Skip to main content

Advertisement

SpringerLink
Log in

Evidence for angiogenesis-independent contribution of VEGFR1 (FLT1) in gastric cancer recurrence

  • Short Communication
  • Published:
Medical Oncology Aims and scope Submit manuscript

Abstract

Angiogenesis plays an important role in cancer progression and involves activation of multiple signaling cascades. This study investigated the relationships between microvessel density, expression of VEGF and VEGFR1 (FLT1), and gastric cancer (GC) recurrence. Twenty-nine surgically treated GC cases with similar initial clinical presentation were selected for the study; 11 of these cases recurred within 3 years, while the remaining 18 did not. Microvessel density correlated with VEGF mRNA content, but neither of these parameters was associated with the disease outcome. When tumors were ranked according to the level of expression of angiogenic molecules, 9 out of 10 cases with the highest VEGFR1 expression belonged to the recurrence group, while none of the 10 GC with the lowest content of VEGFR1 mRNA had the disease relapse (p = 0.000). VEGFR1 expression did not show even a trend to correlation with the level of cancer tissue vascularization. Immunofluorescent staining by anti-VEGFR1 antibody revealed VEGFR1 expression in tumor cells but not in other cell types. Our data provide indirect support to the evidence for a non-angiogenic contribution of VEGFR1 in cancer pathogenesis.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

References

  1. Hartgrink HH, Jansen EP, van Grieken NC, van de Velde CJ. Gastric cancer. Lancet. 2009;374:477–90.

    Article  PubMed  Google Scholar 

  2. Kerbel RS. Tumor angiogenesis. N Engl J Med. 2008;358:2039–49.

    Article  PubMed  CAS  Google Scholar 

  3. Nico B, Benagiano V, Mangieri D, Maruotti N, Vacca A, Ribatti D. Evaluation of microvascular density in tumors: pro and contra. Histol Histopathol. 2008;23:601–7.

    PubMed  Google Scholar 

  4. Carmeliet P, Jain RK. Molecular mechanisms and clinical applications of angiogenesis. Nature. 2011;473:298–307.

    Article  PubMed  CAS  Google Scholar 

  5. Weis SM, Cheresh DA. Tumor angiogenesis: molecular pathways and therapeutic targets. Nat Med. 2011;17:1359–70.

    Article  PubMed  CAS  Google Scholar 

  6. Imyanitov EN, Suspitsin EN, Buslov KG, Kuligina ESh, Belogubova EV, Togo AV, Hanson KP. Isolation of nucleic acids from paraffin-embedded archival tissues and other difficult sources. In: Kieleczawa J, editor. The DNA book: protocols and procedures for the modern molecular biology laboratory. Sudbury: Jones and Bartlett Publishers; 2006. p. 85–97.

    Google Scholar 

  7. Iyevleva AG, Buslov KG, Togo AV, Matsko DE, Filimonenko VP, Moiseyenko VM, Imyanitov EN. Measurement of DPD and TS transcripts aimed to predict clinical benefit from fluoropyrimidines: confirmation of the trend in Russian colorectal cancer series and caution regarding the gene referees. Onkologie. 2007;30:295–300.

    Article  PubMed  CAS  Google Scholar 

  8. Livak KJ, Schmittgen TD. Analysis of relative gene expression data using real-time quantitative PCR and the 2(−delta delta C(T)) method. Methods. 2001;25:402–8.

    Article  PubMed  CAS  Google Scholar 

  9. Weidner N. Intratumor microvessel density as a prognostic factor in cancer. Am J Pathol. 1995;147:9–19.

    PubMed  CAS  Google Scholar 

  10. Tsujitani S, Saito H, Maeta Y, Yamaguchi K, Tatebe S, Kondo A, Kaibara N. Neoangiogenesis in patients with gastric carcinoma in relation to the expression of vascular endothelial growth factor and thymidine phosphorylase. Anticancer Res. 2004;24:1853–9.

    PubMed  CAS  Google Scholar 

  11. Kolev Y, Uetake H, Iida S, Ishikawa T, Kawano T, Sugihara K. Prognostic significance of VEGF expression in correlation with COX-2, microvessel density, and clinicopathological characteristics in human gastric carcinoma. Ann Surg Oncol. 2007;14:2738–47.

