Well-differentiated thyroid carcinoma has a favorable prognosis with a 5-year survival rate of over 95%.However,the undifferentiated or anaplastic type accounting for<0.2%,usually in elderly individuals,exhibits a ...Well-differentiated thyroid carcinoma has a favorable prognosis with a 5-year survival rate of over 95%.However,the undifferentiated or anaplastic type accounting for<0.2%,usually in elderly individuals,exhibits a dismal prognosis with rapid growth and disappointing outcomes.It is the most aggressive form of thyroid carcinoma,with a median survival of 5 mo and poor quality of life(airway obstruction,dysphagia,hoarseness,persistent pain).Early diagnosis and staging are crucial.Diagnostic tools include biopsy(fine needle aspiration,core needle,open surgery),high-resolution ultrasound,computed tomography,magnetic resonance imaging,[(18)F]fluoro-D-glucose positron emission tomography/computed tomography,liquid biopsy and microRNAs.The BRAF gene(BRAF-V600E and BRAF wild type)is the most often found molecular factor.Others include the genes RET,KRAS,HRAS,and NRAS.Recent management policy is based on surgery,even debulking,chemotherapy(cisplatin or doxorubicin),radiotherapy(adjuvant or definitive),targeted biological agents and immunotherapy.The last two options constitute novel hopeful management modalities improving the overall survival in these otherwise condemned patients.Anti-programmed death-ligand 1 antibody immunotherapy,stem cell targeted therapies,nanotechnology achievements and artificial intelligence implementation provide novel promising alternatives.Genetic mutations determine molecular pathways,thus indicating novel treatment strategies such as anti-BRAF,anti-vascular endothelial growth factor-A,and anti-epidermal growth factor receptor.Treatment with the combination of the BRAF inhibitor dabrafenib and the MEK inhibitor trametinib has been approved by the Food and Drug Administration in cases with BRAF-V600E gene mutations and is currently the standard care.This neoadjuvant treatment followed by surgery ensures a twoyear overall survival of 80%.Prognostic factors for improved outcomes have been found to be younger age,earlier tumor stage and radiation therapy.A multidisciplinary approach is necessary,and the therapeutic plan should be individu alized based on surveillance and epidemiology end results.展开更多
BACKGROUND Anaplastic thyroid cancer(ATC)is a rare but aggressive type of thyroid carcinoma.BRAF V600E-mutation,which is found in 10%-50%of ATCs,is associated with poor prognosis.A recent clinical trial reported a sub...BACKGROUND Anaplastic thyroid cancer(ATC)is a rare but aggressive type of thyroid carcinoma.BRAF V600E-mutation,which is found in 10%-50%of ATCs,is associated with poor prognosis.A recent clinical trial reported a substantial clinical benefit of concomitant treatment of dabrafenib(BRAF inhibitor)and trametinib(MEK inhibitor)for treating BRAF V600E-mutant ATC.However,reports on patients with ATC treated with this regimen following surgery are lacking.CASE SUMMARY We report the case of a 63-year-old female patient diagnosed with BRAF V600Emutant ATC.Following three surgeries—total thyroidectomy,total laryngectomy,and neck dissection—she was diagnosed with lung metastasis during follow-up.The metastatic ATC was successfully treated with dabrafenib and trametinib.The patient achieved a complete response at the 32-mo follow-up.CONCLUSION Adjuvant chemotherapy with dabrafenib plus trametinib is efficacious for treatment and prevention of recurrent ATC with BRAF mutation following surgery.展开更多
BACKGROUND Anaplastic thyroid carcinoma(ATC),also called undifferentiated thyroid cancer,is the least common but most aggressive and deadly thyroid gland malignancy of all thyroid cancers[1].It has poor prognosis,and ...BACKGROUND Anaplastic thyroid carcinoma(ATC),also called undifferentiated thyroid cancer,is the least common but most aggressive and deadly thyroid gland malignancy of all thyroid cancers[1].It has poor prognosis,and is the leading cause of death from malignant thyroid tumors.The one-year survival rate is 20%,with a median overall survival(OS)of only 5 mo[2].The aim of this report is to provide our experience in the diagnosis and treatment of ATC.CASE SUMMARY A patient with a thyroid mass underwent surgical treatment after developing symptoms of hoarseness.The resected tumor was pathologically diagnosed