Abstract
ABSTRACTAlthough non-medullary thyroid cancer (NMTC) generally has a good prognosis, 30–40% of patients with distant metastases develop resistance to radioactive iodine (RAI) therapy due to tumor dedifferentiation. For these patients, treatment options are limited and prognosis is poor. In the present study, expression and activity of autophagy was assessed in large sets of normal, benign and malignant tissues and was correlated with pathology, SLC5A5/hNIS (solute carrier family 5 member 5) protein expression, and with clinical response to RAI ablation therapy in NMTC patients. Fluorescent immunostaining for the autophagy marker LC3 was performed on 100 benign and 80 malignant thyroid tissues. Semiquantitative scoring was generated for both diffuse LC3-I intensity and number of LC3-II-positive puncta and was correlated with SLC5A5 protein expression and clinical parameters. Degree of diffuse LC3-I intensity and number of LC3-II-positive puncta scoring were not discriminative for benign vs. malignant thyroid lesions. Interestingly, however, in NMTC patients significant associations were observed between diffuse LC3-I intensity and LC3-II-positive puncta scoring on the one hand and clinical response to RAI therapy on the other hand (odds ratio [OR] = 3.13, 95% confidence interval [CI] =1.91–5.12, P = 0.01; OR = 5.68, 95%CI = 3.02–10.05, P = 0.002, respectively). Mechanistically, the number of LC3-II-positive puncta correlated with membranous SLC5A5 expression (OR = 7.71, 95%CI = 4.15–11.75, P<0.001), number of RAI treatments required to reach remission (P = 0.014), cumulative RAI dose (P = 0.026) and with overall remission and recurrence rates (P = 0.031). In conclusion, autophagy activity strongly correlates with clinical response of NMTC patients to RAI therapy, potentially by its capacity to maintain tumor cell differentiation and to preserve functional iodide uptake.
Highlights
Patients diagnosed with non-medullary thyroid cancer (NMTC) are, in addition to determination of the histological subtype, regularly classified according to the differentiation status of the tumor, ranging from well-differentiated to severely dedifferentiated NMTC.[1,2] The first-line therapeutic regimen consists of thyroidectomy followed by ablation of thyroid remnants by 131I radioactive iodine therapy (RAI)
In order to validate immunofluorescent LC3-II staining for reliable quantification of autophagy activity, electron microscopy images were generated in parallel from fresh material obtained from 2 PTC patients
Additional validations were performed on the non-medullary thyroid cancer cell line TPC-1 that was treated with either vehicle or with 10 mM 3-methyladenine (3-MA, an autophagy inhibitor), which demonstrated corresponding changes in LC3-II-positive puncta and left LC3-I intensity unaffected (Fig. 1B)
Summary
Patients diagnosed with non-medullary thyroid cancer (NMTC) are, in addition to determination of the histological subtype, regularly classified according to the differentiation status of the tumor, ranging from well-differentiated to severely dedifferentiated NMTC.[1,2] The first-line therapeutic regimen consists of thyroidectomy followed by ablation of thyroid (tumor) remnants by 131I radioactive iodine therapy (RAI). Identification of prognostic markers with high predictive value is warranted in order to reliably estimate RAI treatment response and to optimize the therapeutic strategy for the individual patient. Identification of these markers and understanding of the mechanisms involved in the dedifferentiation process could potentially facilitate the development of novel therapeutic approaches to improve the clinical response to RAI therapy
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