The relationship between lymphatic vascular density and vascular endothelial growth factor A (VEGF-A) expression with clinical-pathological features and survival in pancreatic adenocarcinomas

Diagnostic Pathology

Alfredo Ribeiro-Silva²  Fernando A Soares¹  Danilo F Soave²  João Paulo Oliveira-Costa²  Giórgia G Silveira²  Verônica A Zorgetto² 

[1] Departament of Pathologic Anatomy A. C. Camargo Cancer Center São Paulo, São Paulo, Brazil;Departament of Pathology, Ribeirão Preto Medical School, University of São Paulo, 3900 Bandeirantes Avenue, Ribeirão Preto, São Paulo, Brazil

关键词: Prognosis;    Tissue microarray;    Immunohistochemistry;    Lymphangiogenesis;    Angiogenesis;    VEGF-A;    Pancreatic cancer;   

Others  :  804313
DOI  :  10.1186/1746-1596-8-170

 received in 2013-07-02, accepted in 2013-10-07,  发布年份 2013

【 摘 要 】

Background

Pancreatic cancer is a rare tumor with an extremely low survival rate. Its known risk factors include the chronic use of tobacco and excessive alcohol consumption and the presence of chronic inflammatory diseases, such as pancreatitis and type 2 diabetes. Angiogenesis and lymphangiogenesis, which have been the focus of recent research, are considered prognostic factors for cancer development. Knowing the angiogenic and lymphangiogenic profiles of a tumor may provide new insights for designing treatments according to the different properties of the tumor. The aim of this study was to evaluate the density of blood and lymphatic vessels, and the expression of VEGF-A, in pancreatic adenocarcinomas, as well as the relationship between blood and lymphatic vascular density and the prognostically important clinical-pathological features of pancreatic tumors.

Methods

Paraffin blocks containing tumor samples from 100 patients who were diagnosed with pancreatic cancer between 1990 and 2010 were used to construct a tissue microarray. VEGF expression was assessed in these samples by immunohistochemistry. To assess the lymphatic and vascular properties of the tumors, 63 cases that contained sufficient material were sectioned routinely. The sections were then stained with the D2-40 antibody to identify the lymphatic vessels and with a CD34 antibody to identify the blood vessels. The vessels were counted individually with the Leica Application Suite v4 program. All statistical analyses were performed using SPSS 18.0 (Chicago, IL, USA) software, and p values ≤ 0.05 were considered significant.

Results

In the Cox regression analysis, advanced age (p=0.03) and a history of type 2 diabetes (p=0.014) or chronic pancreatitis (p=0.02) were shown to be prognostic factors for pancreatic cancer. Blood vessel density (BVD) had no relationship with clinical-pathological features or death. Lymphatic vessel density (LVD) was inversely correlated with death (p=0.002), and by Kaplan-Meyer survival analysis, we found a significant association between low LVD (p=0.021), VEGF expression (p=0.023) and low patient survival.

Conclusions

Pancreatic carcinogenesis is related to a history of chronic inflammatory processes, such as type 2 diabetes and chronic pancreatitis. In pancreatic cancer development, lymphangiogenesis can be considered an early event that enables the dissemination of metastases. VEGF expression and low LVD can be considered as poor prognostic factors as tumors with this profile are fast growing and highly aggressive.

Virtual slides

The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/5113892881028514 webcite

【 授权许可】

   
2013 Zorgetto et al.; licensee BioMed Central Ltd.

【 图 表 】

Figure 1.

Figure 2.

