Summary
Several groups have shown that quantitation of tumor angiogenesis by counting blood vessels in primary breast cancer gives an independent assessment of prognosis. Poor prognosis is associated with high blood vessel counts. We have shown that the rate of cell division in endothelial cells is much higher in breast tumours than in normal breast. Breast cancer cell lines and primary human breast tumours express a wide range of vascular growth factors, including VEGF, placenta growth factor, pleiotrophin, TGFβ1, acidic and basic FGF, and platelet-derived endothelial cell growth factor. Inhibiting angiogenesis by blocking vascular growth factors would be difficult with highly specific agents, but drugs with a broader spectrum of antagonism may be effective. We have developed several suramin analogues which are less toxic than suraminin vivo but more potent in inhibiting angiogenesis, and these have been developed for Phase I. A combination of anti-angiogenesis agents with drugs activated by hypoxia may also be useful, because anti-angiogenesis alone may not kill cells, whereas activation of hypoxic drugs could synergize.
New endpoints may be necessary because inhibition of new blood vessel formation may not cause tumour regression. Thus, the endpoint of stable disease and biochemical assessment of inhibition of angiogenesis may be much more important in therapeutic studies and for drug development in the future. The prognostic importance of angiogenesis suggests that this should be a major new therapeutic target.
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References
Folkman JJ: What is the evidence that tumours are angiogenesis dependent? J Natl Cancer Inst 82:4–6, 1990
Blood CH, Zetter BR: Tumour interactions with the vasculature: angiogenesis and tumour metastasis. Biochim Biophys Acta, 1032:89–118, 1990
Nguyen M, Strubel NA, Bischoff J: A role for sialyl Lewis-X/A glycoconjugates in capillary morphogenesis. Nature 365:267–269, 1993
Hart IR, Saini A: Biology of tumour metastasis. Lancet 339:1453–1457, 1992
Weidner N, Semple JP, Welch WR, Folkman J: Tumour angiogenesis and metastasis — correlation in invasive breast carcinoma. New Engl J Med 324:1–8, 1991
Craft PS, Harris AL: Clinical prognostic significance of tumour angiogenesis. Ann Oncol 5:305–311, 1994
Hayes DF: Angiogenesis and breast cancer. Hematol Oncol Clin North Am 8:51–71, 1994
Jain RK: Determinants of tumour blood flow: a review. Cancer Res 48:2641–2658, 1988
Less JR, Skalak TC, Sevick EM, Jain RK: Microvascular architecture in a mammary carcinoma: Branching patterns and vessel dimensions. Cancer Res 51:265–273, 1991
Stratford IJ, Adams GE, Bremner J, Cole S, Edwards HS, Robertson N, Wood PJ: Manipulation and exploitation of the tumor environment for therapeutic benefit. Int J Radiat Biol 65:85–94, 1994
Brown JM, Giaccia AJ: Tumour hypoxia: the picture has changed in the 1990's. Int J Radiat Biol 65:95–102, 1994
Denekamp J: Angiogenesis, neovascular proliferation and vascular pathophysiology as targets for cancer therapy. Br J Radiol 66:181–196, 1993
Bicknell R: Vascular targeting and the inhibition of angiogenesis. Ann Oncol 5:S45-S50, 1994
Burrows F, Thorpe P: Eradication of large solid tumours in mice with an immunotoxin directed against tumour vasculature. Proc Natl Acad Sci USA 90: 8996–9000, 1993
Harris AL, Fox S, Bicknell R, Relf M, Lejeune S, Gatter K, Leek R: Breast cancer angiogenesis: Major independent prognostic factor in node negative breast cancer, regulation by multiple angiogenic factors [Abstract #1106]. Proc AACR, 85th Annual Meeting, Vol 25, 1994
Ingber D, Fujita T, Kishimoto S, Sudo K, Kanamara T, Brem H, Folkman J: Synthetic analogues of fumagillin that inhibit angiogenesis and suppress tumour growth. Nature 348:555–557, 1990
Wellstein A, Zugmaier G, Califano JA, Kern F, Paik S, Lippman ME: Tumour growth dependent on Kaposi's sarcoma-derived fibroblast growth factor inhibited by pentosan polysulfate. J Natl Cancer Inst 83:716–720, 1991
Zugmaier G, Lippman ME, Wellstein A: Inhibition by pentosan polysulfate (PPS) of heparin-binding growth factors released from tumor cells and blockage by PPS of tumor growth in animals. J Natl Cancer Inst 84: 1716–1724, 1992
Gasparini G, Harris AL: Does improved control of tumour growth require an anticancer therapy targeting both neoplastic and intratumoral endothelial cells? Eur J Cancer 30A:201–206, 1994