as ATC.Imaging examination revealed organ and lymph node metastasis.After multiple cycles of chemotherapy and local radiotherapy,the metastases were not relieved and gradually increased in size and new metastases appeared.The patient immediately received immunotherapy combined with targeted therapy.During treatment,immune-related adverse reactions occurred,which were improved after symptomatic treatment,and tolerated by the patient.The OS of the patient was more than 30 mo after immunotherapy combined with targeted therapy.CONCLUSION For metastatic ATC,surgical treatment,radiotherapy and chemotherapy have no significant effect on remission of the disease.However,immunotherapy has made a breakthrough in the treatment of ATC。展开更多
Anaplastic thyroid carcinoma(ATC)is a rare but extremely lethal malignancy.However,little is known about the pathogenesis of ATC.Given its high mortality,it is critical to improve our understanding of ATC pathogenesis...Anaplastic thyroid carcinoma(ATC)is a rare but extremely lethal malignancy.However,little is known about the pathogenesis of ATC.Given its high mortality,it is critical to improve our understanding of ATC pathogenesis and to find new diagnostic biomarkers.In the present study,two gene microarray profiles(GSE53072 and GSE65144),which included 17 ATC and 17 adjacent non-tumorous tissues,were obtained.Bioinformatic analyses were then performed.Immunohistochemistry(IHC)and receiver operating characteristic(ROC)curves were then used to detect transmembrane protein 158(TMEM158)expression and to assess diagnostic sensitivity.A total of 372 differentially expressed genes(DEGs)were identified.Through protein-protein interaction(PPI)analysis,we identified a significant module with 37 upregulated genes.Most of the genes in this module were related to cell-cycle processes.After co-expression analysis,132 hub genes were selected for further study.Nine genes were identified as both DEGs and genes of interest in the weighted gene co-expression network analysis(WGCNA).IHC and ROC curves confirmed that TMEM158 was overexpressed in ATC tissue as compared with other types of thyroid cancer and normal tissue samples.We identified 8 KEGG pathways that were associated with high expression of TMEM158,including aminoacyl-tRNA biosynthesis and DNA replication.Our results suggest that TMEM158 may be a potential oncogene and serve as a diagnostic indicator for ATC.展开更多
Anaplastic thyroid carcinoma (ATC) is a poorly differentiated thyroid cancer. It cannot uptake iodine or synthesis thyroglobulin. The incidence is low;about 2% - 5% of thyroid cancer. The peak age incidence is 60 - 70...Anaplastic thyroid carcinoma (ATC) is a poorly differentiated thyroid cancer. It cannot uptake iodine or synthesis thyroglobulin. The incidence is low;about 2% - 5% of thyroid cancer. The peak age incidence is 60 - 70 years and it is more common in females (55% - 77% of all patients). In recent years, the incidence has declined;however, it may be higher in areas of endemic goiter. ATC may occur with a coexisting carcinoma and may represent transformation of a well-differentiated thyroid cancer. Patients typically present with a rapidly growing anterior neck mass and aggressive symptoms. The most reliable tool in detecting thyroid malignancies is fine-needle aspiration cytology (FNAC). Sensitivity of FNAC for thyroid malignancy ranged from 61% to 97.7%. Fine-needle aspiration can diagnose ATC by the demonstration of spindled or giant cells, bizarre neoplastic cells that may be multinucleated, or atypical cells with high mitotic activity. A syncytial pattern is the predominant cellular pattern of anaplastic thyroid carcinoma. Other laboratory tests, including tumor markers (cytokeratin, vimentin, and carcinoembryogenic antigen) are helpful in diagnosis and follow-up of the patients. Multimodality therapy (surgery, external beam radiation, and chemotherapy) is the recommended treatment and it seems to have slightly improved outcomes. The prognosis is not as bad in younger patients with smaller tumors. The most common cause of death is lung metastasis. The mean survival time is less than 6 months from the time of diagnosis. The prompt diagnosis and aggressive treatment are essential modality to achieve optimal outcomes.展开更多
