Abstract
Numerous studies in many tumor types have demonstrated that quantitation by microvessel as a measure of angiogenesis is a powerful prognostic tool. However, the ability to exploit tumor angiogenesis as a prognostic marker is limited by the methods currently used for capillary identification and quantitation. This report critically evaluates all aspects of the techniques and their associated problems used for assessing tumor angiogenesis in tissue sections including the area of tumor assessed, the vascular parameter measured, the method of quantitation, the stratification of patients and the practical utility of computer image analysis systems. The potential of angiogenic factors assays, proteolytic enzymes, and cell adhesion molecules as surrogate endpoints for quantifying tumor angiogenesis are discussed and other methods for quantifying tumor angiogenesis are described. The potential clinical applications of these angiogenic markers in prognosis, stratification for adjuvant treatments (both cytotoxic and anti-angiogenic/vascular targeting) and other aspects of patient management is also discussed, particularly design of phase I and II trials.
Similar content being viewed by others
References
Folkman J: Tumour angiogenesis: Therapeutic implications. N. Engl J Med 285:82–86, 1971
Brem S, Cotran R, Folkman J: Tumor angiogenesis: a quantitative method for histological grading. J Natl Cancer Inst 48:347–356, 1972
Mlynek M, van Beunigen D, Leder L-D, et al.: Measurement of the grade of vascularisation in histological tumor tissue sections. Br J Cancer 52:945–948, 1985
Svrivastava A, Laidler P, Davies R, et al.: The prognostic significance of tumor vascularity in intermediate-thickness (0.76–4.0 thick) skin melanoma. Am J Pathol 133:419–423, 1988
Porschen R, Classen S, Piontek M, et al.: Vascularization of carcinomas of the esophagus and its correlation with tumor proliferation. Cancer Res 54:587–591, 1994
Weidner N, Semple JP, Welch WR, et al.: Tumor angiogenesis and metastasis-correlation in invasive breast carcinoma. N Engl J Med 324:1–8, 1991
Weidner N, Folkman J, Pozza F, et al.: Tumor angiogenesis: a new significant and independent prognostic indicator in early-stage breast carcinoma (see comments). J Natl Cancer Inst 84:1875–1887, 1992
Weidner N, Carroll PR, Flax J, et al.: Tumor angiogenesis correlates with metastasis in invasive prostate carcinoma. Am J Pathol 143:401–409, 1993
Bosari S, Lee AK, DeLellis RA, et al.: Microvessel quantitation and prognosis in invasive breast carcinoma. Hum Pathol 23:755–761, 1992
Macchiarini P, Fontanini G, Hardin MJ, et al.: Relation of neovascularisation to metastasis of non-small cell lung cancer. Lancet 340:145–146, 1992
Macchiarini P, Fontanini G, Dulmet E, et al.: Angiogenesis: an indicator of metastasis in non-small cell lung cancer invading the thoracic inlet. Ann Thor Surg 57:1534–1539, 1994
Toi M, Kashitani J, Tominaga T: Tumor angiogenesis is an independent prognostic indicator in primary breast carcinoma. Int J Cancer 55:371–374, 1993
Wakui S, Furusato M, Itoh T, et al.: Tumour angiogenesis in prostatic carcinoma with and without bone marrow metastasis: a morphometric study. J Pathol 168:257–262, 1992
Horak ER, Leek R, Klenk N, et 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
Barnhill RL, Mihm MJ, Ceballos PI: Angiogenesis and regressing cutaneous malignant melanoma (letter). Lancet 339:991–992, 1992
Bigler S, Deering R, Brawer M: Comparisons of microscopic vascularity in benign and malignant prostate tissue. Human Pathol 24:220–226, 1993
Ogawa Y, Chung Y, Nakata B, et al.: An evaluation of angiogenesis in breast cancer with factor VIII related antigen staining. Proc Am Asoc Cancer Res 35:186 (abstr 1113), 1994
