Hypoxia-inducible factor signaling in pheochromocytoma: turning the rudder in the right direction.
Many solid tumors, including pheochromocytoma (PHEO) and paraganglioma (PGL), are characterized by a (pseudo)hypoxic signature. (Pseudo)hypoxia has been shown to promote both tumor progression and resistance to therapy. The major mediators of the transcriptional hypoxic response are hypoxia-inducible factors (HIFs). High levels of HIFs lead to transcription of hypoxia-responsive genes, which are involved in tumorigenesis. PHEOs and PGLs are catecholamine-producing tumors arising from sympathetic- or parasympathetic-derived chromaffin tissue. In recent years, substantial progress has been made in understanding the metabolic disturbances present in PHEO and PGL, especially because of the identification of some disease-susceptibility genes. To date, fifteen PHEO and PGL susceptibility genes have been identified. Based on the main transcription signatures of the mutated genes, PHEOs and PGLs have been divided into two clusters, pseudohypoxic cluster 1 and cluster 2, rich in kinase receptor signaling and protein translation pathways. Although these two clusters seem to show distinct signaling pathways, recent data suggest that both clusters are interconnected by HIF signaling as the important driver in their tumorigenesis, and mutations in most PHEO and PGL susceptibility genes seem to affect HIF-α regulation and its downstream signaling pathways. HIF signaling appears to play an important role in the development and growth of PHEOs and PGLs, which could suggest new therapeutic approaches for the treatment of these tumors.
Program in Reproductive and Adult Endocrinology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892-1109, USA.
Ivana
I
Jochmanová
Chunzhang
C
Yang
Zhengping
Z
Zhuang
Karel
K
Pacak
D000310:Adrenal Gland Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism; D015687:Cell Hypoxia; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051793:Hypoxia-Inducible Factor 1 / Q000235:genetics* / Q000378:metabolism*; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism; D018813:Multiple Endocrine Neoplasia Type 2a / Q000378:metabolism / Q000473:pathology; D009154:Mutation; D009456:Neurofibromatosis 1 / Q000378:metabolism / Q000473:pathology; D010235:Paraganglioma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D010673:Pheochromocytoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D015398:Signal Transduction; D015854:Up-Regulation; D006623:von Hippel-Lindau Disease / Q000378:metabolism / Q000473:pathology; D000099162:Endothelial PAS Domain-Containing Protein 1
D051792:Basic Helix-Loop-Helix Proteins; D051793:Hypoxia-Inducible Factor 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D000099162:Endothelial PAS Domain-Containing Protein 1; C497442:HIF1A protein, human