Horak ER, Leek R, Klenk N, LeJeune S, Smith K, Stuart N, Greenall M, Stepniewska K, Harris AL: Angiogenesis, assessed by platelet/endothelial cell adhesion molecule antibodies, as indicator of node metastases and survival in breast cancer. Lancet 340:1120–1124, 1992
Kuzu I, Bicknell R, Harris AL, Jones M, Gatter KC, Mason DY: Heterogeneity of vascular endothelial cells with relevance to diagnosis of vascular tumours. J Clin Pathol 45:143–148, 1992
Horak ER, Harris AL, Stuart N, Bicknell R: Angiogenesis in breast cancer: regulation, prognostic aspects and implications for novel treatment strategies. Ann NY Acad Sci 698:71–84, 1993
Kuzu I, Bicknell R, Fletcher CDH, Gatter KC: The expression of adhesion molecules on the endothelium of normal tissue vessels and vascular tumours. Lab Invest 69:322–328, 1993
Weidner N, Folkman J, Pozza F, Bevilacqua P, Allred EN, Moore DH, Meli S, Gasparini GJ: J Natl Cancer Inst 84:1875–1887, 1992
Gasparini G, Bevilacqua P, Boracchi P, Maluta S, Pozza F, Barbareschi M, Palma PD, Mezzetti M, Harris AL: Prognostic value of p53 expression in early stage breast carcinoma compared with tumour angiogenesis, epidermal growth factor receptor, c-erbB-2, cathepsin D, DNA ploidy, parameters of cell kinetics and conventional features. Int J Oncol 4: 155–162, 1994
Gasparini G, Weidner N, Bevilacqua P, Maluta S, Salla PP, Caffo O, Barbareschi M, Marubini E, Pozza FJ: Clin Oncol 12:454–466, 1994
Bosari S, Lee A, De Lellis D, Wiley B, Heatley G, Silverman M: Microvessel quantitation and prognosis in invasive breast carcinoma. Hum Pathol 23:755–761, 1992
Toi M, Kashitani J, Tominaga T: Tumor angiogenesis is an independent prognostic indicator in primary breast carcinoma. Int J Cancer 55:371–374, 1993
Chalkley HJ: Method for the quantitative morphological analysis of tissues. J Natl Cancer Inst 4:47–53, 1943
Fox SB, Leek RD, Weekes MP, Whitehouse RM, Gatter KC, Harris AL: Quantitation and prognostic value of breast cancer angiogenesis: Comparison of microvessel density, Chalkley count and computer image analysis. In press.
Fox SB, Gatter KC, Bicknell R, Going JJ, Stanton P, Cooke TG, Harris AL: Relationship of endothelial cell proliferation to tumor vascularity in human breast cancer. Cancer Res 53:4161–4163, 1993
Fox SB, Turner G, Gatter KC, Harris AL: The increased expression of the adhesion molecules PECAM, ICAM-1, ICAM-2, ICAM-3, E-selectin and P-selectin in breast cancer endothelium. J Cell Biochem S18A: 331–331, 1994
Ishikawa F, Miyazono K, Hellman U, Drexler H, Wernstedt C, Hagiwara K, Usuki K, Takaku F, Risau W, Heldin CH: Identification of angiogenic activity and the cloning and expression of platelet-derived endothelial cell growth factor. Nature 338:557–562, 1989
Moghaddam A, Bicknell R: Expression of platelet derived endothelial cell growth factor inE.coli and confirmation of its thymidine phosphorylase activity. Biochemistry 31:12141–12146, 1992
Moghaddam A, Zhang H-T, Fan T-PD, Hu D-E, Lees VC, Turley H, Fox SB, Gatter KC, Harris AL, Bicknell R: Thymidine phosphorylase is angiogenic and promotes tumour growth. Proc Natl Acad Sci USA (in press), 1995
Reynolds K, Farzaneh F, Collins WP, Campbell S, Bourne TH, Lawton F, Moghaddam A, Harris AL, Bicknell R: Association of ovarian malignancy with expression of platelet-derived endothelial cell growth factor. J Natl Cancer Inst 86:1234–1238, 1994
Zhang H-T, Craft P, Scott PAE, Ziche M, Weich HA, Harris AL, Bicknell R: Expression of vascular endothelial growth factor in MCF-7 cells enhances tumour growth and vascular density. JNCI, in press
McLeskey SW, Kurebayashi J, Honig SF, Zwiebel J, Lippman ME, Dickson RB, Kern FG: Fibroblast growth factor-IV transfection of MCF-7 cells produces cell lines that are tumorigenic and metastatic in ovariectomized or tamoxifen-treated athymic nude mice. Cancer Res 53:2168–2177, 1993
Kurebayashi J, McLeskey SW, Johnson MD, Lippman ME, Dickson RB, Kern FG: Quantitative demonstration of spontaneous metastasis by MCF-7 human breast cancer cells co-transfected with fibroblast growth factor IV and lacZ. Cancer Res 53:2178–2187, 1993
Braddock PS, Hu D-E, Fan TP, Stratford IJ, Harris AL, Bicknell R: A structure activity analysis of antagonism of the growth factor and angiogenic activity of basic fibroblast growth factor by suramin and related polyanions. Br J Cancer 69:890–898, 1994
Fox SB, Moghaddam A, Westwood M, Turley H, Bicknell R, Gatter KC, Harris AL: Platelet-derived endothelial cell growth factor / thymidine phosphorylase expression in normal tissues: an immunohisto-chemical study. In press.