    Article  PubMed  Google Scholar 

  12. Ma J, Zhang L, Ru GQ, Zhao ZS, Xu WJ. Upregulation of hypoxia inducible factor 1alpha mRNA is associated with elevated vascular endothelial growth factor expression and excessive angiogenesis and predicts a poor prognosis in gastric carcinoma. World J Gastroenterol. 2007;13:1680–6.

    PubMed  CAS  Google Scholar 

  13. Hirashima Y, Yamada Y, Matsubara J, Takahari D, Okita N, Takashima A, Kato K, Hamaguchi T, Shirao K, Shimada Y, Taniguchi H, Shimoda T. Impact of vascular endothelial growth factor receptor 1, 2, and 3 expression on the outcome of patients with gastric cancer. Cancer Sci. 2009;100:310–35.

    Article  PubMed  CAS  Google Scholar 

  14. Okita NT, Yamada Y, Takahari D, Hirashima Y, Matsubara J, Kato K, Hamaguchi T, Shirao K, Shimada Y, Taniguchi H, Shimoda T. Vascular endothelial growth factor receptor expression as a prognostic marker for survival in colorectal cancer. Jpn J Clin Oncol. 2009;39:595–600.

    Article  PubMed  Google Scholar 

  15. Dhakal HP, Naume B, Synnestvedt M, Borgen E, Kaaresen R, Schlichting E, Wiedswang G, Bassarova A, Holm R, Giercksky KE, Nesland JM. Expression of vascular endothelial growth factor and vascular endothelial growth factor receptors 1 and 2 in invasive breast carcinoma: prognostic significance and relationship with markers for aggressiveness. Histopathology. 2012;61:350–64.

    Article  PubMed  Google Scholar 

  16. Li T, Zhu Y, Qin CY, Yang Z, Fang A, Xu S, Ren W. Expression and prognostic significance of vascular endothelial growth factor receptor 1 in hepatocellular carcinoma. J Clin Pathol. 2012;65:808–14.

    Article  PubMed  CAS  Google Scholar 

  17. Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011;144:646–74.

    Article  PubMed  CAS  Google Scholar 

  18. Wey JS, Fan F, Gray MJ, Bauer TW, McCarty MF, Somcio R, Liu W, Evans DB, Wu Y, Hicklin DJ, Ellis LM. Vascular endothelial growth factor receptor-1 promotes migration and invasion in pancreatic carcinoma cell lines. Cancer. 2005;104:427–38.

    Article  PubMed  CAS  Google Scholar 

  19. Wu Y, Hooper AT, Zhong Z, Witte L, Bohlen P, Rafii S, Hicklin DJ. The vascular endothelial growth factor receptor (VEGFR-1) supports growth and survival of human breast carcinoma. Int J Cancer. 2006;119:1519–29.

    Article  PubMed  CAS  Google Scholar 

  20. Yang AD, Camp ER, Fan F, Shen L, Gray MJ, Liu W, Somcio R, Bauer TW, Wu Y, Hicklin DJ, Ellis LM. Vascular endothelial growth factor receptor-1 activation mediates epithelial to mesenchymal transition in human pancreatic carcinoma cells. Cancer Res. 2006;66:46–51.

    Article  PubMed  CAS  Google Scholar 

  21. Lesslie DP, Summy JM, Parikh NU, Fan F, Trevino JG, Sawyer TK, Metcalf CA, Shakespeare WC, Hicklin DJ, Ellis LM, Gallick GE. Vascular endothelial growth factor receptor-1 mediates migration of human colorectal carcinoma cells by activation of Src family kinases. Br J Cancer. 2006;94:1710–7.

    PubMed  CAS  Google Scholar 

  22. Lee TH, Seng S, Sekine M, Hinton C, Fu Y, Avraham HK, Avraham S. Vascular endothelial growth factor mediates intracrine survival in human breast carcinoma cells through internally expressed VEGFR1/FLT1. PLoS Med. 2007;4:e186.

    Article  PubMed  Google Scholar 

  23. Yi ZY, Feng LJ, Xiang Z, Yao H. Vascular endothelial growth factor receptor-1 activation mediates epithelial to mesenchymal transition in hepatocellular carcinoma cells. J Invest Surg. 2011;24:67–76.

