Research Papers:

Implication of vascular endothelial growth factor A and C in revealing diagnostic lymphangiogenic markers in node-positive bladder cancer

Cédric Poyet, Linto Thomas, Tobias M. Benoit, David Aquino Delmo, Laura Luberto, Irina Banzola, Michèle S. Günthart, Giovanni Sais, Daniel Eberli, Tullio Sulser and Maurizio Provenzano _

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Oncotarget. 2017; 8:21871-21883. https://doi.org/10.18632/oncotarget.15669

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Cédric Poyet1, Linto Thomas1, Tobias M Benoit1, David Aquino Delmo1, Laura Luberto1, Irina Banzola1, Michèle S Günthart1, Giovanni Sais1, Daniel Eberli1, Tullio Sulser1, Maurizio Provenzano1

1Oncology Research Unit, Department of Urology and Division of Surgical Research, University Hospital of Zurich, Zurich, Switzerland

Correspondence to:

Maurizio Provenzano, email: [email protected]

Keywords: lymphangiogenesis, bladder cancer, diagnosis, VEGF-A, SLP-76

Received: August 19, 2016     Accepted: January 11, 2017     Published: February 24, 2017


Several lymphangiogenic factors, such as vascular endothelial growth factors (VEGFs), have been found to drive the development of lymphatic metastasis in bladder cancer (BCa).

Here, we have analyzed the gene expression of lymphangiogenic factors in tissue specimens from 12 non-muscle invasive bladder cancers (NMIBC) and 11 muscle invasive bladder cancers (MIBC), considering tumor and tumor-adjacent normal bladder areas obtained from the same organs. We then compared the results observed in patients with those obtained after treating human primary bladder microvascular endothelial cells (MEC) with either direct stimulation with VEGF-A or VEGF-C or by co-culturing (trans-well assay) MEC with bladder cancer cell lines varying in VEGF-A and VEGF-C production based on tumor grade.

The genes of three markers of lymphatic endothelial commitment and development (PDPN, LYVE-1 and SLP-76) were significantly overexpressed in tissues of MIBC patients showing positive lymphovascular invasion (LVI+), lymph node metastasis (Ln+) and tumor progression. Their expression was also significantly enhanced either after direct stimulation of MEC by VEGF-A and VEGF-C or in the trans-well assay with each bladder cancer cell line.

SLP-76 showed the highest gene expression. Both VEGF-A and VEGF-C also enhanced the expression of SLP-76 protein in MEC. However, a correlation between increase of SLP-76 gene expression and the ability of MEC to migrate could only be seen after induction by VEGF-C.

The significant expression of SLP-76 in LVI+/Ln+ progressive MIBC and its overexpression in MEC after VEGF-A and VEGF-C stimulation suggest the need to develop this regulator of developmental lymphangiogenesis as a diagnostic tool in BCa.

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