, L. M., Pe’er, J., Trent, J. M., Meltzer, P. S., and Hendrix, M. J. 1999. Vascular channel formation by human melanoma cells in vivo and in vitro: vasculogenic mimicry. Am. J. Pathol. 155:739–752.PubMedGoogle Scholar
  100. Martin, L., Green, B., Renshaw, C., Lowe, D., Rudland, P., Leinster, S. J., and Winstanley, J. 1997. Examining the technique of angiogenesis assessment in invasive breast cancer. Br. J. Cancer 76:1046–1054.PubMedGoogle Scholar
  101. McCulloch, P., Choy, A., and Martin, L. 1995. Association between tumour angiogenesis and tumour cell shedding into effluent venous blood during breast cancer surgery. Lancet 346:1334–1335.PubMedGoogle Scholar
  102. Mlynek, M., van Beunigen, D., Leder, L.-D., and Streffer, C. 1985. Measurement of the grade of vascularisation in histological tumour tissue sections. Br. J. Cancer 52:945–948.PubMedGoogle Scholar
  103. Morelli, D., Lazzerini, D., Cazzaniga, S., Squicciarini, P., Bignami, P., Maier, J. A., Sfondrini, L., Menard, S., Colnaghi, M. I., and Balsari, A. 1998. Evaluation of the balance between angiogenic and antiangiogenic circulating factors in patients with breast and gastrointestinal cancers. Clin. Cancer Res. 4:1221–1225.PubMedGoogle Scholar
  104. Morphopoulos, G., Pearson, M., et al. 1996. Tumour angiogenesis as a prognostic marker in infiltrating lobular carcinoma of the breast. J. Pathol. 180(1):44–49.PubMedGoogle Scholar
  105. Mortensen, K., Holck, S., Christensen, I. J., Skouv, J., Hougaard, D. M., Blom, J., and Larsson, L. I. 1999. Endothelial cell nitric oxide synthase in peritumoral microvessels is a favorable prognostic indicator in premenopausal breast cancer patients. Clin. Cancer Res. 5:1093–1097.PubMedGoogle Scholar
  106. Narita, M., Nakao, K., et al. 1998. Independent prognostic factors in breast cancer patients. Am. J. Surg. 175(1):73–75.PubMedGoogle Scholar
  107. Nguyen, M. 1997. Angiogenic factors as tumor markers. Invest. New Drugs 15:29–37.PubMedGoogle Scholar
  108. O’Brien, T., Fox, S. B., Dickinson, A., Turley, H., Westwood, M., Moghaddam, A., Gatter, K., Bicknell, R., and Harris, A. 1996. Expression of the angiogenic factor thymidine phosphorylase/platelet derived endothelial cell growth factor in primary bladder cancers. Cancer Res. 56:4799–4804.PubMedGoogle Scholar
  109. Obermair, A., Kucera, E., Mayerhofer, K., Speiser, P., Seifert, M., Czerwenka, K., Kaider, A., Leodolter, S., Kainz, C., and Zeillinger, R. 1997. Vascular endothelial growth factor (VEGF) in human breast cancer: correlation with disease-free survival. Int. J. Cancer 74:455–458.PubMedGoogle Scholar
  110. Ogawa, Y., Chung, Y., et al. 1995. Microvessel quantitation in invasive breast cancer by staining for factor VIII-related antigen. Br. J. Cancer 71:1297–1301.PubMedGoogle Scholar
  111. Olivarez, D., Ulbright, T., DeRiese, W., Foster, R., Reister, T., Einhorn, L., and Sledge, G. 1994. Neovascularization in clinical stage A testicular germ cell tumor: prediction of metastatic disease. Cancer Res. 54:2800–2802.PubMedGoogle Scholar
  112. Omar, W. S., Eissa, S., Moustafa, H., Farag, H., Ezzat, I., and Abdel-Dayem, H. M. 1997. Role of thallium-201 chloride and Tc-99m methoxy-isobutyl-isonitrite (sestaMlBl) in evaluation of breast masses: correlation with the immunohistochemical characteristic parameters (Ki-67, PCNA, Bc1, and angiogenesis) in malignant lesions. Anticancer Res. 17:1639–1644.PubMedGoogle Scholar
  113. Ottinetti, A., and Sapino, A. 1988. Morphometric evaluation of microvessels surrounding hyperplastic and neoplastic mammary lesions. Breast Cancer Res. Treat. 11:241–248PubMedGoogle Scholar
  114. Page, C., Rose, M., Yacoub, M., and Pigott, R. 1992. Antigenic heterogeneity of vascular endothelium. Am. J. Pathol. 141:673–683.PubMedGoogle Scholar