Bundred N, Bowcott M, Walls J, et al.: Angiogenesis in breast cancer predicts node metastasis and survival. Br J Surgery 81:768 (Abstract), 1994
Dickinson AJ, Fox SB, Persad RA, et al.: Quantification of angiogenesis as an independent predictor of prognosis in invasive bladder carcinomas. Br J Urol 74:762–766, 1994
Jaeger T, Weidner N, Chew K, et al.: Tumor angiogenesis predicts lymph node metastasis in invasive bladder cancer. Proc Am Assoc Cancer Res 35:66 (abstract 394), 1994
Li V, Folkerth R, Watanabe H, et al.: Microvessel count and cerebrospinal fluid basic fibroblast growth factor in children with brain tumors. Lancet 344:82–86, 1994
Olivarez D, Ulbright T, DeRiese W, et al.: Neovascularization in clinical stage A testicular germ cell tumor: prediction of metastatic disease. Cancer Res 54:2800–2802, 1994
Vesalainen S, Lipponen P, Talja M, et al.: Tumor vascularity and basement membrane structure as prognostic factors in T1-2M0 prostatic adenocarcinoma. Anticancer Res 14:709–714, 1994
Simpson J, Ahn C, Battifora H, et al.: Vascular surface area as a prognostic indicator in invasive breast carcinoma. Lab Invest 70:22A (abstract), 1994
Smith-McCune K, Weidner N: Demonstration and characterization of the angiogenic properties of cervival dysplasia. Cancer Res 54:800–804, 1994
Brawer MK, Deering RE, Brown M, et al.: Predictors of pathologic stage in prostatic carcinoma. The role of neovascularity. Cancer 73:678–687, 1994
Albo D, Granick M, Jhala N, et al.: The relationship of angiogenesis to biological activity in human squamous cell carcinomas of the head and neck. Ann Plast Surg 32:558–594, 1994
Wiggins DL, Granai CO, Steinhoff MM, et al.: Tumor angiogenesis as a prognostic factor in cervical carcinoma. Gynecol Oncol 56:353–356, 1995
Van HM, Knox WF, Dhesi SS, et al.: Assessment of tumor vascularity as a prognostic factor in lymph node negative invasive breast cancer. Eur J Cancer, 1993
Hall NR, Fish DE, Hunt N, et al.: Is the relationship between angiogenesis and metastasis in breast cancer real? Surg Oncol 1:223–229, 1992
Sightler H, Borowsky A, Dupont W, et al.: Evaluation of tumor angiogenesis as a prognostic marker in breast cancer. Lab Invest 70:22A (abstract), 1994
Rutgers JL, Mattox TF, Vargas MP: Angiogenesis in uterine cervical squamous cell carcinoma. Int J Gynecol Pathol 14:114–118, 1995
Ohsawa M, Tomita Y, Kuratsu S, et al.: Angiogenesis in malignant fibrous histiocytoma. Oncology 52:51–54, 1995
Barnhill R, Busam K, Berwick M, et al.: Tumour vascularity is not a prognostic factor for cutaneous melanoma. Lancet 344:1237–1238, 1994
Axelsson K, Ljung B, Moore II D, et al.: Tumor angiogenesis as a prognostic assay for invasive ductal breast carcinoma. J Natl Cancer Inst 87, 1995
Protopapa E, Delides GS, Revesz L: Vascular density and the response of breast carcinomas to mastectomy and adjuvant chemotherapy. Eur J Cancer, 1993
McCarthy SA, Kuzu I, Gatter KC, et al.: Heterogeneity of the endothelial cell and its role in organ preference of tumor metastasis. Trends Pharmacol Sci 12:462–467, 1991
Kuzu I, Bicknell R, Harris AL, et al.: Heterogeneity of vascular endothelial cells with relevance to diagnosis of vascular tumors. J Clin Pathol 45:143–148, 1992
Parums D, Cordell J, Micklem K, et al.: JC70: a new monoclonal antibody that detects vascular endothelium associated antigen on routinely processed tissue sections. J Clin Pathol 43:752–757, 1990
Fox SB, Leek R, Smith K, et al.: Tumor angiogenesis in node negative breast carcinomas-relationship to epidermal growth factor receptor and survival. Breast Cancer Res Treat 29:109–116, 1994
Ottinetti A, Sapino A: Morphometric evaluation of microvessels surrounding hyperplastic and neoplastic mammary lesions. Breast Cancer Res Treat 11:241–248, 1988