【 参考文献 】

• [1]Bevan R, Young C, Holmes P, Fortunato L, Slack R, Rushton L: Occupational cancer in Britain. Gastrointestinal cancers: liver, oesophagus, pancreas and stomach. Br J Cancer 2012, 107:S33--S40.
• [2]Vainio H: Targeting angiogenesis – a novel mode in cancer chemoprevention. Asian Pacific J Cancer Prev 2003, 4:83-86.
• [3]Alitalo A, Detmar M: Interaction of tumor cells and lymphatic vessels in cancer progression. Oncogene 2012, 31:4499-4508.
• [4]Nagy JA, Dvorak AM, Dvorak HF: VEGF-A and the induction of pathological angiogenesis. Annu Rev Pathol Mech Dis 2007, 2:251-275.
• [5]Whitehurst B, Flister MJ, Bagaitkar J, Volk L, Bivens CM, Pickett B, Castro-Rivera E, Brekken RA, Gerard RD, Ran S: Anti-VEFG-A therapy reduces lymphatic vessel density and expression of VEGFR-3 in an orthotopic breast tumor model. Int J Cancer 2007, 121:2182-2191.
• [6]Christiansen A, Detmar M: Lymphangiogenesis and Cancer. Genes Cancer 2011, 2:1146-1158.
• [7]Zhang LZ, Zhang CQ, Yan ZY, Yang QC, Jiang Y, Zeng BF: Tumor-initiating cells and tumor vascularization. Pediatr Blood Cancer 2011, 56(3):335-340.
• [8]Lin M, Ma SP, Lin HZ, Ji P, Xie D, Yu JX: Intratumoral as well as peritumoral lymphatic vessel invasion correlates with lymph node metastasis and unfavourable outcome in colorectal cancer. Clin Exp Metastasis 2010, 27(3):123-132.
• [9]Leong SP, Nakamura EK, Pollok R, Choti MA, Morton DL, Henner WD, Lal A, Pillai R, Clark OH, Cady B: Unique patterns of metastases in common and rare types of malignancy. J Surg Oncol 2011, 103(6):607-614.
• [10]Sharma RA, Harris AL, Dalgleish AG, Steward WP, O’Byrne KJ: Angiogenesis as a biomarker and target in cancer chemoprevention. Lancet Oncol 2001, 2(12):726-732.
• [11]Kysas PA, Geleff S, Batistatou A, Agnantis NJ, Stefanou D: Evidence for lymphangiogenesis and its prognostic implications in head and neck squamous cell carcinoma. J Pathol 2005, 206(2):170-177.
• [12]Kayser K, Schultz H, Goldmann T, Görtler J, Kayser G, Vollmer E: Theory of sampling and its application in tissue based diagnosis. Diagn Pathol 2009, 4:6. BioMed Central Full Text
• [13]Santini D, Vicenzi B, Perrone G, Rabitti C, Borzomati D, Valeri S, Coppola R, Magistrelli P, Tonini G: Vascular endothelial growth factor (VEGF) expression is not associated with prognosis in patients with radically resected ampullary carcinoma. Ann Oncol 2005, 16(11):1847-1848.
• [14]Smith RA, Tang J, Tudur-Smith C, Neoptolemos JP, Ghaneh P: Meta-analysis of immunohistochemical prognostic markers in resected pancreatic cancer. Br J Cancer 2011, 104(9):1440-1451.
• [15]Weidner N, Semple JP, Welch WR, Folkman J: Tumor angiogenesis and metastasis – correlation in invasive breast carcinoma. N Engl J Med 1991, 324(1):1-8.
• [16]Alexiev BA, Drachenberg CB, Papadimitriou JC: Endocrine tumors of the gastrointestinal tract and pancreas: grading, tumor size and proliferation index do not predict malignant behavior. Diagn Pathol 2007, 2:28. BioMed Central Full Text
• [17]Yeo TP, Lowenfels AB: Demographics and epidemiology of pancreatic cancer. The Cancer Journal 2012, 18(6):477-484.
• [18]Takikita M, Altekruse S, Lynch CF, Goodman MT, Hernandez BY, Green M, Cozen W, Cockburn M, Sibug Saber M, Topor M, Zeruto C, Abedi-Ardekani B, Reichman ME, Hewitt SM: Associations between selected biomarkers and prognosis in a populations-based pancreatic cancer tissue microarray. Cancer Res 2009, 69(7):2950-2955.
• [19]Hidalgo M: Pancreatic cancer. N Engl J Med 2010, 362:1605-1617.
• [20]Klöppel G, Hrubau RH, Longnecker DS, Adler G, Kern SE, Partanen TJ: Ductal Adenocarcinoma of the Pancreas. In Pathology and Genetics of Tumours of the Digestive System. Edited by Hamilton SR, Aaltonen LA. Lyon: ARC Press; 2000:221-230.
• [21]Lins TC, Vieira RG, Abreu BS, Gentil P, Moreno-Lima R, Oliveira RJ, Pereira RW: Genetic heterogeneity of self-reported ancestry groups in an admixed Brazilian population. J Epidemiol 2011, 21(4):240-245.
• [22]Oliveira LR, Jeffrey SS, Ribeiro-Silva A: Stem cells in human breast cancer. Histol Histopathol 2010, 25(3):371-385.
• [23]Braun S, Bitton-Worms K, LeRoith D: The link between the metabolic syndrome and cancer. Int J Biol Sci 2011, 7(7):1003-1015.
• [24]Li D: Diabetes and pancreatic cancer. Mol Carcinog 2012, 51(1):64-74.
• [25]Prizment AE, Gross M, Rasmussen-Torvik L, Peacock JM, Anderson KE: Genes related to diabetes may be associated with pancreatic cancer in a population-based case–control study in Minnesota. Pancreas 2012, 41(1):50-53.