The prognosis of small cell thyroid carcinoma(SCTC)in a large cohort has not been well reported in the literature.In this study,we analyzed the mortality of SCTC,in comparison to medullary thyroid cancer(MTC)and anapl...The prognosis of small cell thyroid carcinoma(SCTC)in a large cohort has not been well reported in the literature.In this study,we analyzed the mortality of SCTC,in comparison to medullary thyroid cancer(MTC)and anaplastic thyroid cancer(ATC),based on the Surveillance,Epidemiology,and End Results(SEER)Program of the National Cancer Institute,to determine the prognosis of SCTC.Information regarding patients with a diagnosis of MTC,ATC,or SCTC,between 2004 and 2013,was acquired from the SEER database.Patient survival curves were assessed by Cox proportional hazards regression analyses,Kaplan-Meier analyses,and log-rank tests.In a Kaplan-Meier analysis of the entire cohort of thyroid cancer patients,cancer-specific survival declined sharply for patients with SCTC,but it declined more modestly for patients with MTC.The cancer-specific survival was not significantly different between SCTC and ATC.Unadjusted Cox regression analysis showed that SCTC had a higher cancer-specific mortality than MTC but a similar prognosis as ATC.SCTC showed a higher cancer-specific mortality than MTC and ATC after adjustments for various confounding factors.SCTC was found to have a more highly lethal clinical course than MTC and had a similar death rate to ATC.Therefore,we recommend that aggressive,radical treatment like surgery or radiation should be performed tor these patients.展开更多
Background: Anaplastic thyroid cancer (ATC), while rare, carries a uniformly poor prognosis. Current treatment includes surgery when possible, radiotherapy, and chemotherapy. Multiple chemotherapeutic agents are in th...Background: Anaplastic thyroid cancer (ATC), while rare, carries a uniformly poor prognosis. Current treatment includes surgery when possible, radiotherapy, and chemotherapy. Multiple chemotherapeutic agents are in the process of clinical testing, and promising agents include those in the tyrosine kinase inhibitor family. Our patient represents a novel case of ATC treated with sunitinib, one such tyrosine kinase inhibitor. Methods/Results: We utilized the experimental sunitinib in conjunction with radiation therapy to treat a patient with aggressive ATC in whom curative resection was unable to be achieved due to carotid sheath and tracheal involvement. The patient had marked clinical response and sustained stable disease for 8 months, which coincides with reported data regarding sunitinib to treat other thyroid malignancies. Conclusion: Our case illustrates the efficacy of sunitinib therapy as a possible adjunct in the treatment of ATC.展开更多
Well-differentiated thyroid carcinoma(WDTC,including papillary thyroid carcinoma and follicular thyroid carcinoma)are fairly slow-growing tumors with an overall low mortality due to the efficacy of combinatory surgery...Well-differentiated thyroid carcinoma(WDTC,including papillary thyroid carcinoma and follicular thyroid carcinoma)are fairly slow-growing tumors with an overall low mortality due to the efficacy of combinatory surgery and postoperative radioiodine therapy.Subsets of WDTCs may dedifferentiate into poorly differentiated thyroid carcinoma(PDTC)and anaplastic thyroid carcinoma(ATC),of which especially the latter has an exceptionally poor patient outcome.The underlying genetics responsible for this tumor progression is only partly understood,and is complicated by the fact that subgroups of ATCs are thought to arise de novo without a demonstrable,pre-existing WDTC.Even so,recent advances using next generation sequencing(NGS)techniques have identified a genetic link between WDTCs and ATCs,suggesting a step-wise accumulation of mutations driving the loss of differentiation for most cases.In this Commentary,recent findings from an NGS study on synchronous FTC,PDTC,and ATC tumor components from the same patient are highlighted.By using whole-genome data,clonality analyses identified a chief ancestral clone carrying mutations in TP53-associated signaling networks regulating genes involved in DNA repair,with sub-clones in each tumor component that were identified also in the less differentiated,neighboring tumor.Moreover,mutational signatures suggested a general mismatch repair(MMR)deficiency along with microsatellite instability.These findings support the chained progression model of dedifferentiation in thyroid cancer,and pinpoint a central role for defective DNA repair.Since effective treatment modalities for ATCs are urgently needed,studies regarding therapeutic agents specifically targeting defective MMR in dedifferentiated thyroid carcinoma could be pursued.展开更多
