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Journal of Molecular Histology

, Volume 49, Issue 4, pp 429–435 | Cite as

VEGFA and VEGFR2 RNAscope determination in gastric cancer

  • Roberto Tamma
  • Tiziana Annese
  • Simona Ruggieri
  • Andrea Marzullo
  • Beatrice Nico
  • Domenico Ribatti
Short Communication
  • 170 Downloads

Abstract

Gastric cancer is the fifth most common cancer and third leading cause of cancer-related death worldwide. Several studies on angiogenic blocking agents in gastric cancer revealing promising results by the use of monoclonal antibodies against VEGFA or its receptor VEGFR2 or against VEGFA activating pathway. The validation of biomarkers useful to better organize the clinical trials involving anti-angiogenic therapies is crucial. Molecular markers such as RNA are increasingly used for cancer diagnosis, prognosis, and therapy guidance as in the case of the targeted therapies concerning the inhibition of angiogenesis. The aim of this study is to set the conditions for evaluating the expression of VEGFA and VEGFR2 in gastric cancer specimens and in healthy gastric mucosa by the use of RNAscope, a novel RNA in situ hybridization (ISH) method that allows the visualization of a specific gene expression in individual cells. We found the increased expression of VEGFA in the tubular glands and VEGFR2 in the endothelium of gastric cancer samples mainly in the T2, T3 and T4 stages of tumor progression as compared to the healthy controls. These results obtained by the application of this highly sensitive method for oligonucleotide detection the role of angiogenesis in gastric cancer progression already highlighted by conventional immunohistochemical methods, and offer significant promise as a new platform for developing and implementing RNA-based molecular diagnostics also in the conditions in which immunohistochemistry is not applicable.

Keywords

Gastric cancer Immunohistochemistry RNAscope VEGFA VEGFR2 

Notes

Acknowledgements

This work was supported by Grant from Associazione “Il Sorriso di Antonio” (Corato, Italy) to D.R. The Authors thanks Mrs. M. De Giorgis for her skillful technical assistance.

Compliance with ethical standards

Conflict of interest

All authors have seen and approved the manuscript being submitted and have no conflict of interest to declare.

