Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Article
  • Published:

Downregulation of VEGF-C expression in lung and colon cancer cells decelerates tumor growth and inhibits metastasis via multiple mechanisms

Oncogene volume 31, pages 1389–1397 (2012)Cite this article

Abstract

Experimental and clinical studies positively correlate expression of vascular endothelial growth factor (VEGF)-C in cancer cells with accelerated tumor progression and/or unfavorable clinical outcome. However, many aspects of tumor-promoting activity of VEGF-C and consequences of its downregulation for tumor progression remain poorly understood. To clarify these points, we created a set of VEGF receptor 3-positive lung carcinoma A549 and colon carcinoma HCT116 cell sublines with stable repression of VEGF-C synthesis. Analysis of the behavior of these cells revealed multiple effects of VEGF-C downregulation, which, in addition to deceleration of cell proliferation and invasion in vitro and inhibition of lymphangiogenesis in tumor and surrounding tissues observed earlier, included previously undescribed effects, in particular, partial restoration of epithelial phenotype, reduction in the percentage of tumor-initiating cells (cancer stem cells) in the cell population and inhibition of metastasis of orthotopic lung cancer xenografts to other lung lobes. These results are consistent with the idea of high potentiality of VEGF-C as a cancer drug target.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6
Figure 7

Similar content being viewed by others

References

  • Arinaga M, Noguchi T, Takeno S, Chujo M, Miura T, Uchida Y . (2003). Clinical significance of vascular endothelial growth factor C and vascular endothelial growth factor receptor 3 in patients with nonsmall cell lung carcinoma. Cancer 97: 457–464.

    Article  CAS  Google Scholar 

  • Bahram F, Claesson-Welsh L . (2010). VEGF-mediated signal transduction in lymphatic endothelial cells. Pathophysiology 17: 253–261.

    Article  CAS  Google Scholar 

  • Chen Y, Jiang L, She F, Tang N, Wang X, Li X et al. (2010). Vascular endohelial growth factor-C promotes the growth and invasion of gallbladder cancer via an autocrine mechanism. Mol Cell Biochem 345: 77–89.

    Article  CAS  Google Scholar 

  • Gu Y, Qi X, Guo S . (2008). Lymphangiogenesis induced by VEGF-C and VEGF-D promotes metastasis and a poor outcome in breast carcinoma: a retrospective study of 61 cases. Clin Exp Metastasis 25: 717–725.

    Article  CAS  Google Scholar 

  • Guarino M, Rubino B, Ballabio G . (2007). The role of epithelial-mesenchymal transition in cancer pathology. Pathology 39: 305–318.

    Article  CAS  Google Scholar 

  • Gupta PB, Chaffer CL, Weinberg RA . (2009). Cancer stem cells: mirage or reality? Nat Med 15: 1010–1012.

    Article  CAS  Google Scholar 

  • He Y, Kozaki K, Karpanen T, Koshikawa K, Yla-Herttuala S, Takahashi T et al. (2002). Suppression of tumor lymphangiogenesis and lymph node metastasis by blocking vascular endothelial growth factor receptor 3 signaling. J Natl Cancer Inst 94: 819–825.

    Article  CAS  Google Scholar 

  • Hoshida T, Isaka N, Hagendoorn J, di Tomaso E, Chen YL, Pytowski B et al. (2006). Imaging steps of lymphatic metastasis reveals that vascular endothelial growth factor-C increases metastasis by increasing delivery of cancer cells to lymph nodes: therapeutic implications. Cancer Res 66: 8065–8075.

    Article  CAS  Google Scholar 

  • Hugo H, Ackland ML, Blick T, Lawrence MG, Clements JA, Williams ED et al. (2007). Epithelial-mesenchymal and mesenchymal-epithelial transitions in carcinoma progression. J Cell Physiol 213: 374–383.

    Article  CAS  Google Scholar 

  • Jackson MW, Roberts JS, Heckford SE, Ricciardelli C, Stahl J, Choong C et al. (2002). A potential autocrine role for vascular endothelial growth factor in prostate cancer. Cancer Res 62: 854–859.

