title: Molecular and cellular biology of pheochromocytomas and extra-adrenal paragangliomas.
abstract: Efforts to understand the pathobiology of pheochromocytomas and extra-adrenal paragangliomas have been spurred by genetic and gene expression profiling studies showing genotype-phenotype correlations in familial pheochromocytoma/paraganglioma syndromes and in some sporadic tumors. The current challenge is to relate catalogs of genetic and phenotypic markers to cell biology. Hypothetical bases for genotype-phenotype correlations include: cell of origin, pathway dependence, and functional and anatomic context. A further consideration is phenotype plasticity. Cross talk between signaling pathways provides a general framework for understanding how mutations of apparently unrelated genes might lead to the same type of tumor, and also suggests that targeted therapies might be directed either at a specific mutated gene or a downstream signal transducer. However, precise mechanisms of tumorigenesis remain unknown. An intriguing hypothesis proposes that mutations of RET, NF1, VHL, or SDH predispose to hereditary pheochromocytoma/ paraganglioma by causing defective apoptotic culling of cells that would normally be destroyed during embryogenesis. An argument favoring survival rather than mitogenesis as a common denominator is that the same mutations are rare in sporadic pheochromocytomas/paragangliomas, suggesting they only need to act during a limited developmental window. An implication is that tumor precursors could be identified and eradicated in individuals who carry the mutations.
authors.affiliation: Department of Pathology, Tufts New England Medical Center, Boston, MA 02111, USA. atischler@tufts-nemc.org
authors.forename: Arthur S
authors.initials: AS
authors.lastname: Tischler
mesh_terms: D000310:Adrenal Gland Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D014408:Biomarkers, Tumor / Q000235:genetics; D020869:Gene Expression Profiling; D005819:Genetic Markers / Q000235:genetics; D020022:Genetic Predisposition to Disease; D006801:Humans; D009154:Mutation; D009363:Neoplasm Proteins / Q000235:genetics; D010236:Paraganglioma, Extra-Adrenal / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D010673:Pheochromocytoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology
chemical_list: D014408:Biomarkers, Tumor; D005819:Genetic Markers; D009363:Neoplasm Proteins