  115. Page, D. L., and Dupont, W. D. 1992. Breast cancer angio-histogenesis: through a narrow window. J. Natl. Cancer Inst. 84:1850–1851.PubMedGoogle Scholar
  116. Page, D. L., and Jensen, R. 1995. Angiogenesis in human breast carcinoma. Hum. Pathol. 26:1173–1174.PubMedGoogle Scholar
  117. Paku, S., and Paweletz, N. 1991. First steps of tumor-related angiogenesis. Lab. Invest. 65:334–346.PubMedGoogle Scholar
  118. Passe, T. J., Bluemke, D. A., and Siegelman, S. S. 1997. Tumor angiogenesis: tutorial on implications for imaging. Radiology 203:593–600.PubMedGoogle Scholar
  119. Paulsen, T., Aas, T., Borresen, A. L., Varhaug, J. E., Lonning, P. E., and Akslen, L. A. 1997. Angiogenesis does not predict clinical response to doxorubicin monotherapy in patients with locally advanced breast cancer. Int. J. Cancer 74:138–140.PubMedGoogle Scholar
  120. Paweletz, N., and Knierim, M. 1989. Tumor-related angiogenesis. Crit. Rev. Oncol. Hematol. 9:197–242.PubMedGoogle Scholar
  121. Pepper, M., and Montesano, R. 1990. Proteolytic balance and capillary morphogenesis. Cell. Differ. Dev. 32:319–328.PubMedGoogle Scholar
  122. Peters-Engl, C., Medl, M., Mirau, M., Wanner, C., Bilgi, S., Sevelda, P., and Obermair, A. 1998. Color-coded and spectral Doppler flow in breast carcinomas-relationship with the tumor microvasculature. Breast Cancer Res. Treat. 47:83–89.PubMedGoogle Scholar
  123. Porschen, R., Classen, S., Piontek, M., and Borchard, F. 1994. Vascularization of carcinomas of the esophagus and its correlation with tumor proliferation. Cancer Res. 54:587–591.PubMedGoogle Scholar
  124. Porter, P., Patton, K., Self, S., Gown, A., and Schmidt, R. 1993. A quantitative study of blood vessel size and density informal and neoplastic breast tissue.Mod. Pathol.6:18Google Scholar
  125. Protopapa, E., Delides, G. S., and Revesz, L. 1993. Vascular density and the response of breast carcinomas to mastectomy and adjuvant chemotherapy. Eur. J. Cancer 29A: 1141–1145.Google Scholar
  126. Relf, M., LeJeune, S., Scott, P. A., Fox, S., Smith, K., Leek, R., Moghaddam, A., Whitehouse, R., Bicknell, R., and Harris, A. L. 1997. Expression of the angiogenic factors vascular endothelial cell growth factor, acidic and basic fibroblast growth factor, tumor growth factor beta-1, platelet-derived endothelial cell growth factor, placenta growth factor, and pleiotrophin in human primary breast cancer and its relation to angiogenesis. Cancer Res. 57:963–969.PubMedGoogle Scholar
  127. Sahin, A., Sneige, N., Singletary, E., and Ayala, A. 1992. Tumor angiogenesis detected by factor-VIII immunostaining in node-negative breast carcinoma (NNBC): a possible predictor of distant metastasis. Mod. Pathol. 5:17A.Google Scholar
  128. Salven, P., Perhoniemi, V., Tykka, H., Maenpaa, H., and Joensuu, H. 1999. Serum VEGF levels in women with a benign breast tumor or breast cancer. Breast Cancer Res. Treat. 53:161–166.PubMedGoogle Scholar
  129. Schadendorf, D., Heidel, J., Gawlik, C., Suter, L., and Czarnetzki, B. M. 1995. Association with clinical outcome of expression of VLA-4 in primary cutaneous malignant melanoma as well as P-selectin and E-selectin on intratumoral vessels. J. Natl. Cancer Inst. 87:366–371.PubMedGoogle Scholar
  130. Schlingemann, R. O., Rietveld, F. J., Kwaspen, F., van d. Kerkhof, P. C., de Waal, R. M., and Ruiter, D. J. 1991. Differential expression of markers for endothelial cells, pericytes, and basal lamina in the microvasculature of tumors and granulation tissue. Am. J. Pathol. 138:1335–1347.PubMedGoogle Scholar
  131. Schor, A. M., Pendleton, N., Pazouki, S., Smither, R. L., Morris, J., Lessan, K., Heerkens, E., Chandrachud, L. M., Carmichael, G., Adi, M., Chisholm, D. M., and Stevenson, H. 1998. Assessment of vascularity in histological sections: effects of methodology and value as an index of angiogenesis in breast tumours. Histochern. J. 30:849–856.Google Scholar