    CAS  PubMed  Google Scholar 

  • Joukov V, Pajusola K, Kaipainen A, Chilov D, Lahtinen I, Kukk E et al. (1996). A novel vascular endothelial growth factor, VEGF-C, is a ligand for the Flt4 (VEGFR-3) and KDR (VEGFR-2) receptor tyrosine kinases. EMBO J 15: 290–298.

    Article  CAS  Google Scholar 

  • Joukov V, Sorsa T, Kumar V, Jeltsch M, Claesson-Welsh L, Cao Y et al. (1997). Proteolytic processing regulates receptor specificity and activity of VEGF-C. EMBO J 16: 3898–3911.

    Article  CAS  Google Scholar 

  • Karkkainen MJ, Saaristo A, Jussila L, Karila KA, Lawrence EC, Pajusola K et al. (2001). A model for gene therapy of human hereditary lymphedema. Proc Natl Acad Sci USA 98: 12677–12682.

    Article  CAS  Google Scholar 

  • Karpanen T, Heckman C, Keskitalo S, Jeltsch M, Ollila H, Alitalo K . (2006). Functional interaction of VEGF-C and VEGF-D with neuropilin receptors. FASEB J 20: 1462–1472.

    Article  CAS  Google Scholar 

  • Khromova NV, Kopnin PB, Stepanova EV, Agapova LS, Kopnin BP . (2009). p53 hot-spot mutants increase tumor vascularization via ROS-mediated activation of the HIF1/VEGF-A pathway. Cancer Lett 276: 143–151.

    Article  CAS  Google Scholar 

  • Kodama M, Kitadai Y, Tanaka M, Kuwai T, Tanaka S, Oue N et al. (2008). Vascular endothelial growth factor C stimulates progression of human gastric cancer via both autocrine and paracrine mechanisms. Clin Cancer Res 14: 7205–7214.

    Article  CAS  Google Scholar 

  • Mandriota SJ, Jussila L, Jeltsch M, Compagni A, Baetens D, Prevo R et al. (2001). Vascular endothelial growth factor-C-mediated lymphangiogenesis promotes tumour metastasis. EMBO J 20: 672–682.

    Article  CAS  Google Scholar 

  • Mani SA, Guo W, Liao MJ, Eaton EN, Ayyanan A, Zhou AY et al. (2008). The epithelial-mesenchymal transition generates cells with properties of stem cells. Cell 133: 704–715.

    Article  CAS  Google Scholar 

  • Miyazaki T, Okada N, Ishibashi K, Ogata K, Ohsawa T, Ishiguro T et al. (2008). Clinical significance of plasma level of vascular endothelial growth factor-C in patients with colorectal cancer. Jpn J Clin Oncol 38: 839–843.

    Article  Google Scholar 

  • Orlandini M, Spreafico A, Bardelli M, Rocchigiani M, Salameh A, Nucciotti S et al. (2006). Vascular endothelial growth factor-D activates VEGFR-3 expressed in osteoblasts inducing their differentiation. J Biol Chem 281: 17961–17967.

    Article  CAS  Google Scholar 

  • Polyak K, Weinberg RA . (2009). Transitions between epithelial and mesenchymal states: acquisition of malignant and stem cell traits. Nat Rev Cancer 9: 265–273.

    Article  CAS  Google Scholar 

  • Shibuya M, Claesson-Welsh L . (2006). Signal transduction by VEGF receptors in regulation of angiogenesis and lymphangiogenesis. Exp Cell Res 312: 549–560.

    Article  CAS  Google Scholar 

  • Singh A, Settleman J . (2010). EMT, cancer stem cells and drug resistance: an emerging axis of evil in the war on cancer. Oncogene 29: 4741–4751.

    Article  CAS  Google Scholar 

  • Skobe M, Brown LF, Tognazzi K, Ganju RK, Dezube BJ, Alitalo K et al. (1999). Vascular endothelial growth factor-C (VEGF-C) and its receptors KDR and flt-4 are expressed in AIDS-associated Kaposi's sarcoma. J Invest Dermatol 113: 1047–1053.