Anaplastic thyroid cancer(ATC)is a rare but highly lethal disease.ATCs are resistant to standard therapies and are extremely difficult to manage.The stepwise cell dedifferentiation results in the impairment of the iod...Anaplastic thyroid cancer(ATC)is a rare but highly lethal disease.ATCs are resistant to standard therapies and are extremely difficult to manage.The stepwise cell dedifferentiation results in the impairment of the iodine-metabolizing machinery and the infeasibility of radioiodine treatment in ATC.Hence,reinducing iodine-metabolizing gene expression to restore radioiodine avidity is considered as a promising strategy to fight against ATC.In the present study,capsaicin(CAP),a natural potent transient receptor potential vanilloid type 1(TRPV1)agonist,was discovered to reinduce ATC cell differentiation and to increase the expression of thyroid transcription factors(TTFs including TTF-1,TTF-2,and PAX8)and iodine-metabolizing proteins,including thyroidstimulating hormone receptor(TSHR),thyroid peroxidase,and sodium iodine symporter(NIS),in two ATC cell lines,8505C and FRO.Strikingly,CAP treatment promoted NIS glycosylation and its membrane trafficking,resulting in a significant enhancement of radioiodine uptake of ATC cells in vitro.Mechanistically,CAP-activated TRPV1 channel and subsequently triggered Ca2þinflux,cyclic adenosine monophosphate(cAMP)generation,and cAMP-responsive element-binding protein(CREB)signal activation.Next,CREB recognized and bound to the promoter of SLC5A5 to facilitate its transcription.Moreover,the TRPV1 antagonist CPZ,the calcium chelator BAPTA,and the PKA inhibitor H-89 effectively alleviated the redifferentiation exerted by CAP,demonstrating that CAP might improve radioiodine avidity through the activation of the TRPV1–Ca2þ/cAMP/PKA/CREB signaling pathway.In addition,our study indicated that CAP might trigger a novel cascade to redifferentiate ATC cells and provide unprecedented opportunities for radioiodine therapy in ATC,bypassing canonical TSH–TSHR pathway.展开更多
文摘Well-differentiated thyroid carcinoma has a favorable prognosis with a 5-year survival rate of over 95%.However,the undifferentiated or anaplastic type accounting for<0.2%,usually in elderly individuals,exhibits a dismal prognosis with rapid growth and disappointing outcomes.It is the most aggressive form of thyroid carcinoma,with a median survival of 5 mo and poor quality of life(airway obstruction,dysphagia,hoarseness,persistent pain).Early diagnosis and staging are crucial.Diagnostic tools include biopsy(fine needle aspiration,core needle,open surgery),high-resolution ultrasound,computed tomography,magnetic resonance imaging,[(18)F]fluoro-D-glucose positron emission tomography/computed tomography,liquid biopsy and microRNAs.The BRAF gene(BRAF-V600E and BRAF wild type)is the most often found molecular factor.Others include the genes RET,KRAS,HRAS,and NRAS.Recent management policy is based on surgery,even debulking,chemotherapy(cisplatin or doxorubicin),radiotherapy(adjuvant or definitive),targeted biological agents and immunotherapy.The last two options constitute novel hopeful management modalities improving the overall survival in these otherwise condemned patients.Anti-programmed death-ligand 1 antibody immunotherapy,stem cell targeted therapies,nanotechnology achievements and artificial intelligence implementation provide novel promising alternatives.Genetic mutations determine molecular pathways,thus indicating novel treatment strategies such as anti-BRAF,anti-vascular endothelial growth factor-A,and anti-epidermal growth factor receptor.Treatment with the combination of the BRAF inhibitor dabrafenib and the MEK inhibitor trametinib has been approved by the Food and Drug Administration in cases with BRAF-V600E gene mutations and is currently the standard care.This neoadjuvant treatment followed by surgery ensures a twoyear overall survival of 80%.Prognostic factors for improved outcomes have been found to be younger age,earlier tumor stage and radiation therapy.A multidisciplinary approach is necessary,and the therapeutic plan should be individu alized based on surveillance and epidemiology end results.
