Summary
To evaluate whether angiogenic factors are of clinical relevance to actual human pancreatic cancers, we studied the intratumoral microvessel density (IMD), and PD-ECGF, VEGF protein expression in 40 pancreatic cancers using immunohistochemistry. We also investigated PD-ECGF and VEGF gene expression using reverse transcriptase-PCR (RT-PCR). Of the 40 pancreatic cancers studied, 30 carcinomas (75.0%) were evaluated to be PD-ECGF-positive and 10 carcinomas (25.0%) were determined to be PD-ECGF-negative. In contrast, 27 carcinomas (67.5%) were evaluated to be VEGF-positive, whereas 13 carcinomas (32.5%) were VEGF-negative. VEGF gene expression was moderately associated with an increase in the IMD (r2 = 0.181, P = 0.006), but no significant relationship was found between PD-ECGF gene expression and the IMD (r2 = 0.093, P = 0.059). However, tumours with positive expression for both PD-ECGF and VEGF had a higher IMD (P = 0.027). The results of the immunohistochemistry agreed well with the results of the quantitative RT-PCR. The median survival time of the hypervascular group was significantly shorter than that of the hypovascular group (P < 0.0001). In comparing the survival according to PD-ECGF and VEGF gene expression, the median survival time of the patients with positive PD-ECGF expression was significantly shorter than those with negative PD-ECGF expression (P = 0.040). Furthermore, the median survival time of the patients with positive VEGF expression was significantly shorter than those with negative VEGF expression (P = 0.048). However, the Cox multivariate analysis indicated that the IMD and VEGF expression were independent prognostic factors of the various clinicopathologic variables in pancreatic cancer patients (P = 0.0021 and P = 0.0443, respectively).
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Aiello, L. P., Avery, R. L., Arrigg, P. G., Keyt, B. A., Jampel, H. D., Shah, S. T., Pasquale, L. R., Thieme, H., Iwamoto, M. A., Park, J. E., Nguyen, H. V., Aiello, L. M., Ferrara, N. & King, G. L. (1994). Vascular endothelial growth factor in ocular fluid of patients with diabetic retinopathy and other retinal disorders. N Engl J Med 331: 1480–1487.
Barton, C. M., Hall, P. A., Hughes, C. M., Gullick, W. J. & Lemoine, N. R. (1991). Transforming growth factor alpha and epidermal growth factor in human pancreatic cancer. J Pathol 163: 111–116.
Bramhall, S. R., Allum, W. H., Jones, A. G., Allwood, A., Cummins, C. & Neoptolemos, J. P. (1995). Treatment and survival in 13 560 patients with pancreatic cancer, and incidence of the disease, in the West Midlands: an epidemiological study. Br J Surg 82: 111–115.
Brogi, E., Schatteman, G., Wu, T., Kim, E. A., Varticovski, L., Keyt, B. & Isner, J. M. (1996). Hypoxia-induced paracrine regulation of vascular endothelial growth factor receptor expression. J Clin Invest 97: 469–476.
Chomczynski, P. & Sacchi, N. (1987). Single-step method of RNA isolation by acid guanidinium thiocyanate–phenol–chloroform extraction. Anal Biochem 162: 156–159.
Cox, D. R. (1972). Regression models and life-tables. J R Stat Soc B 34: 187–220.
Detmar, M., Brown, L. F., Claffey, K. B., Yeo, K. T., Kocher, O., Jackman, R. W., Berse, B. & Dvorak, H. F. (1994). Overexpression of vascular permeability factor/vascular endothelial growth factor and its receptors in psoriasis. J Exp Med 180: 1141–1146.
Dvorak, H. F., Brown, L. F., Detmar, M. & Dvorak, A. M. (1995). Vascular permeability factor/vascular endothelial growth factor, microvascular hyperpermeability, and angiogenesis. Am J Pathol 146: 1029–1039.
Fava, R. A., Olsen, N. J., Spencer-Green, G., Yeo, K. T., Yeo, T. K., Berse, B., Jackman, R. W., Senger, D. R., Dvorak, H. F. & Brown, L. F. (1994). Vascular permeability factor/endothelial growth factor (VPF/VEGF): accumulation and expression in human synovial fluids and rheumatoid synovial tissue. J Exp Med 180: 341–346.
Fidler, I. J. & Ellis, L. M. (1994). The implications of angiogenesis for the biology and therapy of cancer metastasis. Cell 79: 185–188.
Folkman, J. (1995a). Clinical applications of research on angiogenesis. N Engl J Med 333: 1757–1763.