  132. Sightler, H., Borowsky, A., Dupont, W., Page, D., and Jensen, R. 1994. Evaluation of tumor angiogenesis as a prognostic marker in breast cancer. Lab. Invest. 70:22A.Google Scholar
  133. Siitonen, S., Haapasalo, H., Rantala, I., Helin, H., and Isola, J. 1995. Comparison of different immunohistochemical methods in the assessment of angiogenesis: lack of prognostic value in a group of 77 selected node-negative breast carcinomas. Mod. Pathol. 8:745–752.PubMedGoogle Scholar
  134. Simpson, J., Ahn, C., Battifora, H., and Esteban, J. 1996. Endothelial surface area as a prognostic indicator for invsasive breast carcinoma. Cancer 77(10):2077–2085.PubMedGoogle Scholar
  135. Sipkins, D. A., Cheresh, D. A., Kazemi, M. R., Nevin, L. M., Bednarski, M. D., and Li, K. C. 1998. Detection of tumor angiogenesis in vivo by alphavbeta3-targeted magnetic resonance imaging. Nat. Med. 4:623–626.PubMedGoogle Scholar
  136. Skinner, S. A., Frydman, G. M., and O’Brien, P. E. 1995. Microvascular structure of benign and malignant tumors of the colon in humans. Dig. Dis. Sci. 40:373–384.PubMedGoogle Scholar
  137. Sterns, E., Zee, B., SenGupta, S., and Saunders, F. 1996. Thermography: its relation to pathologic characteristics, vascularity, proliferation rate and survival of patients with invasive ductal carcinoma of the breast. Cancer 77:1324–1328.PubMedGoogle Scholar
  138. Stomper, P. C., Winston, J. S., Herman, S., Klippenstein, D. L., Arredondo, M. A., and Blumenson, L. E. 1997. Angiogenesis and dynamic MR imaging gadolinium enhancement of malignant and benign breast lesions. Breast Cancer Res. Treat. 45:39–46.PubMedGoogle Scholar
  139. Svrivastava, A., Laidler, P., Davies, R., Horgan, K., and Hughes, L. 1988. The prognostic significance of tumor vascularity in intermediate-thickness (0.76–4.0 mm thick) skin melanoma. Am. J. Pathol. 133:419–423.Google Scholar
  140. Tan, P., Cady, B., et al. 1997. The cell cycle inhibitor p27 is an independent prognostic marker in small (T1a,b) invasive breast carcinomas. Cancer Res.57(7):1259–1263.PubMedGoogle Scholar
  141. Tanigawa, N., Matsumura, M., Amaya, H., Kitaoka, A., Shimomatsuya, T., Lu, C., Muraoka, R., and Tanake, T. 1997. Tumor vascularity correlates with the prognosis of patients with esophageal squamous carcinoma. Cancer 79:220–225.PubMedGoogle Scholar
  142. Toi, M., Hoshina, S., Taniguchi, T., Yamamoto, Y., Ishitsuka, H., and Tominaga, T. 1995. Expression of platelet derived endothelial cell growth factor/thymidine phosphorylase in human breast cancer. Int. J. Cancer 64:79–82.PubMedGoogle Scholar
  143. Toi, M., Kashitani, J., and Tominaga, T. 1993. Tumor angiogenesis is an independent prognostic indicator in primary breast carcinoma. Int. J. Cancer 55:371–374.PubMedGoogle Scholar
  144. Toi, M., Kondo, S., Suzuki, H., Yamamoto, Y, Inada, K., Imazawa, T., Taniguchi, T., and Tominaga, T. 1996a. Quantitative analysis of vascular endothelial growth factor in primary breast cancer. Cancer 77:1101–1106.PubMedGoogle Scholar
  145. Toi, M., Taniguchi, T., Yamamoto, Y., Kurisaki, T., Suzuki, H., and Tominaga, T. 1996b. Clinical significance of the determination of angiogenic factors. Eur. J. Cancer 32A:2513–2519.PubMedGoogle Scholar
  146. van Diest, P. J. 1999. Ductal carcinoma in situ in breast carcinogenesis. J. Pathol. 187:383–384.PubMedGoogle Scholar
  147. van Hoef, M. E., Knox, W. F., Dhesi, S. S., Howell, A., and Schor, A. M. 1993. Assessment of tumour vascularity as a prognostic factor in lymph node negative invasive breast cancer. Eur. J. Cancer 29A:1141–1145.PubMedGoogle Scholar