基金Supported by the 2023 Yeungnam University Research Grant.
文摘BACKGROUND Anaplastic thyroid cancer(ATC)is a rare but aggressive type of thyroid carcinoma.BRAF V600E-mutation,which is found in 10%-50%of ATCs,is associated with poor prognosis.A recent clinical trial reported a substantial clinical benefit of concomitant treatment of dabrafenib(BRAF inhibitor)and trametinib(MEK inhibitor)for treating BRAF V600E-mutant ATC.However,reports on patients with ATC treated with this regimen following surgery are lacking.CASE SUMMARY We report the case of a 63-year-old female patient diagnosed with BRAF V600Emutant ATC.Following three surgeries—total thyroidectomy,total laryngectomy,and neck dissection—she was diagnosed with lung metastasis during follow-up.The metastatic ATC was successfully treated with dabrafenib and trametinib.The patient achieved a complete response at the 32-mo follow-up.CONCLUSION Adjuvant chemotherapy with dabrafenib plus trametinib is efficacious for treatment and prevention of recurrent ATC with BRAF mutation following surgery.
文摘BACKGROUND Anaplastic thyroid carcinoma(ATC),also called undifferentiated thyroid cancer,is the least common but most aggressive and deadly thyroid gland malignancy of all thyroid cancers[1].It has poor prognosis,and is the leading cause of death from malignant thyroid tumors.The one-year survival rate is 20%,with a median overall survival(OS)of only 5 mo[2].The aim of this report is to provide our experience in the diagnosis and treatment of ATC.CASE SUMMARY A patient with a thyroid mass underwent surgical treatment after developing symptoms of hoarseness.The resected tumor was pathologically diagnosed as ATC.Imaging examination revealed organ and lymph node metastasis.After multiple cycles of chemotherapy and local radiotherapy,the metastases were not relieved and gradually increased in size and new metastases appeared.The patient immediately received immunotherapy combined with targeted therapy.During treatment,immune-related adverse reactions occurred,which were improved after symptomatic treatment,and tolerated by the patient.The OS of the patient was more than 30 mo after immunotherapy combined with targeted therapy.CONCLUSION For metastatic ATC,surgical treatment,radiotherapy and chemotherapy have no significant effect on remission of the disease.However,immunotherapy has made a breakthrough in the treatment of ATC。
基金This study was supported by grants from Tongji Medical College,Huazhong University of Science and Technology(CN)(No.5001540018)Young Scientists Fund(No.81802676).