Sahin A, Sneige N, Singletary E, et al.: Tumor angiogenesis detected by Factor-VIII immunostaining in node-negative breast carcinoma (NNBC): a possible predictor of distant metastasis. Mol Pathol 5:17A (abstract), 1992
Weidner N, Gasparini G: Determination of epidermal growth factor receptor provides additional prognostic information to measuring tumor angiogenesis in breast carcinoma patients. Breast Cancer Res Treat 29:97–108, 1994
Carnochan P, Briggs JC, Westbury G, et al.: The vascularity of cutaneous melanoma: a quantitative histological study of lesions 0.85–1.25 mm in thickness. Br J Cancer 64:102–107, 1991
Barnhill RL, Fandrey K, Levy MA, et al.: Angiogenesis and tumor progression of melanoma. Quantification of vascularity in melanocytic nevi and cutaneous malignant melanoma. Lab Invest 67:331–337, 1992
Visscher D, Smilanetz S, Drozdowicz S, et al.: Prognostic significance of image morphometric microvessel enumeration in breast carcinoma. Anal Quant Cytol 15:88–92, 1993
Visscher D, DeMattia F, Boman S: Technical factors affecting image morphometric microvessel density counts in breast carcinomas. Lab Invest 70:168A (abstract), 1994
Burrows FJ, Thorpe PE: Vascular targeting — a new approach to the therapy of solid tumors. Pharmacol Ther 64:155–174, 1994
Weidner N, Gasparini G, Bevilacqua P, et al.: Tumor microvessel density, p53 expression, and tumor size area relevant prognostic markers in node negative breast carcinomas. Lab Invest 70:A24 (abstract), 1994
Barbareschi M, Weidner N, Gasparini G, et al.: Microvessel quantitation in breast carcinomas. Appl Immunochem 3:75–84, 1995
Fox SB, Leek RD, Weekes. M P, et al.: Quantitation and prognostic value of breast cancer angiogenesis: comparison of microvessel density, Chalkley count and computer image analysis. J Pathol in press, 1995
Furusato M, Wakui S, Sasaki H, et al.: Tumour angiogenesis in latent prostatic carcinoma. Br J Cancer 70:1244–1246, 1994
Williams JK, Carlson GW, Cohen C, et al.: Tumor angiogenesis as a prognostic factor in oral cavity tumors. Am J Surg 168:373–380, 1994
Wesseling P, Vandersteenhoven JJ, Downey BT, et al.: 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 (Berl) 85:508–514, 1993
Charpin C, Devictor B, Bergeret D, et al.: CD31 Quantitative immunocytochemical assays in breast carcinomas. Am J Clin Pathol 103:443–448, 1995
Chalkley H: Method for the quantative morphological analysis of tissues. J Nat Cancer Inst 4:47–53, 1943
Guinebretiere JM, Le MG, Gavoille A, et al.: Angiogenesis and risk of breast cancer in women with fibrocystic disease (letter). J Natl Cancer Inst 86:635–636, 1994
Paweletz N, Knierim M: Tumor-related angiogenesis. Crit Rev Oncol Hematol 9:197–242, 1989
Blood CH, Zetter BR: Tumor interactions with the vasculature: angiogenesis and tumor metastasis. Biochim Biophys Acta 1032:89–118, 1990
Bicknell R, Harris AL: Novel growth regulatory factors and tumor angiogenesis. Eur J Cancer 27:781–785, 1991
Takahashi Y, Kitadai Y, Bucana CD, et al.: Expression of vascular endothelial growth factor and its receptor, KDR, correlates with vascularity, metastasis and proliferation of human colon cancer. Cancer Res 55:3964–3968, 1995
Brown LF, Berse B, Jackman RW, et al.: Expression of vascular permeability factor (vascular endothelial growth factor) and its receptors in breast cancer. Hum Pathol 26:86–91, 1995
Moghaddam A, Zhang HT, Fan TP, et al.: Thymidine phosphorylase is angiogenic and promotes tumor growth. Proc Natl Acad Sci USA 92:998–1002, 1995
Anandappa SY, Winstanley JH, Leinster S, et al.: Comparative expression of fibroblast growth factor mRNAs in benign and malignant breast disease. Br J Cancer 69:772–776, 1994
