CONTEXT: Pheochromocytoma and paraganglioma are rare neural-crest-derived tumors. They are metastatic in 15% of cases, and the identification of a germline mutation in the SDHB gene is a predictive risk factor for malignancy and poor prognosis. To date, the link between SDHB mutations and malignancy is still missing. OBJECTIVE: Epithelial to mesenchymal transition (EMT) is a developmental event, reactivated in cancer cells to promote cell mobility and invasiveness. The aim of this study was to address the participation of EMT in the metastatic evolution of pheochromocytoma/paraganglioma. DESIGN AND PATIENTS: Transcriptomic profiling of EMT was performed on 188 tumor samples, using a set of 94 genes implicated in this pathway. Activation of EMT was further confirmed at protein level by immunohistochemistry in a second set of 93 tumors. RESULTS: Hierarchical unsupervised classification showed that most SDHB-metastatic samples clustered together, indicating that EMT is differently regulated in these tumors. Major actors of EMT, metalloproteases and components of cellular junctions, were either up-regulated (LOXL2, TWIST, TCF3, MMP2, and MMP1) or down-regulated (KRT19 and CDH2) in SDHB-metastatic tumors compared with nonmetastatic ones. Interestingly, within metastatic tumors, most of these genes (LOXL2, TWIST, TCF3, MMP2, and KRT19) also allowed us to discriminate SDHB-mutated from non-SDHB-related tumors. In the second set of tumors, we studied Snail1/2 expression by immunohistochemistry and observed its specific nuclear translocation in all SDHB-metastatic tumors. CONCLUSION: We have identified the first pathway that distinguishes SDHB-metastatic from all other types of pheochromocytomas/paragangliomas and suggest that activation of the EMT process might play a critical role in the particularly invasive phenotype of this group of tumors.
CONTEXT: Pheochromocytoma and paraganglioma are rare neural-crest-derived tumors. They are metastatic in 15% of cases, and the identification of a germline mutation in the SDHB gene is a predictive risk factor for malignancy and poor prognosis. To date, the link between SDHB mutations and malignancy is still missing. OBJECTIVE: Epithelial to mesenchymal transition (EMT) is a developmental event, reactivated in cancer cells to promote cell mobility and invasiveness. The aim of this study was to address the participation of EMT in the metastatic evolution of pheochromocytoma/paraganglioma. DESIGN AND PATIENTS: Transcriptomic profiling of EMT was performed on 188 tumor samples, using a set of 94 genes implicated in this pathway. Activation of EMT was further confirmed at protein level by immunohistochemistry in a second set of 93 tumors. RESULTS: Hierarchical unsupervised classification showed that most SDHB-metastatic samples clustered together, indicating that EMT is differently regulated in these tumors. Major actors of EMT, metalloproteases and components of cellular junctions, were either up-regulated (LOXL2, TWIST, TCF3, MMP2, and MMP1) or down-regulated (KRT19 and CDH2) in SDHB-metastatic tumors compared with nonmetastatic ones. Interestingly, within metastatic tumors, most of these genes (LOXL2, TWIST, TCF3, MMP2, and KRT19) also allowed us to discriminate SDHB-mutated from non-SDHB-related tumors. In the second set of tumors, we studied Snail1/2 expression by immunohistochemistry and observed its specific nuclear translocation in all SDHB-metastatic tumors. CONCLUSION: We have identified the first pathway that distinguishes SDHB-metastatic from all other types of pheochromocytomas/paragangliomas and suggest that activation of the EMT process might play a critical role in the particularly invasive phenotype of this group of tumors.
Authors: David Taïeb; Alexandre Kaliski; Carsten C Boedeker; Victoria Martucci; Tito Fojo; John R Adler; Karel Pacak Journal: Endocr Rev Date: 2014-07-17 Impact factor: 19.871
Authors: Lyndsay V Rhodes; Chandra R Tate; H Chris Segar; Hope E Burks; Theresa B Phamduy; Van Hoang; Steven Elliott; Diari Gilliam; F Nell Pounder; Muralidharan Anbalagan; Douglas B Chrisey; Brian G Rowan; Matthew E Burow; Bridgette M Collins-Burow Journal: Breast Cancer Res Treat Date: 2014-05-09 Impact factor: 4.872
Authors: Uma Shankavaram; Stephanie M J Fliedner; Abdel G Elkahloun; Jenifer J Barb; Peter J Munson; Thanh T Huynh; Joey C Matro; Hana Turkova; W Marston Linehan; Henri J Timmers; Arthur S Tischler; James F Powers; Ronald de Krijger; Bora E Baysal; Martina Takacova; Silvia Pastorekova; David Gius; Hendrik Lehnert; Kevin Camphausen; Karel Pacak Journal: Neoplasia Date: 2013-04 Impact factor: 5.715
Authors: Hana Turkova; Tamara Prodanov; Marek Maly; Victoria Martucci; Karen Adams; Jiri Widimsky; Clara C Chen; Alexander Ling; Electron Kebebew; Constantine A Stratakis; Tito Fojo; Karel Pacak Journal: Endocr Pract Date: 2015-11-02 Impact factor: 3.443