文摘Anaplastic thyroid carcinoma(ATC)is a rare but extremely lethal malignancy.However,little is known about the pathogenesis of ATC.Given its high mortality,it is critical to improve our understanding of ATC pathogenesis and to find new diagnostic biomarkers.In the present study,two gene microarray profiles(GSE53072 and GSE65144),which included 17 ATC and 17 adjacent non-tumorous tissues,were obtained.Bioinformatic analyses were then performed.Immunohistochemistry(IHC)and receiver operating characteristic(ROC)curves were then used to detect transmembrane protein 158(TMEM158)expression and to assess diagnostic sensitivity.A total of 372 differentially expressed genes(DEGs)were identified.Through protein-protein interaction(PPI)analysis,we identified a significant module with 37 upregulated genes.Most of the genes in this module were related to cell-cycle processes.After co-expression analysis,132 hub genes were selected for further study.Nine genes were identified as both DEGs and genes of interest in the weighted gene co-expression network analysis(WGCNA).IHC and ROC curves confirmed that TMEM158 was overexpressed in ATC tissue as compared with other types of thyroid cancer and normal tissue samples.We identified 8 KEGG pathways that were associated with high expression of TMEM158,including aminoacyl-tRNA biosynthesis and DNA replication.Our results suggest that TMEM158 may be a potential oncogene and serve as a diagnostic indicator for ATC.
文摘Anaplastic thyroid carcinoma (ATC) is a poorly differentiated thyroid cancer. It cannot uptake iodine or synthesis thyroglobulin. The incidence is low;about 2% - 5% of thyroid cancer. The peak age incidence is 60 - 70 years and it is more common in females (55% - 77% of all patients). In recent years, the incidence has declined;however, it may be higher in areas of endemic goiter. ATC may occur with a coexisting carcinoma and may represent transformation of a well-differentiated thyroid cancer. Patients typically present with a rapidly growing anterior neck mass and aggressive symptoms. The most reliable tool in detecting thyroid malignancies is fine-needle aspiration cytology (FNAC). Sensitivity of FNAC for thyroid malignancy ranged from 61% to 97.7%. Fine-needle aspiration can diagnose ATC by the demonstration of spindled or giant cells, bizarre neoplastic cells that may be multinucleated, or atypical cells with high mitotic activity. A syncytial pattern is the predominant cellular pattern of anaplastic thyroid carcinoma. Other laboratory tests, including tumor markers (cytokeratin, vimentin, and carcinoembryogenic antigen) are helpful in diagnosis and follow-up of the patients. Multimodality therapy (surgery, external beam radiation, and chemotherapy) is the recommended treatment and it seems to have slightly improved outcomes. The prognosis is not as bad in younger patients with smaller tumors. The most common cause of death is lung metastasis. The mean survival time is less than 6 months from the time of diagnosis. The prompt diagnosis and aggressive treatment are essential modality to achieve optimal outcomes.
文摘The prognosis of small cell thyroid carcinoma(SCTC)in a large cohort has not been well reported in the literature.In this study,we analyzed the mortality of SCTC,in comparison to medullary thyroid cancer(MTC)and anaplastic thyroid cancer(ATC),based on the Surveillance,Epidemiology,and End Results(SEER)Program of the National Cancer Institute,to determine the prognosis of SCTC.Information regarding patients with a diagnosis of MTC,ATC,or SCTC,between 2004 and 2013,was acquired from the SEER database.Patient survival curves were assessed by Cox proportional hazards regression analyses,Kaplan-Meier analyses,and log-rank tests.In a Kaplan-Meier analysis of the entire cohort of thyroid cancer patients,cancer-specific survival declined sharply for patients with SCTC,but it declined more modestly for patients with MTC.The cancer-specific survival was not significantly different between SCTC and ATC.Unadjusted Cox regression analysis showed that SCTC had a higher cancer-specific mortality than MTC but a similar prognosis as ATC.SCTC showed a higher cancer-specific mortality than MTC and ATC after adjustments for various confounding factors.SCTC was found to have a more highly lethal clinical course than MTC and had a similar death rate to ATC.Therefore,we recommend that aggressive,radical treatment like surgery or radiation should be performed tor these patients.