Reynolds K, Farzaneh F, Collins WP, et al.: Correlation of ovarian malignancy with expression of platelet-derived endothelial cell growth factor. J Natl Cancer Inst. In press, 1994
Garver RJ, Radford DM, Donis KH, et al.: Midkine and pleiotrophin expression in normal and malignant breasttissue. Cancer 74:1584–1590, 1994
Janot F, el Nagar NA, Morrison RS, et al.: Expression of basic fibroblast growth factor in squamous cell carcinoma of the head and neck is associated with degree of histologic differentiation. Int J Cancer 64:117–123, 1995
Gomm JJ, Smith J, Ryall GK, et al.: Localisation of basic fibroblast growth factor and transforming growth factor bl in the human mammary gland. Cancer Res 51:4685–4692, 1991
Zarnegar R, DeFrances MC: Expression of HGF-SF in normal and malignant human tissues. Exs 65:181–199, 1993
Daa T, Kodama M, Kashima K, et al.: Identification of basic fibroblast growth factor in papillary carcinoma of the thyroid. Acta Pathol Jpn 43:582–589, 1993
Wong SY, Purdie AT, Han P: Thrombospondin and other possible related matrix proteins in malignant and benign breast disease. Am J Pathol 140:1473–1482, 1992
Schultz-Hector S, Haghayegh S: B-Fibroblast growth factor expression in human and murine squamous cell carcinomas and its relationship to regional endothelial cell proliferation. Cancer Res 53:1444–1449, 1993
Alvarez JA, Baird A, Tatum A, et al.: Localisation of basic fibroblast growth factor and vascular endothelial cell growth factor in human glial neoplasms. Mod Pathol 5:303–307, 1992
Guidi A, Abu-Jawdeh G, Berse B, et al.: Vascular permeability factor (vascular endothelial growth factor) expression and angiogenesis in cervical neoplasia. J Natl Cancer Instit 87:1237–1245, 1995
Zagzag D, Brem S, Robert F: Neovascularization and tumor growth in the rabbit brain. A model for experimental studies of angiogenesis and the blood-brain barrier. Am J Pathol 131:361–372, 1988
Visscher DW, DeMattia F, Ottosen S, et al.: Biologic and clinical significance of basic fibroblast growth factor immunostaining in breast carcinoma. Mod Pathol 8:665–670, 1995
O'Brien T, Cranston D, Fuggle S, et al.: Different angiogenic pathways characterize superficial and invasive bladder cancer. Cancer Res 55:510–513, 1995
Toi M, Hoshina S, Takayanagi T, et al.: 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
Toi M, Hoshina S, Taniguchi T, et al.: Expression of platelet derived endothelial cell growth factor/thymidine phosphorylase in human breast cancer. Int J Cancer 64:79–82, 1995
Fox SB, Westwood M, Moghaddam A, et al.: The angiogenic factor platelet derived endothelial cell growth factor/thymidine phosphorylase is upregulated in breast cancer epithelium and endothelium. Br J Cancer (in press), 1995
Fujimoto K, Ichimori Y, Kakizoe T, et al.: Increased serum levels of basic fibroblast growth factor in patients with renal cell carcinoma. Biochem Biophys Res Comm 180:386–392, 1991
Kondo S, Asano M, Matsuo K, et al.: Vascular endothelial grwoth factor/vascular permeability factor is detectable in the sera of tumor-bearing mice and cancer patients. Biochim Biophys Acta 1221:211–214, 1994
Nguyen M, Watanabe H, Budson AE, et al.: Elevated levels of the angiogenic peptide basic fibroblast growth factor in urine of bladder cancer patients. J Natl Cancer Inst 85:241–242, 1993
Nguyen M, Watanabe H, Budson AE, et al.: Elevated levels of an angiogenic peptide, basic fibroblast growth factor, in the urine of patients with a wide spectrum of cancers (see comments). J Natl Cancer Inst 86:356–361, 1994
O'Brien T, Smith K, Cranston D, et al.: Urinary basic fibroblast growth factor in patients with bladder cancer and benign prostatic hypertrophy. Br J Urol 76:311–314, 1995
