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Clinical significance of angiogenic factors in breast cancer

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Abstract

Growth, progression, and metastasis of breast cancer, as well as of most of the other tumors, are angiogenesis-dependent processes.

Several pro-angiogenic growth factors and endogenous inhibitors of angiogenesis have been identified and sequenced, and experimental studies suggest that angiogenic activity of a tumor may result from down-regulation of inhibitors of angiogenesis or up-regulation of endothelial growth factors. The mechanisms leading to the alteration of the balance between positive and negative modulators of angiogenesis are only partially known.

We are at the beginning of research to identify the more active angiogenic factors in human breast cancer, and little information is presently available on their clinical significance. Preliminary results suggest that among the known angiogenic peptides, both vascular endothelial growth factor (VEGF) and platelet-derived endothelial cell growth factor / thymidine phosphorylase (PD-ECGF/TP) have promising prognostic and, perhaps, predictive value.

No data are available on the clinical value of co-determination of positive and negative regulators of angiogenesis to look at the angiogenic balance of each single tumor. Only a few studies have assessed the role of endogenous inhibitors of angiogenesis in human breast cancer, with results available only on thrombospondin-1 and -2 (TSP-1, -2).

Finally, the determination of some integrins such as α6 and αvβ3 and of some other endothelial-adhesion molecules seems to be of potential prognostic value.

Recognizing which are the more biologically active positive and negative angiogenic factors is the key for the identification not only of new prognostic markers but also of targets for antiangiogenic therapy in human breast cancer.

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References

  1. Folkman J: What is the evidence that tumors are angiogenesis dependent? J Natl Cancer Inst 82:4-6, 1989

    Google Scholar 

  2. Folkman J: Angiogenesis in cancer, vascular, rheumatoid and other disease. Nature Med 1:27-31, 1995

    Google Scholar 

  3. Risau W: Mechanisms of angiogenesis. Nature 386:671-674, 1997

    Google Scholar 

  4. Asahara T, Murohara T, Sullivan A, Silver M, van der Zee R, Li T, Witzenbichler B, Schatteman G, Isner JM: Isolation of putative progenitor endothelial cells for angiogenesis. Science 275:964-967, 1997

    Google Scholar 

  5. Hunt BJ, Jurd KM: Endothelial cell activation. A central pathophysiological process. Br Med J 316:1328-1329, 1998

    Google Scholar 

  6. Folkman J: Clinical applications of research on angiogenesis. New Engl J Med 333:1757-1763, 1995

    Google Scholar 

  7. Folkman J: How is blood vessel growth regulated in normal and neoplastic tissue? — GHA Clowes Memorial Award Lecture. Cancer Res 46:467-473, 1986

    Google Scholar 

  8. Hanahan D, Folkman J: Patterns of emerging mechanisms of the angiogenic switch during tumorigenesis. Cell 86:353-364, 1996

    Google Scholar 

  9. Kerbel RS: Commentaries on tumor angiogenesis: an introduction. Cancer Metastasis Rev 15:145-147, 1996

    Google Scholar 

  10. Marx J: Cellular changes on the route to metastasis. Science 259:626-629, 1993

    Google Scholar 

  11. Strömblad S, Becker JC, Yebra M, Brooks PC, Cheresh DA: Suppression of p53 activity and p21WAF1/CIP1 expression by vascular cell integrin αvβ3 during angiogenesis. J Clin Invest 98:426-433, 1996

    Google Scholar 

  12. Gasparini G, Harris AL: p53 and angiogenesis in neoplasia. In: Klijn JGM (ed) Prognostic and Predictive Value of p53. Elsevier Science BV, London, 1997, pp 115-130

    Google Scholar 

  13. Rak J, Filmus J, Finkenzeller G, Grugel S, Marmé D, Kerbel RS: Oncogenes as inducers of tumor angiogenesis. Cancer Metastasis Rev 14:263-277, 1995