    Article  CAS  Google Scholar 

  • Strizzi L, Catalano A, Vianale G, Orecchia S, Casalini A, Tassi G et al. (2001). Vascular endothelial growth factor is an autocrine growth factor in human malignant mesothelioma. J Pathol 193: 468–475.

    Article  CAS  Google Scholar 

  • Su JL, Yang PC, Shih JY, Yang CY, Wei LH, Hsieh CY et al. (2006). The VEGF-C/Flt-4 axis promotes invasion and metastasis of cancer cells. Cancer Cell 9: 209–223.

    Article  CAS  Google Scholar 

  • Su JL, Chen PS, Chien MH, Chen PB, Chen YH, Lai CC et al. (2008). Further evidence for expression and function of the VEGF-C/VEGFR-3 axis in cancer cells. Cancer Cell 13: 557–560.

    Article  CAS  Google Scholar 

  • Tammela T, Alitalo K . (2010). Lymphangiogenesis: molecular mechanisms and future promise. Cell 140: 460–476.

    Article  CAS  Google Scholar 

  • Thiery JP, Acloque H, Huang RY, Nieto MA . (2009). Epithelial-mesenchymal transitions in development and disease. Cell 139: 871–890.

    Article  CAS  Google Scholar 

  • Timoshenko AV, Rastogi S, Lala PK . (2007). Migration-promoting role of VEGF-C and VEGF-C binding receptors in human breast cancer cells. Br J Cancer 97: 1090–1098.

    Article  CAS  Google Scholar 

  • Wang X, Fu X, Hoffman RM . (1992). A patient-like metastasizing model of human lung adenocarcinoma constructed via thoracotomy in nude mice. Anticancer Res 12: 1399–1401.

    CAS  PubMed  Google Scholar 

  • Wu C, Alman BA . (2008). Side population cells in human cancers. Cancer Lett 268: 1–9.

    Article  CAS  Google Scholar 

  • Xu Y, Yuan L, Mak J, Pardanaud L, Caunt M, Kasman I et al. (2010). Neuropilin-2 mediates VEGF-C-induced lymphatic sprouting together with VEGFR3. J Cell Biol 188: 115–130.

    Article  CAS  Google Scholar 

  • Yamashita T, Uramoto H, Onitsuka T, Ono K, Baba T, So T et al. (2010). Association between lymphangiogenesis-/micrometastasis- and adhesion-related molecules in resected stage I NSCLC. Lung Cancer 70: 320–328.

    Article  Google Scholar 

  • Yamaura T, Murakami K, Doki Y, Sugiyama S, Misaki T, Yamada Y et al. (2000). Solitary lung tumors and their spontaneous metastasis in athymic nude mice orthotopically implanted with human non-small cell lung cancer. Neoplasia 2: 315–324.

    Article  CAS  Google Scholar 

  • Zeisberg M, Neilson EG . (2009). Biomarkers for epithelial-mesenchymal transitions. J Clin Invest 119: 1429–1437.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

The work was supported by grants from Russian Fund for Basic Research (BK, # 08-04-00252), PROTEK-CRC Program for Basic Research in Oncology and Russian Federal Program ‘Scientific and pedagogical personnel of innovative Russia’ (BK, # 02.740.11.0085).

Author information

Author notes

  1. N Khromova and P Kopnin: These authors contributed equally to this work

Authors and Affiliations

  1. Institute of Carcinogenesis, Blokhin Russian Cancer Research Center, Moscow, Russia

    N Khromova, P Kopnin, V Rybko & B P Kopnin

Authors
  1. N Khromova
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. P Kopnin
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. V Rybko
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. B P Kopnin
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to P Kopnin.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Additional information

Supplementary Information accompanies the paper on the Oncogene website

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Cite this article

Khromova, N., Kopnin, P., Rybko, V. et al. Downregulation of VEGF-C expression in lung and colon cancer cells decelerates tumor growth and inhibits metastasis via multiple mechanisms. Oncogene 31, 1389–1397 (2012). https://doi.org/10.1038/onc.2011.330

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/onc.2011.330

Keywords

This article is cited by

Search

Advanced search

Quick links