Kendall RL, Thomas KA: Inhibition of vascular endothelial cell growth factor activity by an endogenously encoded soluble receptor. Proc Natl Acad Sci USA 90:10705–10709, 1993
Blann AD, McCollum CN: Circulating endothelial-cell leukocyte adhesion molecules in atherosclerosis. Thromb Haemost 72:151–154, 1994
Frater-Schroder M, Risau W, Hallmann R, et al.: Tumor necrosis factor type alpha, a potent inhibitor of endothelial cell growth in vitro, is angiogenic in vivo. Proc Natl Acad Sci USA 84:5277–5281, 1987
Schweigerer L, Malerstein B, Gospodarowicz D: Tumor necrosis factor inhibits the proliferation of cultured capillary endothelial cells. Biochem Biophys Res Commun 143:997–1004, 1987
Pepper M, Montesano R: Proteolytic balance and capilary morphogenesis. Cell Differentiation and Development 32:319–328, 1990
Fisher C, Gilbertson BS, Powers EA, et al.: Interstitial collagenase is required for angiogenesis in vitro. Dev Biol 162:499–510, 1994
Kristensen P, Larsson L, Nielsen L, et al.: Human endothelial cells contain one type of plasminogen activator. FEBS Lett 168:33–37, 1994
Larsson L, Skriver L, Nielsen J, et al.: Distribution of urokinase-type activator immunoreactivity in the mouse. J Cell Biol 98:894–903, 1984
Pepper MS, Ferrara N, Orci L, et al.: Vascular endothelial growth factor (VEGF) induces plasminogen activators and plasminogen activator inhibitor-1 in microvascular endothelial cells. Biochem Biophys Res Commun 181:902–906, 1991
Pepper MS, Belin D, Montesano R, et al.: Transforming growth factor-beta 1 modulates basic fibroblast growth factor-induced proteolytic and angiogenic properties of endothelial cells in vitro. J Cell Biol 111:743–755, 1990
Pepper MS, Ferrara N, Orci L, et al.: Protent synergism between vascular endothelial growth factor and basic fibroblast growth factor in the induction of angiogenesis in vitro. Biochem Biophys Res Commun 189:824–831, 1992
Grondahl HJ, Christensen IJ, Rosenquist C, et al.: High levels of urokinase-type plasminogen activator and its inhibitor PAI-1 in cytosolic extracts of breast carcinomas are associated with poor prognosis. Cancer Res 53:2513–2521, 1993
Janicke F, Schmitt M, Pache L, et al.: Urokinase (uPA) and its inhibitor PAI-1 are strong and independent prognostic factors in node-negative breast cancer. Breast Cancer Res Treat 24:195–208, 1993
Foekens JA, Schmitt M, van PW, et al.: Prognostic value of urokinase-type plasminogen activator in 671 primary breast cancer patients. Cancer Res 52:6101–6105, 1992
Duffy MJ, Reilly D, O'Sullivan C, et al.: Urokinase-plasminogen activator, a new and independent prognostic marker in breast cancer. Cancer Res 50:6827–6829, 1990
Schmitt M, Janicke F, Moniwa N, et al.: Tumor-associated urokinase-type plasminogen activator: biological and clinical significance. Biol Chem Hoppe Seyler 373:611–622, 1992
Spyratos F, Martin PM, Hacene K, et al.: Multiparametric prognostic evaluation of biological factors in primary breast cancer. J Natl Cancer Inst 84:1266–1272, 1992
Sumiyoshi K, Serizawa K, Urano T, et al.: Plasminogen activator system in human breast cancer. Int J Cancer 50:345–348, 1992
Ganesh S, Sier CFM, Heerding MM, et al.: Urokinase receptor and colorectal cancer survival. Lancet 344:401–402, 1994
Fox SB, Stuart N, Smith K, et al.: High levels of uPA and PAI-1 are associated with highly angiogenic breast carcinomas. J Pathol 170(suppl):388A, 1993
Nguyen M, Strubel NA, Bischoff J: A role for sialyl Lewis-X/A glycoconjugates in capillary morphogenesis. Nature 365:267–269, 1993
Kaplanski G, Farnarier C, Benoliel A, et al.: A novel role for E-and P-selectins: shape of endothelial cell monolayers. J Cell Sci 107:2449–2457, 1994