    Google Scholar 

  14. Brooks PC, Clark RAF, Cheresh DA: Requirement of vascular αvβ3 for angiogenesis. Science 264:569-571, 1994

    Google Scholar 

  15. Marshall JF, Hart IR: The role of αv-integrins in tumor progression and metastasis. Sem Cancer Biol 7:129-138, 1996

    Google Scholar 

  16. Polunovsky VA, Wendt CH, Ingbar DH, Peterson MS, Bitterman PB: Induction of endothelial cell apoptosis by TNFα: Modulation by inhibitors of protein synthesis. Exp Cell Res 214:548-594, 1994

    Google Scholar 

  17. Wojnowski L, Zimmer AM, Beck TW, Hahn H, Bernal R, Rapp UR, Zimmer A: Endothelial apoptosis in braf-deficient mice. Nature Genetics 16:293-297, 1997

    Google Scholar 

  18. O'Reilly MS, Holmgren L, Chen C, Folkman J: Angiostatin induces and sustains dormancy of human primary tumors. Nature Med 2:689-692, 1996

    Google Scholar 

  19. O'Reilly MS, Boehm T, Shing Y, Fukai N, Vasios G, Lane WS, Flynn E, Birkhead JR, Olsen BR, Folkman J: Endostatin: an endogenous inhibitor of angiogenesis and tumor growth. Cell 88:277-285, 1997

    Google Scholar 

  20. Melder RJ, Koerig GC, Witner BP, et al: During angiogenesis, vascular endothelial growth factor and basic fibroblast growth factor regulate natural killer cell adhesion to tumor endothelium. Nature Med 2:992-997, 1996

    Google Scholar 

  21. Ferrara N: Natural killer cells, adhesion and tumor angiogenesis. Nature Med 2:971-972, 1996

    Google Scholar 

  22. Gabrilovich DL, Chen HL, Girgis KR, et al: Production of vascular endothelial growth factor by human tumors inhibits the functional maturation of dendritic cells. Nature Med 2:1096-1103, 1996

    Google Scholar 

  23. Adams DH, Yannelli JR, Newman W, et al: Adhesion of tumor-infiltrating lymphocytes to endothelium: a phenotypic and functional analysis. Br J Cancer 75:1421-1431, 1997

    Google Scholar 

  24. Terman BI, Dougher-Vermazen M: Biological properties of VEGF/VPF receptors. Cancer Metastasis Rev 15:159-163, 1996

    Google Scholar 

  25. Dvorak HF, Brown LF, Detmar M, Dvorak AM: Vascular permeability factor/vascular endothelial growth factor, microvascular hyperpermeability, and angiogenesis. Am J Pathol 146:1029-1039, 1995

    Google Scholar 

  26. Kieser A, Wiech HA, Brandner G, Marmé D, Kolch W: Mutant p53 potentiates protein kinase C induction of vascular endothelial growth factor expression. Oncogene 9:963-969, 1994

    Google Scholar 

  27. Hyder SM, Murthy L, Stancel GM: Progestin regulation of vascular endothelial growth factor in human breast cancer cells. Cancer Res 58:392-395, 1998

    Google Scholar 

  28. Nicosia RF: What is the role of vascular endothelial growth factor-related molecules in the tumor angiogenesis? Am J Pathol 153:11-16, 1998

    Google Scholar 

  29. Salven P, Lymboussaki A, Heikkilä P, Jääskela-Saari H, Enholm B, Aase K, Von Euler G, Eriksson U, Alitalo K, Joensuu K: Vascular endothelial growth factors VEGF-B and VEGF-C are expressed in human tumors. Am J Pathol 153:103-108, 1998

    Google Scholar 

  30. Guidi AJ, Schnitt SJ, Fischer L, Tognazzi K, Harris JR, Dvorak HF, Brown LF: Vascular permeability factor (vascular endothelial growth factor) expression and angiogenesis in patients with ductal carcinoma in situ of the breast. Cancer 80:1945-1953, 1997

    Google Scholar 

  31. Toi M, Insada K, Hoshina S, Suzuki H, Kondo S, Tominaga T: Vascular endothelial growth factor and platelet-derived endothelial cell growth factor are frequently coexpressed in highly vascularized human breast cancer. Clin Cancer Res 1:961-964, 1995

