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Abstract
Oncocytic cell tumors are characterized by the accumulation of morphologically abnormal mitochondria in their cells, suggesting a role for abnormal mitochondrial biogenesis in oncocytic cell transformation. Little is known about the reason for the dysmorphology of accumulated mitochondria. The proteins regulating the morphology of mitochondria, the "mitochondria-shaping" proteins, can modulate their size and number; however, nothing is known hitherto about a possible involvement of mitochondrial dynamics in oncocytic cell transformation in tumors. Our aim was to assess the status of the mitochondria morphology and its role in oncocytic cell transformation. We therefore evaluated the expression pattern of the main mitochondrial fusion and fission proteins in a series of thyroid cell tumor samples, as well as in thyroid tumor cell lines, with and without oncocytic cell features. The expression of mitochondrial fusion (Opa1, Mfn1 and Mfn2) and fission (Drp1 and Fis1) proteins were evaluated by immunohistochemistry (IHC) in a series of 88 human thyroid tumors. In vitro studies, for comparative purposes and to deepen the study, were performed using TPC1 - a papillary thyroid carcinoma derived cell line—and XTC.UC1, an oncocytic follicular thyroid carcinoma-derived cell line. Both IHC and in vitro protein analyses showed an overall increase in the levels of "mitochondrial-shaping" proteins in oncocytic thyroid tumors. Furthermore, overexpression of the pro-fission protein Drp1 was found to be associated with malignant oncocytic thyroid tumors. Interestingly, genetic and pharmacological blockage of Drp1 activity was able to influence thyroid cancer cells’ migration/invasion ability, a feature of tumor malignancy. In this study we show that unbalanced mitochondrial dynamics characterize the malignant features of thyroid oncocytic cell tumors, and participate in the acquisition of the migrating phenotype.
Highlights
Cancer cells are known to undergo a shift in their basal metabolic pathways, a process often described as the “Warburg effect”, whereby even under high oxygen tension they produce most of their ATP by glycolysis[1]
Mfn2, optic atrophy 1 (Opa1), dynamin related protein 1 (Drp1) and fission 1 (Fis1), are overexpressed in oncocytic cell tumors and Drp1 overexpression is associated with malignant oncocytic cell tumors
Once the oncocytic cell tumors differ from the non-ococytic ones by an abnormal accumulation of mitochondria with an altered morphology in the cell cytoplasm, we hypothesized that mitochondrial dynamics might have a role in the phenotypic and physiological oncocytic definition [11,12,13]
Summary
Cancer cells are known to undergo a shift in their basal metabolic pathways, a process often described as the “Warburg effect”, whereby even under high oxygen tension they produce most of their ATP by glycolysis[1]. Electron microscopy has shown that this swollen appearance is due to an anomalous accumulation of mitochondria displaying abnormal morphology[11,12,13] These tumors are described as oncocytic-, oxyphilic-, eosinophilic, “Hürthle-cell (when referring to the thyroid) tumors” or as “oncocytomas”. The criteria for diagnosis of the oncocytic cell variants of papillary thyroid carcinoma (PTC) and follicular thyroid carcinoma (FTC) include nuclear characteristics, signs of capsular and/or vascular invasion which are shared with the non-oncocytic cell tumors of the same kind, as well as the mitochondrial proliferation typical for oncocytic cell tumors[5,6,7]. The first recommendations considered all oncocytic thyroid tumors malignant, later studies have demonstrated that as long as the cases were correctly stratified according to their clinico-pathological features-such as patients’ age, staging of the tumors and surgical procedure- the prognosis of patients with oncocytic cell PTC and FTC variants is similar to that of patients with respective conventional, non-oncocytic carcinomas [3,5,17,19]
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