Koch A, Halloran MM, Haskell CJ, et al.: Angiogenesis mediated by soluble forms of E-selectin and vascular cell adhesion molecule-1. Nature 376:517–519, 1995
Fox SB, Turner G, Gatter K, et al.: The increased expression of adhesion molecules ICAM-3, E and P selectin on breast cancer endothelium. J Pathol in press, 1995
Zocchi MR, Poggi A: Lymphocyte-endothelial cell adhesion molecules at the primary tumor site in human lung and renal cell carcinomas (letter). J Natl Cancer Inst 85:246–247, 1993
Fox SB, Gatter KC, Bicknell R, et al.: Relationship of endothelial cell proliferation to tumor vascularity in human breast cancer. Cancer Res 53:9161–9163, 1993
Dvorak HF: Thrombosis and cancer. Hum Pathol 18:275–284, 1987
Palabrica T, Lobb R, Furie BC, et al.: Leukocyte accumulation promoting fibrin deposition is mediated in vivo by P-selectin on adherent platelets. Nature 359:848–851, 1992
Senger DR, Van DWL, Brown LF, et al.: Vascular permeability factor (VPF, VEGF) in tumor biology. Cancer Metastasis Rev 12:303–324, 1993
Leavesley DI, Schwartz MA, Rosenfeld M, et al.: Integrin beta 1-and beta 3-mediated endothelial cell migration is triggered through distinct signaling mechanisms. J Cell Biol 121:163–170, 1993
Gamble JR, Matthias LJ, Meyer G, et al.: Regulation of in vitro capillary tube formation by anti-integrin antibodies. J Cell Biol 121:931–943, 1993
Davis CM, Danehower SC, Laurenza A, et al.: Identification of a role of the vitronectin receptor and protein kinase C in the induction of endothelial cell vascular formation. J Cell Biochem 51:206–218, 1993
Bauer J, Margolis M, Schreiner C, et al.: In vitro model of angiogenesis using a human endothelium-derived permanent cell line: contributions of induced gene expression, G-proteins, and integrins. J Cell Physiol 153:437–449, 1992
Jackson CJ, Knop A, Giles I, et al.: VLA-2 mediates the interaction of collagen with endothelium during in vitro vascular tube formation. Cell Biol Int 18:859–867, 1994
Luscinskas FW, Lawler J: Integrins as dynamic regulators of vascular function. Faseb J 8:929–938, 1994
Brooks PC, Clark RA, Cheresh DA: Requirement of vascular integrin alpha v beta 3 for angiogenesis. Science 264:569–571, 1994
Brooks PC, Montgomery AM, Rosenfeld M, et al.: Integrin alpha v beta 3 antagonists promote tumor regression by inducing apoptosis of angiogenic blood vessels. Cell 79:1157–1164, 1994
Brooks PC, Stromblad S, Klemke R, et al.: Antiintegrin β 3 αv blocks human breast cancer growth and angiogenesis in human skin. J Clin Invest 96:1815–1822, 1995
Iozzo RV: Tumor stroma as a regulator of neoplastic behaviour. Lab Invest 73:157–160, 1995
Lochter A, Bissell MJ: Involvement of extracellular matrix constituents in breast cancer. Cancer Biol 6:165–173, 1995
Schadendorf D, Heidel J, Gawlik C, et al.: Association with clinical outcome of expression of VLA-4 in primary cutaneous malignant melanoma as well as P-selectin and E-selection on intratumoral vessels. J Natl Cancer Inst 87:366–371, 1995
Kageshita T, Yoshii A, Kimura T, et al.: Clinical relevance of ICAM-1 expression in primary lesions and serum of patients with malignant melanoma. Cancer Res 53:4927–4932, 1993
Banks RE, Gearing AJ, Hemingway IK, et al.: Circulating intercellular adhesion molecule-1 (ICAM-1), E-selectin and vascular cell adhesion molecule-1 (VCAM-1) in human malignancies. Br J Cancer 68:122–124, 1993
Warren B: The vascular morphology of tumors. In: Peterson H (ed). Tumor Blood Circulation Boca Raton, Fla: CRC Press, 1979, pp 1–47
Paku S, Lapis K: Morphological aspects of angiogenesis in experimental liver metastases. Am J Pathol 143:926–936, 1993