Patterson AV, Zhang H-T, Moghaddam A, Bicknell R, Talbot DC, Stratford IJ, Harris AL: Increased sensitivity to the prodrug 5′-deoxy-5-fluorouridine and modulation of 5-fluoro-2′-deoxyuridine sensitivity in MCF-7 cells transfected with thymidine phosphorylase. In press.
Bligh JFJ, Bartoszek A, Robson CN, Hickson ID, Kasper CB, Beggs JD, Wolf CR: Activation of mitomycin C by NADPH:cytochrome P450 reductase. Cancer Res 50:7789–7792, 1990
Hoban PR, Walton M, Robson CN, Godden J, Stratford IJ, Workman P, Harris AL, Hickson ID: Mitomycin C resistance under aerobic but not hypoxic conditions in a mammalian cell line: association with impaired drug activation and reduced NADPH cytochrome P450 reductase activity. Cancer Res 50:4692–4697, 1990
Silva JM, Khan S, O'Brien PJ: Contrasting molecular cytotoxic mechanisms of mitomycin C and its two analogs, BMY 25282 and BMY 25067, in isolated rat hepatocytes. Biochem Pharmacol 45:2303–2309, 1993
Philip PA, Kaklamanis L, Ryley N, Stratford I, Wolf R, Harris AL, Carmichael J: Expression of xenobiotic-metabolizing enzymes by primary and secondary hepatic tumours in man. Int J Radiat Oncol Biol Phys 29:277–283, 1994
Davies B, Brown PD, East N, Crimmin MJ, Balkwill FR: A synthetic matrix metalloproteinase inhibitor decreases tumour burden and prolongs survival of mice bearing human ovarian carcinoma xenografts. Cancer Res 53:2087–2091, 1993
Philip PA, Thompson CH, Carmichael J, Rea D, Mitchell K, Taylor DJ, Stuart NSA, Dennis I, Rajagopolan B, Ganesan TS, Radda GK, Harris AL: A phase I study of the left-shifting agent BW12C79 plus mitomycin C and the effect on the skeletal muscle metabolism using31P magnetic resonance spectroscopy. Cancer Res 53:5649–5653, 1993
Gasparini G, Pozza F, Harris AL: Evaluating the potential usefulness of new prognostic and predictive indicators in node-negative breast cancer patients. J Natl Cancer Inst 85:1206–1219, 1993
Fox S, Leek R, Smith K, Hollyer J, Greenall M, Harris A: Tumor angiogenesis in node negative breast carcinomas — relationship to epidermal growth factor receptor and survival. Breast Cancer Res Treat 29: 109–116, 1994
Kalra R, Wade KE, Hands L, Styles P, Camplejohn R, Greenall M, Adams GE, Harris AL, Radda GK: Phosphomonoester is associated with proliferation in human breast cancer: a31P MRS study. Br J Cancer 67:1145–1153, 1993
Harris AL, Fox S, Bicknell R, Leek R, Relf M, LeJeune S, Kaklamanis L: Gene therapy through signal transduction pathways and angiogenic growth factors as therapeutic targets in breast cancer. Cancer (Suppl) 74:1021–1025, 1994
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Harris, A.L., Zhang, H., Moghaddam, A. et al. Breast cancer angiogenesis — new approaches to therapy via antiangiogenesis, hypoxic activated drugs, and vascular targeting. Breast Cancer Res Tr 38, 97–108 (1996). https://doi.org/10.1007/BF01803788
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DOI: https://doi.org/10.1007/BF01803788