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NDT Advance Access published online on October 13, 2009
Nephrology Dialysis Transplantation, doi:10.1093/ndt/gfp525
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© The Author 2009. Published by Oxford University Press [on behalf of ERA-EDTA]. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org


An in-vitro tumour microenvironment model using adhesion to type I collagen reveals Akt-dependent radiation resistance in renal cancer cells

Lina Krasny1, Nilly Shimony1, Keren Tzukert1, Raphael Gorodetsky2, Shimon Lecht3, Dirk M. Nettelbeck4 and Yosef S. Haviv1

1 Department of Medicine 2 Department of Oncology 3 School of Pharmacy, Hadassah-Hebrew University Medical Center, Jerusalem, Israel 4 Oncolytic Virus Group, DKFZ, Heidelberg, Germany

Correspondence and offprint requests to: Yosef S. Haviv; E-mail: yhaviv{at}hadassah.org.il



  Abstract

Background. Renal cell carcinoma (RCC) is considered resistant to ionizing radiation. Recently, the extracellular matrix (ECM) has been shown to play a role in both drug resistance and radiation resistance (RR). While fibronectin has been extensively investigated in the context of RR, the role of type I collagen [col(I)], a principal constituent of the ECM in tumour metastases, in RR of RCC is unknown.

Methods. RCC cell adhesion to matrix was studied via pre-coating a variety of ECM glycoproteins onto plates. Cancer cell apoptosis and cell cycle were evaluated with flow cytometry using annexin V and propidium iodide stains, respectively. Activation of cellular survival signalling was analysed with western blots, and specific molecular inhibitors were correspondingly employed to block signalling. Hypoxia (<1%) was induced via N2/CO2 gas flow in a specialized chamber.

Results. While adherence to col(I) enhanced RCC cell proliferation in general, col(I) and fibronectin, but not fibrinogen, could confer specific anti-apoptotic RR to RCC cells. The radioprotective effect of col(I) was maintained during both hypoxia/reoxygenation and normoxia conditions. In contrast to intact col(I), micronized col(I), lacking the natural fibrillar structure, was not radioprotective. The effect of col(I) in RCC cells is mediated via attenuation of apoptosis rather than cell cycle redistribution, involving the PI3 kinase/Akt pathway but not the MAP kinase pathway.

Conclusions. Adherence to col(I) appears to be a relevant environmental cue enhancing RR in RCC cells, Akt dependently. Our results support inhibition of the PI3-kinase/Akt pathway as a radiosensitizing approach.

Keywords: Akt; collagen type I; hypoxia; ionizing radiation; renal cell carcinoma

Received for publication: 29.12.08
Accepted in revised form: 11. 9.09


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