Lauk S, Zietman A, Skates S, et al.: Comparative morphometric study of tumor vasculature in human squamous cell carcinomas and their xenotransplants in athymic nude mice. Cancer Res 49:4557–4561, 1989
Smolle J, Soyer HP, Hofmann-Wellenhof, et al.: Vascular archictecture of melanocytic skin tumors. Path Res Pract 185:740–745, 1989
Cockerell CJ, Sonnier G, Kelly L, et al.: Comparative analysis of neovascularisation in primary cutaneous melanoma and Spitz nevus. Am J Dermatopathol 16:9–13, 1994
Folberg R, Rummelt V, Ginderdeuren R-V, et al.: The prognostic value of tumor blood vessel morphology in primary uveal melanoma. Ophthalmology 100:1389–1398, 1993
Vaupel P, Kallinowski F, Okunieff P: Blood flow, oxygen and nutrient supply, and metabolic microenvironment of human tumors: a review. Cancer Res 49:6449–6465, 1989
Jain RK: Barriers to drug delivery in solid tumors. Sci Am 271:58–65, 1994
Jain RK: Vascular and interstitial barriers to delivery of therapeutic agents in tumors. Cancer Metastasis Rev 9:253–266, 1990
Mitchell BS, Schumacher U, Kaiserling E: Are tumors innervated? Immunohistological investigations using antibodies against the neuronal marker protein gene product 9.5 (PGP 9.5) in benign, malignant and experimental tumors. Tumour Biol 15:269–274, 1994
Nystrom C, Forssman L, Roos B: Myometrial blood flow studies in carcinoma of the corpus uteri. Acta Radiol Ther 8:193–198, 1969
Frouge C, Guinbretiere J, Contesso G, et al.: Correlation between contrast enhancement in dynamic magnetic resonance imaging of the breast and tumor angiogenesis. Invest Radiol 29:1043–1049, 1994
Lee WJ, Chu JS, Houng SJ, et al.: Breast cancer angiogenesis: a quantitative morphologic and Doppler imaging study. Ann Surg Oncol 2:246–251, 1995
Antonic J, Rakar S: Colour and pulsed doppler US and tumor marker CA125 in differentiation between benign and malignant ovarian masses. Anticancer Res 15:1527–1532, 1995
Wu CC, Lee CN, Chen TM, et al.: Incremental angiogenesis assessed by color Doppler ultrasound in the tumorigenesis of ovarian neoplasms. Cancer 73:1251–1256, 1994
Toi M, Inada K, Suzuki H, et al.: Tumor angiogenesis in breast cancer: its importance as a prognostic indicator and the association with vascular endothelial growth factor expression. Breast Cancer Res Treat 36:193–204, 1995
Ogawa Y, Chung Y, Nakata B, et al.: Microvessel quantitation in invasive breast cancer by staining for factor VIII-related antigen. Br J Cancer 71:1297–1301, 1995
Gasparini G, Weidner N, Bevilacqua P, et al.: Tumor microvessel density, p53 expression, tumor size, and peritumoral lymphatic vessel invasion are relevant prognostic markers in node-negative breast carcinoma (see comments). J Clin Oncol 12:454–466, 1994
Lipponen P, Ji H, Aaltomaa S, et al.: Tumour vascularity and basement membrane structure in breast cancer as related to tumor histology and prognosis. J Cancer Res Clin Oncol 120:645–650, 1994
Palczak R, Splawinski J: Angiogenic activity and neovascularization in adenocarcinoma of endometrium. Int J Gynaecol Obstet 29:343–357, 1989
Hollingsworth HC, Kohn EC, Steinberg SM, et al.: Tumor angiogenesis in advanced stage ovarian carcinoma (see comments). Am J Pathol 147:33–41, 1995
Hall MC, Troncoso P, Pollack A, et al.: Significance of tumor angiogenesis in clinically localized prostate carcinoma treated with external beam radiotherapy. Urology 44:869–875, 1994
Jaeger T, Weidner N, Chew K, et al.: Tumor angiogenesis correlates with lymph node metastasis in invasive bladder cancer. J Urol 154:69–71, 1995
Giatromanolaki A, Koukourakis, O'Byrne K, et al.: Prognostic value of angiogenesis in operable non-small cell lung cancer. J Pathol in press, 1995
Macda K, Chung YS, Takatsuka S, et al.: Tumor angiogenesis as a predictor of recurrence in gastric carcinoma. J Clin Oncol 13:477–481, 1995