    Google Scholar 

  32. Anan K, Morisaki T, Katano M, Ikubo A, Kitsuki R, Uchiyama A, Kuroki S, Taoaka M, Torisu M: Vascular endothelial growth factor and platelet-derived growth factor are potential angiogenic and metastatic factors in human breast cancer. Surgery 119:333-339, 1996

    Google Scholar 

  33. Obermair A, Kucera E, Mayerhofer K, Speiser P, Seifert M, Czerwenka K, Kaider A, Leodalter S, Kaintz C, Zeillinger R: Vascular endothelial growth factor (VEGF) in human breast cancer: correlation with disease-free survival. Int J Cancer 74:455-458, 1997

    Google Scholar 

  34. Toi M, Gion M, Biganzoli E, Dittadi R, Boracchi P, Miceli R, Meli S, Mori K, Tominaga T, Gasparini G: Co-determination of the angiogenic factors thymidine phosphorylase and vascular endothelial growth factor in node-negative breast cancer: prognostic implications. Angiogenesis 1:71-83, 1997

    Google Scholar 

  35. Gasparini G, Toi M, Gion M, Verderio P, Dittadi R, Hanatani M, Matsubara I, Vinante O, Bonoldi E, Boracchi P, Gatti C, Suzuki I, Tominaga T: Prognostic significance of vascular endothelial growth factor protein in node-negative breast carcinoma. J Natl Cancer Inst 89:139-147, 1997

    Google Scholar 

  36. Relf M, LeJeune S, Scott PAE, Fox S, Smith K, Leek R, Moghaddam A, Whitehouse R, Bicknell R, Harris AL: Expression of the angiogenic factors vascular endothelial cell growth factor, acidic and basic fibroblast growth factor, tumor growth factor β-1, platelet-derived endothelial growth factor, placenta growth factor, and pleiotrephin in human primary breast cancer and its relation to angiogenesis. Cancer Res 57:963-969, 1997

    Google Scholar 

  37. Vermeulen PB, Dirix LY, Salven P, Benoy L, Ranieri G, Toi M, Gasparini G: Assessing angiogenic factor concentrations in body fluids of cancer patients and in tumor cytosols: a review. Angiogenesis, in press

  38. Vermeulen PB, Salven P, Benoy L, Gasparini G, Dirix LY: Blood platelets and serum VEGF in cancer patients. Br J Cancer, in press

  39. Verheul HMW, Haekman K, Luykx-de Bakker S, Eekman CA, Folman CC, Broxterman HJ, Pinedo HM: Platelet: transporter of vascular endothelial growth factor. Clin Cancer Res 3:2187-2190, 1997

    Google Scholar 

  40. Folkman J: What is the role of thymidine phosphorylase in tumor angiogenesis? J Natl Cancer Inst 88:1091-1092, 1996

    Google Scholar 

  41. Griffths L, Stratford IJ: Platelet-derived endothelial cell growth factor thymidine phosphorylase in tumor growth and response to therapy. Br J Cancer 76:689-693, 1997

    Google Scholar 

  42. Piper AA, Tattersall MHN, Fox RM: The activities of thymidine metabolising enzymes during the cell cycle of human lymphocyte cell line LAZ-007 synchronised by centrifugal elutriation. Biochim Biophys Acta 633:400-409, 1980

    Google Scholar 

  43. Fox SB, Westwood M, Moghaddam A, Comley M, Turley H, Whitehouse RM, Bicknell R, Gatter KC, Harris AL: 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, 1996

    Google Scholar 

  44. Toi M, Hoshina S, Taniguchi T, Yamamoto Y, Ishitsuka H, Tominaga T: Expression of platelet-derived endothelial cell growth factor/thymidine phosphorylase in human breast cancer. Int J Cancer 64:79-82, 1995

    Google Scholar 

  45. Seymour L, Bezwoda WR: Positive immunostaining for platelet derived growth factor (PDGF) is an adverse prognostic factor in patients with advanced breast cancer. Breast Cancer Res Treat 32:229-233, 1994

