Molecular pathways associated with aggressiveness of papillary thyroid cancer

Abstract

The most common thyroid malignancy is papillary thyroid cancer (PTC). Mortality rates from PTC mainly depend on its aggressiveness. Geno- and phenotyping of aggressive PTC has advanced our understanding of treatment failures and of potential future therapies. Unraveling molecular signaling pathways of PTC including its aggressive forms will hopefully pave the road to reduce mortality but also morbidity from this cancer. The mitogen-activated protein kinase and the phosphatidylinositol 3-kinase signaling pathway as well as the family of RAS oncogenes and BRAF as a member of the RAF protein family and the aberrant expression of microRNAs miR-221, miR-222, and miR-146b all play major roles in tumor initiation and progression of aggressive PTC. Small molecule tyrosine kinase inhibitors targeting BRAF-mediated events, vascular endothelial growth factor receptors, RET/PTC rearrangements, and other molecular targets, show promising results to improve treatment of radioiodine resistant, recurrent, and aggressive PTC.

Keywords: BRAF; P13/Akt; Papillary thyroid cancer; Signaling; Tyrosine kinase; VEGF..

Fig. (1)

Molecular mechanisms of oncogenesis for non-medullary thyroid cancers (adapted with permission from Springer publisher). Koch CA, Sarlis NJ. Thyroid cancer. In: Encyclopedic Reference “Molecular Mechanisms of Disease”-Endocrinology and Diabetes section (Textbook). Editor-in-Chief: F. Lang, Section Editors: S.R. Bornstein and D. LeRoith. Springer Publisher GmbH Berlin, Germany (online and in print; 2009, Tome:LXXXVI; doi: 10.1007/978-3-540-29676-8_1743; web address: http://www.springerlink.com/content/g7t66546 38x483g8/fulltext.html (ref. 36 in this manuscript) Abbreviations: AC: adenyl cyclase, APC: adenomatous polyposis coli gene, cAMP: cyclic AMP, Cdk: cyclin-dependent kinase, DAG: diacylglycerol, 5’-DI: 5’-deiodinase, EGF: epidermal growth factor, ICAM: intercellular adhesion molecules, IGF-1: insulin-like growth factor-1, IP3: inositol triphosphate, MAPK: mitogen-activated protein kinase, MAPKK: MAPK kinase, NIS: sodium/iodide symporter, PDGF: platelet-derived growth factor, PI3: phosphatidylinositol-3-phosphokinase, PKA: protein kinase A, PKC: protein kinase C, PLC: phospholipase C, PTEN: phosphatase-tensin gene product, RB: retinoblastoma-gene protein, T3: triiodothyronine, T4: thyroxine, Tg: thyroglobulin, TSH: thyroid stimulating hormone, TSHR: TSH receptor, TPO: thyroid peroxidase, TTF: thyroid specific transcription factor.