Research Papers:

The role of netrin-1 in metastatic renal cell carcinoma treated with sunitinib

Sebastian Frees, Betty Zhou, Kyung Seok Han, Zheng Tan, Peter Raven, Alexander Wong, Ninadh D’Costa, Ladan Fazli, Werner Struss, Igor Moskalev, Claudia Chavez-Munoz and Alan So _

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Oncotarget. 2018; 9:22631-22641. https://doi.org/10.18632/oncotarget.25201

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Sebastian Frees1,2,*, Betty Zhou1,*, Kyung Seok Han1, Zheng Tan1, Peter Raven1, Alexander Wong1, Ninadh D’Costa1, Ladan Fazli1, Werner Struss1, Igor Moskalev1, Claudia Chavez-Munoz1 and Alan So1

1Department of Urologic Sciences, Vancouver Prostate Centre, University of British Columbia, Vancouver, Canada

2Department of Urology, University Medical Centre Mainz, Mainz, Germany

*These authors have contributed equally to this work

Correspondence to:

Alan So, email: [email protected]

Keywords: renal cell carcinoma; sunitinib; resistance; netrin-1; tyrosine kinase inhibitor

Received: June 20, 2017    Accepted: March 17, 2018    Published: April 27, 2018


Introduction: Clear-cell renal cell carcinoma (ccRCC) is the sixth most common malignancy in men in North America. Since ccRCC is a malignancy dependent on neovascularization, current first line systemic therapies like sunitinib, target the formation of new vessels allowing nutrient deprivation and cell death. However, recent studies have shown that patients develop resistance after approximately 1 year of treatment and show disease progression while on therapy. Therefore, we propose to identify the protein(s) responsible for increased migration with the aim of developing a new therapy that will target the identified protein and potentially slow down the progression of the disease.

Material and Methods: Human renal cancer cell lines (Caki-1, Caki-2, ACHN) were treated with increasing doses of sunitinib to develop a sunitinib-conditioned renal cell carcinoma cell line. mRNA microarray and qPCR were performed to compare the differences in gene expression between Caki-1 sunitinib-conditioned and non-conditioned cells. NTN1 was assessed in our in vivo sunitinib-conditioned mouse model using immunostaining. xCELLigence and scratch assays were used to evaluate migration and MTS was used to evaluate cell viability.

Results: Human renal cell carcinoma sunitinib-conditioned cell lines showed upregulation of netrin-1 in microarray and q-PCR. Increased migration was demonstrated in Caki-1 sunitinib-conditioned cells when compared to the non-treated ones as well as, increased endothelial cell migration. Silencing of netrin-1 in sunitinib-conditioned Caki-1 cells did not demonstrate a significant reduction in cell migration.

Conclusion: Netrin-1 is highly upregulated in renal cell carcinoma treated with sunitinib, but has no influence on cell viability or cell migration in metastatic RCC.

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