• [26]Elena JW, Steplowski E, Yu K, Hartge P, Tobias GS, Brotzman MJ, Chanock SJ, Stolzenberg-Solomon RZ, Arslan AA, Bueno-de-Mesquita HB, Helzlsouer K, Jacobs EJ, LaCroix A, Petersen G, Zheng W, Albanes D, Allen NE, Amundadottir L, Bao Y, Boeing H, Boutron-Ruault MC, Buring JE, Gaziano JM, Giovannucci EL, Duell EJ, Hallmans G, Howard BV, Hunter DJ, Hutchinson A, Jacobs KB, et al.: Diabetes and risk of pancreatic cancer: a pooled analysis from the pancreatic cancer cohort consortium. Cancer Causes Control 2013, 24(1):13-25.
• [27]Kayser K, Nwoye JO, Kosjerina Z, Goldmann T, Vollmer E, Kaltner H, André S, Gabius HJ: Atypical adenomatous hyperplasia of lung: its incidence and analysis of clinical, glycohistochemical and structural features including newly defined growth regulators and vascularization. Lung Cancer 2003, 42(2):171-182.
• [28]Kawauchi S, Fukuda T, Tsuneyoshi M: Angiogenesis does not correlate with prognosis or vascular endothelial growth factor in synovial sarcomas. Oncol Rep 1999, 6(5):959-1023.
• [29]Sullu Y, Gun S, Atmaca S, Karagoz F, Kandemir B: Poor prognostic clinicopathologic features correlate with VEGF expression but not with PTEN expression in squamous cell carcinoma of the larynx. Diagn Pathol 2010, 5:35. BioMed Central Full Text
• [30]Kayser G, Baumhäkel JD, Szöke T, Trojan I, Riede U, Werner M, Kayser K: Vascular diffusion density and survival of patients with primary lung carcinomas. Virchows Arch 2003, 442(5):462-467.
• [31]Sleeman JP, Thiele W: Tumor metastasis and the lymphatic vasculature. Int J Cancer 2009, 125(12):2747-2756.
• [32]Sleeman JP, Schmid A, Thiele W: Tumor lymphatics. Semin Cancer Biol 2009, 19(5):285-297.
• [33]Rubbia-Brandt L, Terris B, Giostra E, Dousset B, Morel P, Pepper MS: Lymphatic vessel density and vascular endothelial growth factor-C expression correlate with malignant behavior in human pancreatic endocrine tumors. Clin Cancer Res 2004, 10(20):6919-6928.
• [34]Sipos B, Kojima M, Tiemann K, Klapper W, Kruse ML, Kalthoff H, Schniewind B, Tepel J, Weich H, Keriaschki D, Klöppel G: Lymphatic spread of ductal pancreatic adenocarcinoma is independent of lymphangiogenesis. J Pathol 2005, 207(3):301-312.
• [35]Padera TP, Kadambi A, di Tomaso E, Carreira CM, Brown EB, Boucher Y, Choi NC, Mathinsen D, Wain J, Mark EJ, Jain RK: Lymphatic metastasis in the absence of functional intratumor lymphatics. Science 2002, 296(5574):1883-1886.
• [36]Schopmann SF, Birner P, Stöckl J, Kalt R, Ullrich R, Cauciq C, Kriehuber E, Nagy K, Alitalo K, Keriaschki D: Tumor-associated macrophages express lymphatic endothelial growth factors and are related to peritumoral lymphangiogenesis. Am J Pathol 2002, 161(3):947-956.
• [37]Yin N, Zhang N, Lal G, Xu J, Yan M, Ding Y, Bromberg JS: Lymphangiogenesis is required for pancreatic islet inflammation and diabetes. PLoS One 2011, 6(11):e28023.
• [38]Wang Z, Wu J, Li G, Zhang X, Tong M, Wu Z, Lui Z: Lymphangiogenesis and biological behavior in pancreatic carcinoma and other pancreatic tumors. Mol Med Rep 2012, 5(4):959-963.
• [39]Kerbel RS: Tumor angiogenesis: past, present and the near future. Carcinogenesis 2000, 21(3):505-515.
• [40]Folkman J: Role of angiogenesis in tumor growth and metastasis. Semin Oncol 2002, 29(6 Suppl 16):15-18.
• [41]Folkman J: Angiogenesis. Annu Rev Med 2006, 57:1-18.
• [42]Cao Y, Langer R: A review of Judah Folkman’s remarkable achievements in biomedicine. Proc Natl Acad Sci U S A 2008, 105(36):13203-13205.
• [43]Otrock ZK, Makarem JA, Shamseddine AI: Vascular endothelial growth factor family of ligands and receptors: review. Blood Cells Mol Dis 2007, 38(3):258-268.
• [44]Nowak DG, Woolard J, Amin EM, Konopatskaya O, Saleem MA, Churchill AJ, Ladomery MR, Harper SJ, Bates DO: Expression of pro- and anti-angiogenic isoforms of VEGF is differentially regulated by splicing and growth factors. J Cell Sci 2008, 121(Pt 20):3487-3495.
• [45]Woolard J, Bevan HS, Harper SJ, Bates DO: Molecular diversity of VEGF-A as a regulator of its biological activity. Microcirculation 2009, 16(7):572-592.
• [46]Wirzenius M, Tammela T, Uutela M, He Y, Odorisio T, Zambruno G, Nagy JA, Dvorak HF, Ylä-Herrttuala S, Shibuya M, Alitalo K: Distinct vascular endothelial growth factor signals for lymphatic vessel enlargement and sprouting. J Exp Med 2007, 204(6):1431-1440.
• [47]Liang QL, Wang BR, Chen GQ, Li GH, Xu YY: Clinical significance of vascular endothelial growth factor and connexin43 for predicting pancreatic cancer clinicopathologic parameters. Med Oncol 2010, 27(4):1164-1170.
• [48]Cao Y: Why and how do tumors stimulate lymphangiogenesis? Lymphat Res Biol 2008, 6(3–4):145-148.