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Differential vascular expression and regulation of oncofetal tenascin-C and fibronectin variants in renal cell carcinoma (RCC): implications for an individualized angiogenesis-related targeted drug delivery

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Abstract

The study was aimed at determining the vascular expression of oncofetal fibronectin (oncfFn) and tenascin-C (oncfTn-C) isoforms in renal cell carcinoma (RCC) and its metastases which are well-known targets for antibody-based pharmacodelivery. Furthermore, the influence of tumour cells on endothelial mRNA expression of these molecules was investigated. Evaluation of vascular ED-A+ and ED-B+ Fn as well as A1+ and C+ Tn-C was performed after immunofluorescence double and triple staining using human recombinant antibodies on clear cell, papillary and chromophobe primary RCC and metastases. The influence of hypoxic RCC-conditioned medium on oncfFn and oncfTn-C mRNA expression was examined in human umbilical vein endothelial cells (HUVEC) by real time RT-PCR. There are RCC subtype specific expression profiles of vascular oncfFn and oncfTn-C and corresponding patterns when comparing primary tumours and metastases. Within one tumour, there are different vessel populations with regard to the incorporation of oncfTn-C and oncfFn into the vessel wall. In vitro tumour-derived soluble mediators induce an up regulation of oncfTn-C and oncfFn mRNA in HUVEC which can be blocked by Avastin®. Vascular expression of oncFn and oncTn-C variants depends on RCC subtype and may reflect an individual tumour stroma interaction or different stages of vessel development. Therefore, oncFn or oncTn-C variants can be suggested as molecular targets for individualized antibody based therapy strategies in RCC. Tumour-derived VEGF could be shown to regulate target expression.

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Acknowledgments

The authors are grateful to Claudia Seliger, Beate Ziegenhardt, Valentina Scarlato and Elke Teuscher for excellent technical assistance. The research leading to the results has received funding from the European Community’s Seventh Framework Programme (FP7/2007-2013) under grant agreement no Health-F2-2008-201342 (ADAMANT).

Conflict of interest

Dario Neri is a co-founder and shareholder of Philogen, the company which owns the rights over the F8, L19, F16 and G11 antibodies.

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Authors and Affiliations

  1. Institute of Pathology, University Hospital Jena, Jena, Germany

    Kerstin Galler, Petra Richter, Mieczyslaw Gajda, Angela Göhlert & Alexander Berndt

  2. Department of Urology, University Hospital Jena, Jena, Germany

    Kerstin Junker & Heiko Wunderlich

  3. Department of Internal Medicine I, University Hospital of Jena, Erlanger Allee 101, 07740, Jena, Germany

    Marcus Franz

  4. Core Unit Chip Application, Institute of Human Genetics, University Hospital Jena, Jena, Germany

    Julia Hentschel & Ferdinand von Eggeling

  5. Center for Molecular Biomedicine, FSU, Jena, Germany

    Regine Heller

  6. Mario Negri Institute for Pharmacological Research, Milan, Italy

    Raffaella Giavazzi

  7. ETH, Institute of Pharmaceutical Sciences, Zurich, Switzerland

    Dario Neri

  8. Institute of Pathology, HELIOS Klinikum, Erfurt, Germany

    Hartwig Kosmehl

Authors
  1. Kerstin Galler
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  2. Kerstin Junker
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  3. Marcus Franz
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  4. Julia Hentschel
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  5. Petra Richter
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  6. Mieczyslaw Gajda
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  7. Angela Göhlert
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  8. Ferdinand von Eggeling
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  9. Regine Heller
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  10. Raffaella Giavazzi
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  11. Dario Neri
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  12. Hartwig Kosmehl
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  13. Heiko Wunderlich
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  14. Alexander Berndt
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Corresponding author

Correspondence to Marcus Franz.

Additional information

K. Galler and K. Junker contributed equally to the study.

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Galler, K., Junker, K., Franz, M. et al. Differential vascular expression and regulation of oncofetal tenascin-C and fibronectin variants in renal cell carcinoma (RCC): implications for an individualized angiogenesis-related targeted drug delivery. Histochem Cell Biol 137, 195–204 (2012). https://doi.org/10.1007/s00418-011-0886-z

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  • DOI: https://doi.org/10.1007/s00418-011-0886-z

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