Gene expression profile of renal cell carcinomas after neoadjuvant treatment with sunitinib: new pathways revealed.
BACKGROUND
In renal cell carcinoma (RCC) of the clear cell type, inactivity of the VHL gene induces overexpression of HIF1 α and its targets, the tyrosine kinase receptors, promoting RCC development and progression. The discovery of tyrosine kinase inhibitors (TKIs) changed the treatment of these tumors. Other molecular pathways involved in the TKI mechanisms of action have not been described in the literature. The aim of our study was to elucidate alternative mechanisms of action of sunitinib in tumor tissue after neoadjuvant treatment of RCC.


METHODS
The gene expression profile was accessed using microarray (Affymetrix Human Genome U133 Plus 2.0 platform) and frozen RCC tissues collected from 5 patients with locally advanced non-metastatic tumors who underwent nephrectomy after being treated with 2 cycles of neoadjuvant sunitinib. The results were compared with matched controls comprising 6 patients with no neoadjuvant intervention.


RESULTS
There was underexpression of the majority of genes after sunitinib treatment. The lower expression levels of IGFBP1, CCL20, CXCL6 and FGB were confirmed by qRT-PCR in all cases. The downregulation of gene expression leads us to search for methylation as a mechanism of action of the TKI. IGFBP1 was shown to be methylated by methylation-sensitive high-resolution melting technique.


CONCLUSIONS
The ultimate genetic effects of sunitinib may explain its actions as an antitumor drug that apparently suppresses the expression of important genes related to cell survival, adhesion, invasion and immunomodulation. The methylation of gene promoters was shown to be part of the mechanism of action of this class of drugs.
ICESP - Sao Paulo Cancer Institute, Sao Paulo - Brazil.
Carlos
C
Dzik
Laboratory of Medical Research, Urology Department - LIM55, University of Sao Paulo Medical School, Sao Paulo - Brazil.
Sabrina T
ST
Reis
Laboratory of Medical Research, Urology Department - LIM55, University of Sao Paulo Medical School, Sao Paulo - Brazil.
Nayara I
NI
Viana
ICESP - Sao Paulo Cancer Institute, Sao Paulo - Brazil.
Glauber
G
Brito
Laboratory of Medical Research, Urology Department - LIM55, University of Sao Paulo Medical School, Sao Paulo - Brazil.
Isis
I
Paloppi
ICESP - Sao Paulo Cancer Institute, Sao Paulo - Brazil.
Willian
W
Nahas
Laboratory of Medical Research, Urology Department - LIM55, University of Sao Paulo Medical School, Sao Paulo - Brazil.
Miguel
M
Srougi
Laboratory of Medical Research, Urology Department - LIM55, University of Sao Paulo Medical School, Sao Paulo - Brazil.
Katia R M
KRM
Leite
D000328:Adult; D000368:Aged; D002292:Carcinoma, Renal Cell / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D054418:Chemokine CCL20 / Q000235:genetics*; D054427:Chemokine CXCL6 / Q000235:genetics*; D019175:DNA Methylation / Q000187:drug effects; D005260:Female; D005340:Fibrinogen / Q000235:genetics*; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D007211:Indoles / Q000008:administration & dosage*; D018970:Insulin-Like Growth Factor Binding Protein 1 / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D020360:Neoadjuvant Therapy / Q000009:adverse effects; D011758:Pyrroles / Q000008:administration & dosage*; D015398:Signal Transduction / Q000187:drug effects; D000077210:Sunitinib; D059467:Transcriptome / Q000187:drug effects
C108355:CCL20 protein, human; C515503:CXCL6 protein, human; D054418:Chemokine CCL20; D054427:Chemokine CXCL6; C000592498:FGB protein, human; C032231:IGFBP1 protein, human; D007211:Indoles; D018970:Insulin-Like Growth Factor Binding Protein 1; D011758:Pyrroles; D005340:Fibrinogen; D000077210:Sunitinib