    Google Scholar 

  46. Engels K, Fox SB, Whitehouse RM, Gatter KC, Harris AL: 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, 1997

    Google Scholar 

  47. Fox SB, Engels K, Comley M, Whitehouse RM, Turley H, Gatter KC, Harris AL: Relationship of elevated tumor thymidine phosphorylase in node-positive breast carcinomas to the effects of adjuvant CMF. Ann Oncol 8:271-275, 1997

    Google Scholar 

  48. Nagaoka H, Iino Y, Takei H, Morishita Y: Platelet-derived endothelial cell growth factor/thymidine phosphorylase expression in macrophages correlates with tumor angiogenesis and prognosis in invasive breast cancer. Int J Oncol 13:449-454, 1998

    Google Scholar 

  49. Gion M, Toi M, Dirix L, Dittadi R, Fanelli M, Vermeulen P, Gasparini G: Clinical significance of cytosolic levels in primary node-positive breast cancer of vascular endothelial growth factor and thymidine phosphorylase [Abstr 412]. Proc Amer Soc Clin Oncol, 1998, p 107a

  50. Leek RD, Landers R, Fox SB, Ng F, Harris AL, Lewis CE: Association of tumor necrosis factor alpha and its receptors with thymidine phosphorylase expression in invasive breast carcinoma. Br J Cancer 77:2246-2251, 1998

    Google Scholar 

  51. Nagy J, Curry GW, Hillan KJ, Mallon E, Purushotham AD, George WD: Hepatocyte growth factor/scatter factor, angiogenesis and tumor cell proliferation in primary breast cancer. Breast 5:105-109, 1996

    Google Scholar 

  52. Laterra J, Nam M, Rosen E, Rao JS, Lamszus K, Goldberg ID, Johnston P: Scatter factor/hepatocyte growth factor gene transfer enhances glioma growth and angiogenesis in vivo. Lab Invest 76:565-577, 1997

    Google Scholar 

  53. Taniguchi T, Toi M, Inada K, Imazawa T, Yamamoto Y, Tominaga T: Serum concentrations of hepatocyte growth factor in breast cancer patients. Clin Cancer Res 1:1031-1034, 1995

    Google Scholar 

  54. Mason IJ: The ins and outs of fibroblast growth factors. Cell 78:547-552, 1994

    Google Scholar 

  55. Kern FG, Lippman ME: The role of angiogenic growth factors in breast cancer progression. Cancer Metastasis Rev 15:213-219, 1996

    Google Scholar 

  56. Zhang L, Kharbanda S, Chen D, Bullocks J, Miller DL, Ding IY, Hanfelt J, McLeskey SW, Kern FG: MCF-7 breast carcinoma cells overexpressing FGF-1 form vascularized, metastatic tumors in ovariectomized or tamoxifen-treated nude mice. Oncogene 15:2093-2108, 1997

    Google Scholar 

  57. Colomer R, Aparicio J, Montero S, Guzmán C, Larrodera L, Cortés-Funes H: Low levels of basic fibroblast growth factor (bFGF) are associated with a poor prognosis in human breast carcinoma. Br J Cancer 76:1215-1220, 1997

    Google Scholar 

  58. Yiangou C, Gomm JJ, Coope RC, Law M, Luqmani YA, Shousha S, Coombes RC, Johnston CL: Fibroblast growth factor 2 in breast cancer: occurrence and prognostic significance. Br J Cancer 75:28-33, 1997

    Google Scholar 

  59. Visscher DW, De Mattia F, Ottosen S, Sarkar FH, Crissman JD: Biologic and clinical significance of basic fibroblast growth factor immunostaining in breast carcinoma. Modern Pathol 8:665-670, 1995

    Google Scholar 

  60. Dirix LY, Vermeulen PB, Pawinski A, Prové A, Benoy I, De Pooter C, Martin M, Van Oosterom AT: Elevated levels of the angiogenic cytokines basic fibroblast growth factor and vascular endothelial growth factor in sera of cancer patients. Br J Cancer 76:238-243, 1997

