Epithelial to mesenchymal transition is activated in metastatic pheochromocytomas and paragangliomas caused by SDHB gene mutations.

Abstract

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: Céline Loriot, Nelly Burnichon, Noémie Gadessaud, Laure Vescovo, Laurence Amar, Rossella Libé, Jérôme Bertherat, Pierre-François Plouin, Xavier Jeunemaitre, Anne-Paule Gimenez-Roqueplo, Judith Favier
• Journal: The Journal of clinical endocrinology and metabolism (J Clin Endocrinol Metab) Vol. 97 Issue 6 Pg. E954-62 (Jun 2012) ISSN: 1945-7197 [Electronic] United States
• PMID: 22492777 (Publication Type: Journal Article)

Chemical References

• Basic Helix-Loop-Helix Transcription Factors
• Nuclear Proteins
• SNAI1 protein, human
• Snail Family Transcription Factors
• TCF3 protein, human
• TWIST1 protein, human
• Transcription Factors
• Twist-Related Protein 1
• SDHB protein, human
• Succinate Dehydrogenase
• Amino Acid Oxidoreductases
• LOXL2 protein, human

Topics

• Adrenal Gland Neoplasms (epidemiology, genetics, pathology)
• Amino Acid Oxidoreductases (genetics, metabolism)
• Basic Helix-Loop-Helix Transcription Factors (genetics, metabolism)
• Cell Communication (physiology)
• Epithelial-Mesenchymal Transition (genetics)
• Gene Expression Regulation, Neoplastic
• Genetic Predisposition to Disease (epidemiology, genetics)
• Humans
• Hypoxia (epidemiology, genetics, pathology)
• Intercellular Junctions (physiology)
• Mutation (genetics)
• Nuclear Proteins (genetics, metabolism)
• Paraganglioma (epidemiology, genetics, pathology)
• Pheochromocytoma (epidemiology, genetics, secondary)
• Prognosis
• Risk Factors
• Signal Transduction (physiology)
• Snail Family Transcription Factors
• Succinate Dehydrogenase (genetics, metabolism)
• Transcription Factors (genetics, metabolism)
• Transcriptome
• Twist-Related Protein 1 (genetics, metabolism)