Saclarides TJ, Speziale NJ, Drab E, et al.: Tumor angiogenesis and rectal carcinoma. Dis Colon Rectum 37:921–926, 1994
Klijanienko J, El-Naggar A, de Braud F, et al.: Tumor vascularisation, mitotic index, histopathological grade, and DNA ploidy in the assessment of 114 head and neck squamous cell carcinomas. Cancer 75:1649–1656, 1995
Leedy DA, Trune DR, Kronz JD, et al.: Tumor angiogenesis, the p53 antigen, and cervical metastasis in squamous carcinoma of the tongue. Otolaryngol Head Neck Surg 111:417–422, 1994
Gasparini G, Weidner N, Maluta S, et al.: Intratumoral microvessel density and p53 protein: correlation with metastasis in head-and-neck squamous-cell carcinoma. Int J Cancer 55:739–744, 1993
Brem SS, M. JH, Gullino PM: Angiogenesis as a marker of pre-neoplastic lesions of the human breast. Cancer 41:239–248, 1978
Jensen HM, Chen I, DeVault MR, et al.: Angiogenesis induced by “normal” human breast tissue: a probable marker for precancer. Science 218:293–295, 1982
Guidi A, Fischer L, Harris J, et al.: Microvessel density and distribution in ductal carcinoma in situ of the breast. J Natl Cancer Inst 86:614–619, 1994
Engels K, Fox SB, Gatter KC, et al.: Angiogenesis in ductal carcinoma in situ. J Pathol, 1995
Montironi R, Galluzzi C, Diamanti L, et al.: Prostatic intraepithelial neoplasia. Qualitative and qualitative analysis of the blood capillary architecture. Path Res Pract 189:542–548, 1993
Deering RE, Bigler SA, Brown M, et al.: Microvascularity in benign prostatic hyperplasia. Prostate 26:111–115, 1995
Macaulay VM, Fox SB, Zhang H, et al.: Breast cancer angiogenesis and tamoxifen resistence. Endocr Rel Cancer 2:1–8, 1995
O'Reilly MS, Holmgren L, Shing Y, et al.: Angiostatin: a novel angiogenesis inhibitor that mediates the suppression of metastases by a Lewis lung carcinoma (see comments). Cell 79:315–328, 1994
Gasparini G, Harris AL: Clinical importance of the determination of tumor angiogenesis in breast carcinoma: much more than a new prognostic tool. J Clin Oncol 13:765–782, 1995
Teicher BA, Sotomayor EA, Huang ZD: Antiangiogenic agents potentiate cytotoxic cancer therapies against primary and metastatic disease. Cancer Res 52:6702–6704, 1992
Johnson PW, Burchill SA, Selby PJ: The molecular detection of circulating tumor cells. Br J Cancer 72:268–276, 1995
Larsen NS: Angiogenesis research yields new approaches to cancer treatment and prognosis (news). J Natl Cancer Inst 85:1629–1630, 1993
Wang JM, Kumar S, Pye D, et al.: A monoclonal antibody detects heterogeneity in vascular endothelium of tumors and normal tissues. Int J Cancer 54:363–370, 1993
Rettig WJ, Garin CP, Healey JH, et al.: Identification of endosialin, a cell surface glycoprotein of vascular endothelial cells in human cancer. Proc Natl Acad Sci USA 89:10832–10836, 1992
Hagemeier HH, Vollmer E, Goerdt S, et al.: A monoclonal antibody reacting with endothelial cells of budding vessels in tumors and inflammatory tissues, and non-reactive with normal adult tissues. Int J Cancer 38:481–488, 1986
Schlingemann RO, Dingjan GM, Emeis JJ, et al.: Monoclonal antibody PAL-E specific for endothelium. Lab Invest 52:71–76, 1985
Koch AE, Nickoloff BJ, Holgersson J, et al.: 4A11, a monoclonal antibody recognizing a novel antigen expressed on aberrant vascular endothelium. Upregulation in an in vivo model of contact dermatitis. Am J Pathol 144:244–259, 1994
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Fox, S.B., Harris, A.L. Markers of tumor angiogenesis: clinical applications in prognosis and anti-angiogenic therapy. Invest New Drugs 15, 15–28 (1997). https://doi.org/10.1023/A:1005714527315
Issue Date:
DOI: https://doi.org/10.1023/A:1005714527315