    Google Scholar 

  61. Coope RC, Browne PJ, Yiangou C, Bansal GS, Walters J, Groome N, Shousha S, Johnston CL, Coombes RC, Gomm JJ: The location of acidic fibroblast growth factor in the breast is dependent on the activity of proteases present in breast cancer tissue. Br J Cancer 75:1621-1630, 1997

    Google Scholar 

  62. Scott PA, Smith K, Poulsom R, De Benedetti A, Bicknell R, Harris AL: Differential expression of vascular endothelial growth factor mRNA vs protein isoform expression in human breast cancer and relationship to eIF-4E. Br J Cancer 77:2120-2128, 1998

    Google Scholar 

  63. Morelli D, Lazzerini D, Cazzaniga S, Squicciarini P, Bignami P, Maier JAM, Sfondrini L, Menard S, Colnaghi MI, Bolsari A: Evaluation of the balance between angiogenic and antiangiogenic circulating factors in patients with breast and gastrointestinal cancers. Clin Cancer Res 4:1221-1225, 1998

    Google Scholar 

  64. Yamashita J, Ogawa M, Jamashita S, Nomura K, Kuramoto M, Saishoji T, Shin S: Immunoreactive hepatocyte growth factor is a strong and independent predictor of recurrence and survival in human breast cancer. Cancer Res 54:1630-1633, 1994

    Google Scholar 

  65. Toi M, Hoshima 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 85:1045-1049, 1994

    Google Scholar 

  66. Linderholm B, Tavelin K, Granksit R, Henriksson R: Prognostic value of vascular endothelial growth factor protein in node-negative breast cancer [Abstr 934]. Proc 10th NCI-EORTC symposium on new drugs in cancer therapy, Amsterdam. Ann Oncol 9(suppl 2): 522, 1998

    Google Scholar 

  67. Toi M, Taniguchi T, Yamamoto Y, Kurisaki H, Tominaga T: Clinical significance of the determination of angiogenic factors. Eur J Cancer 32A:2513-2519, 1996

    Google Scholar 

  68. Linderholm B, Tavelin B, Grankvist K, Henriksson R: Vascular endothelial growth factor protein-A predictor of survival in primary breast cancer [Abstr 386]. Proc Amer Soc Clin Oncol, 1998, p100a

  69. Kim KJ, Li B, Winer J, Armanini M, Gillett N, Phillips HS, Ferrara N: Inhibition of vascular endothelial growth factor-induced angiogenesis suppresses tumor growth in vivo. Nature 362:841-844, 1993

    Google Scholar 

  70. Hori A, Sasada R, Matsutani E, Naito K, Sakura Y, Fujita T, Kozai Y: Suppression of solid tumor growth by immunoneutralizing monoclonal antibody against human basic fibroblast growth factor. Cancer Res 51:6180-6184, 1991

    Google Scholar 

  71. Yuan F, Chen Y, Dellian M, Safabakhsh N, Ferrara N, Jain RK: Time-dependent vascular regression and permeability changes in established human tumor xenografts induced by an anti-vascular endothelial growth factor/vascular permeability factor antibody. Proc Natl Acad Sci USA 93:14765-14770, 1996

    Google Scholar 

  72. Gasparini G: Antiangiogenic drugs as a novel anticancer therapeutic strategy. Which are the more promising agents? What are the clinical developments and indications? Crit Rev Oncol Hematol 26:147-162, 1997

    Google Scholar 

  73. Gordon MS, Talpalz M, Margolin K, et al: Phase I trial of recombinant humanized monoclonal anti-vascular endothelial growth factor (anti-VEGF MAB) in patients with metastatic cancer [Abstr 809]. Proc Amer Soc Clin Oncol 17:210, 1998

    Google Scholar 

  74. Bertin N, Clezardin P, Kubiak R, Frappart L: Thrombospondin 1 and 2 messenger RNA expression in normal, benign, and neoplastic human breast tissues: correlation with prognostic factors, tumor angiogenesis, and fibroblastic desmoplasia. Cancer Res 57:396-399, 1997

    Google Scholar 

  75. Roth JJ, Reiver DM, Granik MS, Rothman VL, Nicosia RF, Tuszynski GP: Histopathology and clinical assessment correlate with the cysteine-serine-valine-threonine-cysteine-glycine (CSVTCG) receptor of thrombospondin-1 in breast tumors. Histol Histopathol 12:1013-1018, 1997