References

  1. Araya M et al (1997) Microvessel count predicts metastasis and prognosis in patients with gastric cancer. J Surg Oncol 65:232–236CrossRefPubMedGoogle Scholar
  2. Bang YJ et al (2011) Phase II study of sunitinib as second-line treatment for advanced gastric cancer. Invest New Drugs 29:1449–1458.  https://doi.org/10.1007/s10637-010-9438-y CrossRefPubMedGoogle Scholar
  3. Brown LF, Berse B, Jackman RW, Tognazzi K, Manseau EJ, Senger DR, Dvorak HF (1993) Expression of vascular permeability factor (vascular endothelial growth factor) and its receptors in adenocarcinomas of the gastrointestinal tract. Cancer Res 53:4727–4735PubMedGoogle Scholar
  4. Caporarello N, Lupo G, Olivieri M, Cristaldi M, Cambria MT, Salmeri M, Anfuso CD (2017) Classical VEGF, Notch and Ang signalling in cancer angiogenesis, alternative approaches and future directions (Review). Mol Med Rep 16:4393–4402.  https://doi.org/10.3892/mmr.2017.7179 CrossRefPubMedPubMedCentralGoogle Scholar
  5. Chen S et al (2016) VEGF promotes gastric cancer development by upregulating CRMP4 Oncotarget 7:17074–17086.  https://doi.org/10.18632/oncotarget.7717 PubMedPubMedCentralCrossRefGoogle Scholar
  6. Di Costanzo F, Bozzetti F, Silvestrini R (2011) Basi scientifiche per la definizione di linee-guida in ambito clinico per il Carcinoma Gastrico Istituto Superiore di SanitàGoogle Scholar
  7. Dvorak HF, Brown LF, Detmar M, Dvorak AM (1995) Vascular permeability factor/vascular endothelial growth factor, microvascular hyperpermeability, and angiogenesis. Am J Pathol 146:1029–1039PubMedPubMedCentralGoogle Scholar
  8. Folkman J (1990) What is the evidence that tumors are angiogenesis dependent? J Natl Cancer Inst 82:4–6CrossRefPubMedGoogle Scholar
  9. Gerber HP, Dixit V, Ferrara N (1998) Vascular endothelial growth factor induces expression of the antiapoptotic proteins Bcl-2 and A1 in vascular endothelial cells. J Biol Chem 273:13313–13316CrossRefPubMedGoogle Scholar
  10. Global Burden of Disease Cancer C et al. (2017) Global, regional, and national cancer incidence, mortality, years of life lost, years lived with disability, and disability-adjusted life-years for 32 cancer groups, 1990 to 2015: a systematic analysis for the global burden of disease study JAMA Oncol 3:524–548  https://doi.org/10.1001/jamaoncol.2016.5688 CrossRefGoogle Scholar
  11. Hamburg MA, Collins FS (2010) The path to personalized medicine. N Engl J Med 363:301–304.  https://doi.org/10.1056/NEJMp1006304 CrossRefPubMedGoogle Scholar
  12. Hanahan D, Folkman J (1996) Patterns and emerging mechanisms of the angiogenic switch during tumorigenesis Cell 86:353–364CrossRefPubMedGoogle Scholar
  13. Jia S, Cai J (2016) Update on biomarkers in development of anti-angiogenic drugs in gastric. Cancer. Anticancer Res 36:1111–1118PubMedGoogle Scholar
  14. Jin Z, Yoon HH (2017) Antiangiogenic therapy in gastroesophageal cancer Hematol Oncol. Clin North Am 31:499–510.  https://doi.org/10.1016/j.hoc.2017.01.008 CrossRefPubMedGoogle Scholar
  15. Kim SE, Shim KN, Jung SA, Yoo K, Lee JH (2009) The clinicopathological significance of tissue levels of hypoxia-inducible factor-1alpha and vascular endothelial growth factor in gastric. cancer. Gut Liver 3:88–94.  https://doi.org/10.5009/gnl.2009.3.2.88 CrossRefPubMedPubMedCentralGoogle Scholar
  16. Li T, Yu J, Luo X, Ren W, Zhang Y, Cao B (2018) VEGFR-2 as a novel predictor of survival in gastric cancer: a systematic review and meta-analysis. Pathol Res Pract 214:560–564.  https://doi.org/10.1016/j.prp.2018.02.005 CrossRefPubMedGoogle Scholar
  17. Longo V, Tamma R, Brunetti O, Pisconti S, Argentiero A, Silvestris N, Ribatti D (2018) Mast cells and angiogenesis in pancreatic ductal adenocarcinoma. Clin Exp Med.  https://doi.org/10.1007/s10238-018-0493-6 PubMedCrossRefGoogle Scholar
  18. Lu D et al (2003) Tailoring in vitro selection for a picomolar affinity human antibody directed against vascular endothelial growth factor receptor 2 for enhanced neutralizing activity. J Biol Chem 278:43496–43507.  https://doi.org/10.1074/jbc.M307742200 CrossRefPubMedGoogle Scholar
  19. Macedo F, Ladeira K, Longatto-Filho A, Martins SF (2017) Gastric cancer and angiogenesis: is VEGF a useful biomarker to assess progression and remission? J Gastric Cancer 17:1–10.  https://doi.org/10.5230/jgc.2017.17.e1 CrossRefPubMedPubMedCentralGoogle Scholar
  20. Maeda K et al (1995a) Tumour angiogenesis and tumour cell proliferation as prognostic indicators in gastric carcinoma. Br J Cancer 72:319–323CrossRefPubMedPubMedCentralGoogle Scholar
  21. Maeda K et al (1995b) Tumor angiogenesis as a predictor of recurrence in gastric carcinoma. J Clin Oncol 13:477–481.  https://doi.org/10.1200/JCO.1995.13.2.477 CrossRefPubMedGoogle Scholar
  22. Maeda K et al (1996) Prognostic value of vascular endothelial growth factor expression in gastric carcinoma. Cancer 77:858–863CrossRefPubMedGoogle Scholar