Folkman, J. (1995b). Angiogenesis in cancer, vascular, rheumatoid and other disease. Nature Med 1: 27–31.
Friess, H., Yamanaka, Y., Büchler, M., Ebert, M., Beger, H. G., Gold, L. I. & Korc, M. (1993). Enhanced expression of transforming growth factor β isoforms in pancreatic cancer correlates with decreased survival. Gastroenterology 105: 1846–1856.
Furukawa, T., Yoshimura, A., Sumizawa, T., Haraguchi, M. & Akiyama, S. (1992). Angiogenic factor. Nature (Lond.) 356: 668
Gastrointestinal Tumor Study Group (1987). Further evidence of effective adjuvant combined radiation and chemotherapy following curative resection of pancreatic cancer. Cancer (Phila.) 59: 2006–2010.
Hanahan, D. & Folkman, J. (1996). Patterns and emerging mechanisms of the angiogenic switch during tumorigenesis. Cell 86: 353–364.
Houck, K. A., Leung, D. W., Rowland, A. M., Winer, J. & Ferrara, N. (1992). Dual regulation of vascular endothelial growth factor bioavailability by genetic and proteolytic mechanisms. J Biol Chem 267: 26031–26037.
Ishikawa, F., Miyazono, K., Hellman, U., Drexler, H., Wernstedt, C., Hagiwara, K., Usuki, K., Takaku, F., Risau, W. & Heldin, C. H. (1989). Identification of angiogenic activity and the cloning and expression of platelet-derived endothelial cell growth factor. Nature (Lond.) 338: 557–562.
Itakura, J., Ishiwata, T., Friess, H., Fujii, H., Matsumoto, Büchler, M. W. & Korc, M. (1997). Enhanced expression of vascular endothelial growth factor in human pancreatic cancer correlates with local disease progression. Clin Cancer Res 3: 1309–1316.
Kamthan, A. G., Morris, J. C., Dalton, J., Mandeli, J. P., Chesser, M. R., Leben, D., Cooperman, A. & Bruckner, H. W. (1997). Combined modality therapy for stage II and stage III pancreatic carcinoma. J Clin Oncol 15: 2920–2927.
Kaplan, E. L. & Meier, P. (1958). Nonparametric estimation from incomplete observations. J Am Stat Assoc 53: 457–481.
Kim, K. J., Li, B., Winer, J., Armanini, M., Gillett, N., Phillips, H. S. & Ferrara, N. (1993). Inhibition of vascular endothelial growth factor-induced angiogenesis suppresses tumor growth in vivo. Nature 362: 841–844.
Mantel, N. (1966). Evaluation of survival data and two new rank order statistics arising in its consideration. Cancer Chemother Rep 50: 163–170.
McCulloch, P., Choy, A. & Martin, L. (1995). Association between tumor angiogenesis and tumor cell shedding into effluent venous blood during breast cancer surgery. Lancet 346: 1334–1335.
Millauer, B., Shawver, L. K., Plate, K. H., Risau, W. & Ullrich, A. (1994). Glioblastoma growth inhibited in vivo by a dominant-negative Flk-1 mutant. Nature 367: 576–579.
Minari, Y., Nio, Y., Sato, Y., Omori, H., Takeda, H., Hirahara, N., Sumi, S. & Tamura, K. (1997). The clinicopathological significance of thymidine phosphorylase in human pancreatic cancer: Its different distribution between the primary and the metastatic lesions. J Jpn Soc Cancer Ther 32: 315–325.
Nakajima-Iijima, S., Hamada, H., Reddy, P. & Kakunaga, T. (1985). Molecular structure of the human cytoplasmic β-actin gene: interspecies homology of sequences in the introns. Proc Natl Acad Sci USA 82: 6133–6137.
Nitecki, S. S., Michael, G. S., Colby, T. V. & van Heerden, J. A. (1995). Long-term survival after resection for ductal adenocarcinoma of the pancreas. Is it really improving? Ann Surg 221: 59–66.
Ozaki, H., Kinoshita, T., Kosuge, T., Yamamoto, J., Shimada, K., Inoue, K., Koyama, Y. & Mukai, K. (1996). An aggressive therapeutic approach to carcinoma of the body and tail of the pancreas. Cancer 77: 2240–2245.
Rak, J., Mitsuhashi, Y., Bayko, L., Filmus, J., Shirasawa, S., Sasazuki, T. & Kerbel, R. S. (1995). Mutant ras oncogenes upregulate VEGF/VPF expression: implications for induction and inhibition of tumor angiogenesis. Cancer Res 55: 4575–4580.