    Google Scholar 

  76. Weinstat-Saslow DL, Zabrenetzky VS, VanHoutte K, Frazier WA, Roberts DD, Steeg PS: Transfection of thrombospondin 1 complementary DNA into a human breast carcinoma cell line reduces primary tumor growth, metastatic potential, and angiogenesis. Cancer Res 54:6504-6511, 1994

    Google Scholar 

  77. Volpert O, Stellmach V, Bouck N: The modulation of thrombospondin and other naturally occurring inhibitors of angiogenesis during tumor progression. Breast Cancer Res Treat 36:119-126, 1995

    Google Scholar 

  78. Zajchowski DA, Band V, Trask DK, Kling D, Connolly JL, Sager R: Suppression of tumor-forming ability and related traits in MCF-7 human breast cancer cell by fusion with immortal mammary epithelial cells. Proc Natl Acad Sci USA 87:2314-2318, 1990

    Google Scholar 

  79. Xu M, Kumar D, Strass SA, Mixson AJ: Gene therapy with p53 and fragment of thrombospondin-1 inhibits human breast cancer in vivo. Mol Genet Metab 63:103-109, 1998

    Google Scholar 

  80. Dameron KM, Volpert OV, Tainsky MA, Bouck N: Control of angiogenesis in fibroblasts by p53 regulation of thrombospondin-1. Science 265:1582-1585, 1994

    Google Scholar 

  81. Incardona F, Leivalle JM, Morandi V, Lambert S, Legrand Y, Foidart JM, Legrand C: Thrombospondin modulates human breast adenocarcinoma cell adhesion to human vascular endothelial cells. Cancer Res 55:166-173, 1995

    Google Scholar 

  82. Arnoletti JP, Albo D, Granick MS, Solomon MP, Castiglioni A, Rothman VL, Tuzynski GP: Thrombospondin spondin and transforming growth-factor beta 1 increase expression of urokinase-type plasminogen activator and plasminogen activator inhibitor-1 in human MDA-MB-231 breast cancer cells. Cancer 76:998-1005, 1995

    Google Scholar 

  83. Griscelli F, Li H, Bennaceur-Griscelli A, Soria J, Opolon P, Soria C, Perricaudet M, Yeh P, Lu H: Angiostatin gene transfer: inhibition of tumor growth in vivo by blockage of endothelial cell proliferation associated with a mitosis arrest. Proc Natl Acad Sci 95:6367-6372, 1998

    Google Scholar 

  84. Zhu BT, Conney AH: Is 2-methoxyestradiol an endogenous estrogen metabolite that inhibits mammary carcinogenesis? Cancer Res 58:2269-2277, 1998

    Google Scholar 

  85. Fotsis TH, Zhang Y, Pepper MS, Adlercreutz H, Montesano R, Nawroth PP, Schwelgerer L: The endogenous oestrogen metabolite 2-methoxyoestradiol inhibits angiogenesis and suppresses tumor growth. Nature 368:237-239, 1994

    Google Scholar 

  86. Bischoff J: Cell adhesion and angiogensis. J Clin Invest 99:373-376, 1997

    Google Scholar 

  87. Fox SB, Leek RD, Weekes MP, Whitehouse RM, Gatter KC, Harris AL: Quantitation and prognostic value of breast cancer angiogensis: Comparison of microvessel density, Chalkley count and computer image analysis. J Pathol 177:275-283, 1995

    Google Scholar 

  88. Charpin C, Bergeret D, Garcia S, Andrac L, Martini F, Horschowski N, Choux R, Lavaut MN: ELAM selectin expression in breast carcinomas detected by automated and quantitative immunohistochemical assays. Int J Oncol 12:1041-1048, 1998

    Google Scholar 

  89. Ruoslahti E, Engvall E: Perspectives Series: Cell adhesion in vascular biology. J Clin Invest 99:1149-1152, 1997

    Google Scholar 

  90. Friedrichs K, Ruiz P, Franke F, Gille I, Terpe HJ, Imhof BA: High expression level of α6 integrin in human breast carcinoma is correlated with reduced survival. Cancer Res 55:901-906, 1995