  23. Maeda K et al (1998) Expression of p53 and vascular endothelial growth factor associated with tumor angiogenesis and prognosis in gastric cancer. Oncology 55:594–599.  https://doi.org/10.1159/000011918 CrossRefPubMedGoogle Scholar
  24. Nandikolla AG, Rajdev L (2016) Targeting angiogenesis in gastrointestinal tumors: current challenges. Transl Gastroenterol Hepatol 1:67.  https://doi.org/10.21037/tgh.2016.08.04 CrossRefPubMedPubMedCentralGoogle Scholar
  25. Nienhuser H, Schmidt T (2017) Angiogenesis and anti-angiogenic therapy in gastric cancer Int J Mol Sci 19  https://doi.org/10.3390/ijms19010043
  26. Pepper MS, Ferrara N, Orci L, Montesano R (1991) Vascular endothelial growth factor (VEGF) induces plasminogen activators and plasminogen activator inhibitor-1 in microvascular endothelial cells Biochem Biophys Res Commun 181:902–906CrossRefPubMedGoogle Scholar
  27. Ribatti D et al (1999) Bone marrow angiogenesis and mast cell density increase simultaneously with progression of human multiple myeloma. Br J Cancer 79:451–455.  https://doi.org/10.1038/sj.bjc.6690070 CrossRefPubMedPubMedCentralGoogle Scholar
  28. Ribatti D, Nico B, Ruggieri S, Tamma R, Simone G, Mangia A (2016) Angiogenesis and Antiangiogenesis in Triple-Negative Breast cancer. Transl Oncol 9:453–457.  https://doi.org/10.1016/j.tranon.2016.07.002 CrossRefPubMedPubMedCentralGoogle Scholar
  29. Roskoski R Jr (2007) Vascular endothelial growth factor (VEGF) signaling in tumor progression. Crit Rev Oncol Hematol 62:179–213.  https://doi.org/10.1016/j.critrevonc.2007.01.006 CrossRefPubMedGoogle Scholar
  30. Schulte N, Ebert MP, Hartel N (2014) Gastric cancer: new drugs - new strategies. Gastrointest Tumors 1:180–194.  https://doi.org/10.1159/000380786 CrossRefPubMedGoogle Scholar
  31. Scott LJ (2018) Apatinib: a review in advanced gastric cancer and other advanced cancers drugs  https://doi.org/10.1007/s40265-018-0903-9
  32. Senger DR, Galli SJ, Dvorak AM, Perruzzi CA, Harvey VS, Dvorak HF (1983) Tumor cells secrete a vascular permeability factor that promotes accumulation of ascites fluid. Science 219:983–985CrossRefPubMedGoogle Scholar
  33. Sisic L et al (2018) Postoperative follow-up programs improve survival in curatively resected gastric and junctional cancer patients: a propensity score matched analysis. Gastric Cancer 21:552–568.  https://doi.org/10.1007/s10120-017-0751-4 CrossRefPubMedGoogle Scholar
  34. Takahashi Y, Kitadai Y, Ellis LM, Bucana CD, Fidler IJ, Mai M (2002) Multiparametric in situ mRNA hybridization analysis of gastric biopsies predicts lymph node metastasis in patients with gastric carcinoma. Jpn J Cancer Res 93:1258–1265CrossRefPubMedPubMedCentralGoogle Scholar
  35. Takiuchi H, Hirata I, Kawabe S, Egashira Y, Katsu K (2000) Immunohistochemical expression of vascular endothelial growth factor can predict response to 5-fluorouracil and cisplatin in patients with gastric adenocarcinoma. Oncol Rep 7:841–846PubMedGoogle Scholar
  36. Tanigawa N, Amaya H, Matsumura M, Shimomatsuya T (1997) Correlation between expression of vascular endothelial growth factor and tumor vascularity, and patient outcome in human gastric carcinoma. J Clin Oncol 15:826–832.  https://doi.org/10.1200/JCO.1997.15.2.826 CrossRefPubMedGoogle Scholar
  37. Torre LA, Bray F, Siegel RL, Ferlay J, Lortet-Tieulent J, Jemal A (2015) Global cancer statistics, 2012. CA Cancer J Clin 65:87–108.  https://doi.org/10.3322/caac.21262 CrossRefPubMedGoogle Scholar
  38. Unemori EN, Ferrara N, Bauer EA, Amento EP (1992) Vascular endothelial growth factor induces interstitial collagenase expression in human endothelial cells. J Cell Physiol 153:557–562.  https://doi.org/10.1002/jcp.1041530317 CrossRefPubMedGoogle Scholar
  39. van ‘t Veer LJ et al (2002) Gene expression profiling predicts clinical outcome of breast cancer Nature 415:530–536.  https://doi.org/10.1038/415530a CrossRefPubMedGoogle Scholar
  40. Wang F et al (2012) RNAscope: a novel in situ RNA analysis platform for formalin-fixed, paraffin-embedded tissues. J Mol Diagn 14:22–29.  https://doi.org/10.1016/j.jmoldx.2011.08.002 CrossRefPubMedPubMedCentralGoogle Scholar
  41. Yamamoto S, Yasui W, Kitadai Y, Yokozaki H, Haruma K, Kajiyama G, Tahara E (1998) Expression of vascular endothelial growth factor in human gastric carcinomas. Pathol Int 48:499–506CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media B.V., part of Springer Nature 2018

Authors and Affiliations

  1. 1.Department of Basic Medical Sciences, Neurosciences and Sensory OrgansUniversity of Bari Medical SchoolBariItaly
  2. 2.Department of Emergency and Organ Transplantation, Section of Pathological AnatomyUniversity of Bari Aldo MoroBariItaly

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