  148. van Zijl, P. C., Eleff, S. M., Ulatowski, J. A., Oja, J. M., Ulug, A. M., Traystman, R. J., and Kauppinen, R. A. 1998. Quantitative assessment of blood flow, blood volume and blood oxygenation effects in functional magnetic resonance imaging. Nat. Med. 4:159–167.PubMedGoogle Scholar
  149. Vermeulen, P. B., Gasparini, G., Fox, S. B., Toi, M., Martin, L., McCulloch, P., Pezzella, F., Viale, G., Weidner, N., Harris, A. L., and Dirix, L. Y. 1996. Quantification of angiogenesis in solid human tumours: an international consensus on the methodology and criteria of evaluation. Eur. J. Cancer 32A:2474–2484.PubMedGoogle Scholar
  150. Vesalainen, S., Lipponen, P., Talja, M., Alhava, E., and Syrjanen, K. 1994. Tumor vascularity and basement membrane structure as prognostic factors in T1–2M0 prostatic adenocarcinoma. Anticancer Res. 14:709–714.PubMedGoogle Scholar
  151. Viens, P., Jacquemier, J., Bardou, V. J., Bertucci, F., Penault-Llorca, F., Puig, B., Gravis, G., Oziel-Taieb, S., Resbeut, M., Houvenaeghel, G., Camerlo, J., Birbaum, D., Hassoun, J., and Maraninchi, D. 1999. Association of angiogenesis and poor prognosis in node-positive patients receiving anthracycline-based adjuvant chemotherapy. Breast Cancer Res. Treat. 54:205–212. PubMedGoogle Scholar
  152. Visscher, D., Smilanetz, S., Drozdowicz, S., and Wykes, S. 1993. Prognostic significance of image morphometric microvessel enumeration in breast carcinoma. Anal. Quant. Cytol. 15:88–92.Google Scholar
  153. Wakui, S., Furusato, M., Itoh, T., Sasaki, H., Akiyama, A., Kinoshita, I., Asano, K., Tokuda, T., Aizawa, S., and Ushigome, S. 1992. Tumour angiogenesis in prostatic carcinoma with and without bone marrow metastases: a morphometric study. J. Pathol. 168:257–262.PubMedGoogle Scholar
  154. Wang, J. M., Kumar, S., Pye, D., Haboubi, N., and Al-Nakib, L. 1994. Breast carcinoma: comparative study of tumor vasculature using two endothelial cell markers. J. Natl. Cancer Inst. 86:386–388.PubMedGoogle Scholar
  155. Warren, B. 1979. The vascular morphology of tumors. In: Peterson, H. ed. Tumor Blood Circulation. CRC Press, Boca Raton, FL, pp. 1–47.Google Scholar
  156. Weidner, N., Folkman, J., Pozza, F., Bevilacqua, P., Allred, E. N., Moore, D. H., Meli, S., and Gasparini, G. 1992. Tumor angiogenesis: a new significant and independent prognostic indicator in early-stage breast carcinoma. J. Natl. Cancer Inst. 84:1875–1887.PubMedGoogle Scholar
  157. Weidner, N., Semple, J. P., Welch, W. R., and Folkman, J. 1991. Tumor angiogenesis and metastasis-correlation in invasive breast carcinoma. N. Engl. J. Med. 324:1–8.PubMedGoogle Scholar
  158. Wesseling, P., Vandersteenhoven, J. J., Downey, B. T., Ruiter, D. J., and Burger, P. C. 1993. Cellular components of microvascular proliferation in human glial and metastatic brain neoplasms. A light microscopic and immunohistochemical study of formalin-fixed, routinely processed material. Acta Neuropathol. 85:508–514.PubMedGoogle Scholar
  159. Williams, J. K., Carlson, G. W., Cohen, C., Derose, P. B., Hunter, S., and Jurkiewicz, M. J. 1994. Tumor angiogenesis as a prognostic factor in oral cavity tumors. Am. J. Surg. 168:373–380.PubMedGoogle Scholar
  160. Ziche, M., and Gullino, P. M. 1982. Angiogenesis and neoplastic progression in vitro. J. Natl. Cancer Inst. 69:483–487.PubMedGoogle Scholar
  161. Zimrin, A. B., Pepper, M. S., McMahon, G. A., Nguyen, F., Montesano, R., and Maciag, T. 1996. An antisense oligonucleotide to the notch ligand jagged enhances fibroblast growth factor-induced angiogenesis in vitro. J. Biol. Chem. 271:32499–32502.PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2001

Authors and Affiliations

  • Stephen B. Fox

There are no affiliations available

Personalised recommendations