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Cancer Res. 2017 Mar 1;77(5):1212-1226. doi: 10.1158/0008-5472.CAN-16-3088. Epub 2017 Jan 13.

Sunitinib Stimulates Expression of VEGFC by Tumor Cells and Promotes Lymphangiogenesis in Clear Cell Renal Cell Carcinomas.

Author information

1
University of Nice Sophia Antipolis, Institute for Research on Cancer and Aging of Nice, CNRS UMR 7284, INSERM U1081, Centre Antoine Lacassagne, Nice, France.
2
Biomedical Department, Centre Scientifique de Monaco, Monaco, Principality of Monaco.
3
Central Laboratory of Pathology, Centre Hospitalier Universitaire (CHU) de Nice, Hôpital Pasteur, Nice, France.
4
Radiotherapy Department, Centre Antoine Lacassagne, Nice, France.
5
Center for Genetics and Pharmacology, Roswell Park Cancer Institute, Buffalo, New York.
6
King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia.
7
University of Bordeaux, INSERM U1029, Bordeaux, France.
8
Statistics Department, Centre Antoine Lacassagne, Nice, France.
9
Service d'Urologie, Centre Hospitalier Universitaire (CHU) de Bordeaux, Bordeaux, France.
10
Service d'Oncologie Médicale, Centre Hospitalier Universitaire (CHU) de Bordeaux, Bordeaux, France.
11
Oncology Department, Centre Antoine Lacassagne, Nice, France.
12
University of Nice Sophia Antipolis, Institute for Research on Cancer and Aging of Nice, CNRS UMR 7284, INSERM U1081, Centre Antoine Lacassagne, Nice, France. gpages@unice.fr.

Abstract

Sunitinib is an antiangiogenic therapy given as a first-line treatment for renal cell carcinoma (RCC). While treatment improves progression-free survival, most patients relapse. We hypothesized that patient relapse can stem from the development of a lymphatic network driven by the production of the main growth factor for lymphatic endothelial cells, VEGFC. In this study, we found that sunitinib can stimulate vegfc gene transcription and increase VEGFC mRNA half-life. In addition, sunitinib activated p38 MAPK, which resulted in the upregulation/activity of HuR and inactivation of tristetraprolin, two AU-rich element-binding proteins. Sunitinib stimulated a VEGFC-dependent development of lymphatic vessels in experimental tumors. This may explain our findings of increased lymph node invasion and new metastatic sites in 30% of sunitinib-treated patients and increased lymphatic vessels found in 70% of neoadjuvant treated patients. In summary, a therapy dedicated to destroying tumor blood vessels induced the development of lymphatic vessels, which may have contributed to the treatment failure. Cancer Res; 77(5); 1212-26. ©2017 AACR.

PMID:
28087600
DOI:
10.1158/0008-5472.CAN-16-3088
[Indexed for MEDLINE]
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