Ramakrishnan, S., Olson, T. A., Bautch, V. L. & Mohanraj, D. (1996). Vascular endothelial growth factor-toxin conjugate specifically inhibits KDR/flk-1-positive endothelial cell proliferation in vitro and angiogenesis in vivo. Cancer Res 56: 1324–1330.
Schnall, S. F. & Macdonald, J. S. (1996). Chemotherapy of adenocarcinoma of the pancreas. Seminars in Oncol 23: 220–228.
Shimoyama, S., Gansauge, F., Gansauge, S., Negri, G., Oohara, T. & Beger, H. G. (1996). Increased angiogenin expression in pancreatic cancer is related to cancer aggressiveness. Cancer Res 56: 2703–2706.
Sobin, L. H. & Wittekind, C. H. (1997). TNM classification of malignant tumors. In International Union Against Cancer (UICC), 5th ed. pp. 87–90. John Wiley: New York
Takahashi, Y., Bucana, C. D., Liu, W., Yoneda, J., Kitadai, Y., Cleary, K. R. & Ellis, L. M. (1996). Platelet-derived endothelial cell growth factor in human colon cancer angiogenesis: Role of infiltrating cells. J Natl Cancer Inst 88: 1146–1151.
Takahashi, Y., Bucana, C. D., Akagi, Y., Liu, W., Cleary, K. R., Mai, M. & Ellis, L. M. (1998). Significance of platelet-derived endothelial cell growth factor in the angiogenesis of human gastric cancer. Clin Cancer Res 4: 429–434.
Takebayashi, Y., Akiyama, S., Akiba, S., Yamada, K., Miyadera, K., Sumizawa, T., Yamada, Y., Murata, F. & Aikou, T. (1996). Clinicopathologic and prognostic significance of an angiogenic factor, thymidine phosphorylase, in human colorectal carcinoma. J Natl Cancer Inst 88: 1110–1117.
Tandon, A. K., Clark, G. M., Chamness, G. C., Chirgwin, J. M. & McGuire, W. L. (1990). Cathepsin D and prognosis in breast cancer. N Engl J Med 322: 297–302.
Tischer, E., Mitchell, R., Hartman, T., Silva, M., Gospodarowicz, D., Fiddes, J. C. & Abraham, J. A. (1991). The human gene for vascular endothelial growth factor. Multiple protein forms are encoded through alternative exon splicing. J Biol Chem 266: 11947–11954.
Tsurumi, Y., Murohara, T., Krasinski, K., Chen, D., Witzenbichler, B., Kearney, M., Couffinhal, T. & Isner, J. M. (1997). Reciprocal relation between VEGF and NO in the regulation of endothelial integrity. Nature Med 3: 879–886.
Usuki, K., Saras, J. & Waltenberger, J. (1992). Platelet-derived endothelial cell growth factor has thymidine phosphorylase activity. Biochem Biophys Res Commun 184: 1311–1316.
Weidner, N. & Folkman, J. (1996). Tumoral vascularity as a prognostic factor in cancer. In Important Advances in Oncology 1996, DeVita VT Jr, Hellman S and Rosenburg SA (eds), pp. 167–190, Lippincott-Raven: Philadelphia
Yamamoto, Y., Toi, M., Kondo, S., Matsumoto, T., Suzuki, H., Kitamura, M., Tsuruta, K., Taniguchi, T., Okamoto, A., Mori, T., Yoshida, M., Ikeda, T. & Tominaga, T. (1996). Concentrations of vascular endothelial growth factor in the sera of normal controls and cancer patients. Clin Cancer Res 2: 821–826.
Yamanaka, Y., Friess, H., Buchler, M., Beger, H. G., Uchida, E., Onda, M., Kobrin, M. S. & Korc, M. (1993). Overexpression of acidic and basic fibroblast growth factors in human pancreatic cancer correlates with advanced tumor stage. Cancer Res 53: 5289–5296.
Yoshiji, H., Gomez, D. E., Shibuya, M. & Thorgeirsson, U. P. (1996). Expression of vascular endothelial growth factor, its receptor, and other angiogenic factors in human breast cancer. Cancer Res 56: 2013–2016.
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Ikeda, N., Adachi, M., Taki, T. et al. Prognostic significance of angiogenesis in human pancreatic cancer. Br J Cancer 79, 1553–1563 (1999). https://doi.org/10.1038/sj.bjc.6690248
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DOI: https://doi.org/10.1038/sj.bjc.6690248
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