    Article  PubMed  Google Scholar 

  24. Frank NY, Schatton T, Kim S, Zhan Q, Wilson BJ, Ma J, Saab KR, Osherov V, Widlund HR, Gasser M, Waaga-Gasser AM, Kupper TS, Murphy GF, Frank MH. VEGFR-1 expressed by malignant melanoma-initiating cells is required for tumor growth. Cancer Res. 2011;71:1474–85.

    Article  PubMed  CAS  Google Scholar 

  25. Bang YJ, Kang YK, Kang WK, Boku N, Chung HC, Chen JS, Doi T, Sun Y, Shen L, Qin S, Ng WT, Tursi JM, Lechuga MJ, Lu, Ruiz-Garcia A, Sobrero A. Phase II study of sunitinib as second-line treatment for advanced gastric cancer. Invest New Drugs. 2011;29:1449–58.

    Article  PubMed  CAS  Google Scholar 

  26. Moehler M, Mueller A, Hartmann JT, Ebert MP, Al-Batran SE, Reimer P, Weihrauch M, Lordick F, Trarbach T, Biesterfeld S, Kabisch M, Wachtlin D, Galle PR. German Arbeitsgemeinschaft Internistische Onkologie (AIO) () an open-label, multicentre biomarker-oriented AIO phase II trial of sunitinib for patients with chemo-refractory advanced gastric cancer. Eur J Cancer. 2009;47:1511–20.

    Article  Google Scholar 

Download references

Acknowledgments

This work has been supported by the Russian Federation for Basic Research (Grants 11-04-01643, 12-04-00535, 12-04-31567 and 13-04-01375), the Federal Agency for Science and Innovations, Russia (Contract 14.512.11.0041), the Dynasty Foundation (Contract 18/13) and the President’s Research Council for Support of Young Russian Scientists (Grant MK-261.2012.7). We are cordially thankful to Dr. Mark Q. Benedict (University of Perugia) for his valuable comments.

Conflict of interest

None.

Author information

Authors and Affiliations

  1. N.N. Petrov Institute of Oncology, 197758, St. Petersburg, Russia

    Evgeny N. Suspitsin, Aniruddh Kashyap, Kseniya V. Shelekhova, Anna P. Sokolenko, Ekatherina Sh. Kuligina, Aglaya G. Iyevleva, Alexandr V. Kornilov, Grigoriy A. Yanus, Svetlana N. Aleksakhina, Elena V. Preobrazhenskaya, Olga A. Zaitseva, Olga S. Yatsuk, Valeriy F. Klimashevsky, Alexandr V. Togo & Evgeny N. Imyanitov

  2. St. Petersburg Pediatric Medical University, St. Petersburg, 194100, Russia

    Evgeny N. Suspitsin, Anna P. Sokolenko, Aglaya G. Iyevleva, Grigoriy A. Yanus & Evgeny N. Imyanitov

  3. University of Heidelberg, 69120, Heidelberg, Germany

    Volker Ehemann

  4. I.I. Mechnikov North-Western Medical University, 191015, St. Petersburg, Russia

    Evgeny N. Imyanitov

  5. Laboratory of Molecular Oncology, N.N. Petrov Institute of Oncology, Pesochny-2, 197758, St. Petersburg, Russia

    Evgeny N. Imyanitov

Authors
  1. Evgeny N. Suspitsin
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Aniruddh Kashyap
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Kseniya V. Shelekhova
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Anna P. Sokolenko
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Ekatherina Sh. Kuligina
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Aglaya G. Iyevleva
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Alexandr V. Kornilov
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Volker Ehemann
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Grigoriy A. Yanus
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Svetlana N. Aleksakhina
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Elena V. Preobrazhenskaya
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Olga A. Zaitseva
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Olga S. Yatsuk
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Valeriy F. Klimashevsky
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Alexandr V. Togo
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. Evgeny N. Imyanitov
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Evgeny N. Imyanitov.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Suspitsin, E.N., Kashyap, A., Shelekhova, K.V. et al. Evidence for angiogenesis-independent contribution of VEGFR1 (FLT1) in gastric cancer recurrence. Med Oncol 30, 644 (2013). https://doi.org/10.1007/s12032-013-0644-2

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1007/s12032-013-0644-2

Keywords

Search

Navigation