    Google Scholar 

  91. Tagliabue E, Ghirelli C, Squicciarini P, Aiello P, Colnaghi MI, Menard S: Prognostic value of alpha 6 beta 4 integrin expression in breast carcinoma is affected by laminin production from tumor cells. Clin Cancer Res 4:407-410, 1998

    Google Scholar 

  92. Brooks PC, Stromblad S, Klemke R, Visscher D, Sarkar FH, & Cheresh DA: Antiintegrin αvβ3 blocks human breast cancer growth and angiogenesis in human skin. J Clin Invest 96:1815-1822, 1995

    Google Scholar 

  93. Gasparini G, Brooks PC, Biganzoli E, Vermeulen PB, Bonoldi E, Dirix LY, Ranieri G, Miceli R, Cheresh DA: Blood vessel expression of integrin αvβ3: a prognostic indicator in breast cancer patients. Clin Cancer Res, in press

  94. Gutheil JC, Campbell TN, Pierce PR, et al: Phase I study of vitaxin, an anti-angiogenic humanized monoclonal antibody to vascular integrin αvβ3 [Abstr 832]. Proc Amer Soc Clin Oncol 17:215, 1998

    Google Scholar 

  95. Sipkins DA, Cheresh DA, Kazemi MR, Nevin LM, Bednarski MD, Li KCP: Detection of tumor angiogenesis in vivo by αvβ3-targeted magnetic resonance imaging. Nature Med 4:623-626, 1998

    Google Scholar 

  96. Natali PG, Nicotra MR, Bigotti A, Botti C, Castellani P, Risso AM, Zardi L: Comparative analysis of the expression of the extracellular matrix protein tenascin in normal human fetal, adult and tumor tissues. Int J Cancer 47:811-816, 1991

    Google Scholar 

  97. Ishihara A, Yoshida T, Tamaki H, Sakakura T: Tenascin expression in cancer cells and stroma of human breast cancer and its prognostic significance. Clin Cancer Res 1:1035-1041, 1995

    Google Scholar 

  98. Contrino J, Hair G, Kreutzer DL, Rickles FR: In situ detection of tissue factor in vascular endothelial cells: Correlation with the malignant phenotype of human breast disease. Nature Med 2:209-215, 1996

    Google Scholar 

  99. Gasparini G, Barbareschi M, Boracchi P, Bevilacqua P, Verderio P, Dalla Palma P, Menard S: 67-kDa laminin-receptor expression adds prognostic information to intra-tumoral microvessel density in nodenegative breast cancer. Int J Cancer 60:604-610, 1995

    Google Scholar 

  100. Folkman J: The influence of angiogenesis research on management of patients with breast cancer. Breast Cancer Res Treat 36:109-118, 1995

    Google Scholar 

  101. Gasparini G: Angiogenesis in breast cancer: Role in biology, tumor progression, and prognosis. In: Bowcock A (ed) Breast Cancer. Humana Press, in press, 1998

  102. Gasparini G: Is determination of angiogenic activity in human tumours clinically useful? Eur J Cancer 34:615-618, 1998

    Google Scholar 

  103. Jain RK, Schlenger K, Hockel M, Yuan F: Quantitative angiogenesis assays: Progress and problems. Nature Med 3:1203-1208, 1997

    Google Scholar 

  104. Gasparini G, Presta M: Clinical studies with angiogenesis inhibitors: biological rationale and challenges for their evaluation. Ann Oncol 7:441-444, 1996

    Google Scholar 

  105. Gasparini G: The rationale and future potential of angiogenesis inhibitors in neoplasia. Drugs, in press

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  1. Nathalia Locopo
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  2. Massimo Fanelli
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  3. Giampietro Gasparini
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Locopo, N., Fanelli, M. & Gasparini, G. Clinical significance of angiogenic factors in breast cancer. Breast Cancer Res Treat 52, 159–173 (1998). https://doi.org/10.1023/A:1006175504673

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