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Gas6-Axl signaling in presence of Sunitinib is enhanced, diversified and sustained in renal tumor cells, resulting in tumor-progressive advantages

  • Anna Gustafsson
  • Helena K M Fritz
  • Björn Dahlbäck
Publishing year: 2017-03-19
Language: English
Pages: 47-56
Publication/Series: Experimental Cell Research
Volume: 355
Issue: 1
Document type: Journal article
Publisher: Academic Press

Abstract english

Clear Cell Renal Cell Carcinoma (CCRCC) is a lethal cancer with bad prognosis due to development of chemoresistance and recurrence of more aggressive tumors. Investigation of Gas6-mediated Axl signaling in CCRCC and endothelial cells reveals a Sunitinib resistant Gas6-Axl signaling that is sustained and enhanced and specifically triggers downstream AKT and PRAS40 activation in an intensified manner. Gas6-induced Axl signaling in presence of Sunitinib is also diversified displaying onset of Axl-dependent EGFR and METR activation and activation of classical MAPK pathways. Gas6+Sunitinib-adapted CCRCC cells present increased viability and decreased apoptosis and enhanced production of the multi-tumorigenic Osteopontin (OPN) and of one of its activator matrix metalloproteinase-7. Axl activity is necessary for CCRCC cell sphere formation and the ability of the cells to attach after non-adhesive growth. In addition, Gas6+Sunitinib-adapted CCRCC cells displayed enhanced migration and sphere formation, both mechanisms being Axl and OPN dependent. Altogether, this suggests that Sunitinib while targeting endothelial cells and tumor angiogenesis, simultaneously provides protumorigenic effects due to a constitutively, intensified and divergent Gas6-Axl system. Implications: Gas6-mediated Axl signaling, which is enhanced and diversified in the presence of Sunitinib possibly contributes to acquired chemoresistance, recurrence of aggressive disease and metastasis of CCRCC tumors. Therefore, combinatorial Axl-targeted therapy might be beneficial for CCRCC patients intended for Sunitinib treatment.


  • Cell and Molecular Biology
  • Cancer and Oncology
  • Drug resistance
  • Novel mechanism
  • Receptor tyrosine kinases
  • Renal cancer
  • Tumor progression
  • Tumor promotion


  • Clinical Chemistry, Malmö
  • ISSN: 0014-4827
Helena Fritz
E-mail: helena [dot] fritz [at] med [dot] lu [dot] se

Research engineer

RNA and Stem Cell Biology

+46 46 222 00 00

BMC B1225b

BMC B12, Sölvegatan 19, Lund


Research engineer

Division of Molecular Hematology (DMH)

BMC B1225b

BMC B12, Sölvegatan 19, Lund



Functional zoology

+46 46 222 31 68

+46 72 233 74 00


Sölvegatan 35, Lund


Research group

Animal physiology