ABSTRACT
Differentiated thyroid carcinoma (DTC) accounts for more than 90% of new thyroid cancer diagnoses, and includes papillary, follicular and Hürthle cell carcinoma. The prognosis for the vast majority of individuals diagnosed with DTC is excellent, with current treatment that includes surgery, radioactive iodine ablation and postoperative thyroid-stimulating hormone suppression. Unfortunately, the small proportion of individuals who develop radioactive iodine-resistant recurrent disease have few treatment options, and the vast majority will eventually die from their disease. Recently, several novel targets for anticancer agents have been identified and offer new hope for thyroid cancer patients diagnosed with progressive disease. In addition to targeting genes commonly altered in thyroid cancer, which include mutations in BRAF, RAS and RET, proangiogenic growth factor receptors and the sodium-iodide symporter have also been targeted. Several clinical trials evaluating tyrosine kinase and angiogenesis inhibitors for treatment of individuals diagnosed with metastatic or treatment-refractory DTC are currently underway. The objective of this review is to evaluate recent clinical trials that have studied novel targeted drugs for treatment of DTC.
Subject(s)
Carcinoma , Molecular Targeted Therapy/methods , Neovascularization, Pathologic , Targeted Gene Repair/methods , Thyroid Gland , Thyroid Neoplasms , Angiogenesis Inhibitors/pharmacology , Carcinoma/genetics , Carcinoma/therapy , Cell Dedifferentiation/drug effects , Cell Dedifferentiation/genetics , Clinical Trials, Phase II as Topic , Disease Progression , Disease Resistance , Genes, ras , Humans , Mutation , Neovascularization, Pathologic/drug therapy , Neovascularization, Pathologic/etiology , Neovascularization, Pathologic/genetics , Protein-Tyrosine Kinases/antagonists & inhibitors , Proto-Oncogene Proteins B-raf/genetics , Proto-Oncogene Proteins c-ret/genetics , Therapies, Investigational , Thyroid Gland/blood supply , Thyroid Gland/pathology , Thyroid Neoplasms/complications , Thyroid Neoplasms/genetics , Thyroid Neoplasms/physiopathology , Thyroid Neoplasms/therapyABSTRACT
Tubulobulbar complexes (TBCs) are elaborate cytoskeleton-related structures that are formed in association with intercellular junctions in the seminiferous epithelium. They consist of a cylindrical double-membrane core composed of the plasma membranes of the two attached cells, cuffed by a dendritic network of actin filaments. TBCs are proposed to be subcellular machines that internalize intercellular junctions during the extensive junction remodeling that occurs during spermatogenesis. At the apical sites of attachment between Sertoli cells and spermatids, junction disassembly is part of the sperm release mechanism. In this study, we used immunological probes to explore junction internalization and recycling at apical TBCs in the rat seminiferous epithelium. We demonstrate that ß1-integrin and nectin 2 were concentrated at the ends of TBCs and for the first time show that the early endosome marker RAB5A was also distinctly localized at the ends of TBCs that appear to be the 'bulbar' regions of the complexes. Significantly, we also demonstrate that the 'long-loop' recycling endosome marker RAB11A was co-distributed with nectin 2 at junctions with early spermatids deeper in the epithelium. Our results are consistent with the hypothesis that TBCs associated with late spermatids internalize adhesion junctions and also indicate that some of the internalized junction proteins may be recycled to form junctions with the next generation of spermatids.