文摘Background: Anaplastic thyroid cancer (ATC), while rare, carries a uniformly poor prognosis. Current treatment includes surgery when possible, radiotherapy, and chemotherapy. Multiple chemotherapeutic agents are in the process of clinical testing, and promising agents include those in the tyrosine kinase inhibitor family. Our patient represents a novel case of ATC treated with sunitinib, one such tyrosine kinase inhibitor. Methods/Results: We utilized the experimental sunitinib in conjunction with radiation therapy to treat a patient with aggressive ATC in whom curative resection was unable to be achieved due to carotid sheath and tracheal involvement. The patient had marked clinical response and sustained stable disease for 8 months, which coincides with reported data regarding sunitinib to treat other thyroid malignancies. Conclusion: Our case illustrates the efficacy of sunitinib therapy as a possible adjunct in the treatment of ATC.
基金This work was supported by the Swedish Cancer Society(Junior Clinical Investigator Award).
文摘Well-differentiated thyroid carcinoma(WDTC,including papillary thyroid carcinoma and follicular thyroid carcinoma)are fairly slow-growing tumors with an overall low mortality due to the efficacy of combinatory surgery and postoperative radioiodine therapy.Subsets of WDTCs may dedifferentiate into poorly differentiated thyroid carcinoma(PDTC)and anaplastic thyroid carcinoma(ATC),of which especially the latter has an exceptionally poor patient outcome.The underlying genetics responsible for this tumor progression is only partly understood,and is complicated by the fact that subgroups of ATCs are thought to arise de novo without a demonstrable,pre-existing WDTC.Even so,recent advances using next generation sequencing(NGS)techniques have identified a genetic link between WDTCs and ATCs,suggesting a step-wise accumulation of mutations driving the loss of differentiation for most cases.In this Commentary,recent findings from an NGS study on synchronous FTC,PDTC,and ATC tumor components from the same patient are highlighted.By using whole-genome data,clonality analyses identified a chief ancestral clone carrying mutations in TP53-associated signaling networks regulating genes involved in DNA repair,with sub-clones in each tumor component that were identified also in the less differentiated,neighboring tumor.Moreover,mutational signatures suggested a general mismatch repair(MMR)deficiency along with microsatellite instability.These findings support the chained progression model of dedifferentiation in thyroid cancer,and pinpoint a central role for defective DNA repair.Since effective treatment modalities for ATCs are urgently needed,studies regarding therapeutic agents specifically targeting defective MMR in dedifferentiated thyroid carcinoma could be pursued.
基金supported by grants from the National Natural Science Foundation of China(81972503 and 82103656).
文摘Anaplastic thyroid cancer(ATC)is a rare but highly lethal disease.ATCs are resistant to standard therapies and are extremely difficult to manage.The stepwise cell dedifferentiation results in the impairment of the iodine-metabolizing machinery and the infeasibility of radioiodine treatment in ATC.Hence,reinducing iodine-metabolizing gene expression to restore radioiodine avidity is considered as a promising strategy to fight against ATC.In the present study,capsaicin(CAP),a natural potent transient receptor potential vanilloid type 1(TRPV1)agonist,was discovered to reinduce ATC cell differentiation and to increase the expression of thyroid transcription factors(TTFs including TTF-1,TTF-2,and PAX8)and iodine-metabolizing proteins,including thyroidstimulating hormone receptor(TSHR),thyroid peroxidase,and sodium iodine symporter(NIS),in two ATC cell lines,8505C and FRO.Strikingly,CAP treatment promoted NIS glycosylation and its membrane trafficking,resulting in a significant enhancement of radioiodine uptake of ATC cells in vitro.Mechanistically,CAP-activated TRPV1 channel and subsequently triggered Ca2þinflux,cyclic adenosine monophosphate(cAMP)generation,and cAMP-responsive element-binding protein(CREB)signal activation.Next,CREB recognized and bound to the promoter of SLC5A5 to facilitate its transcription.Moreover,the TRPV1 antagonist CPZ,the calcium chelator BAPTA,and the PKA inhibitor H-89 effectively alleviated the redifferentiation exerted by CAP,demonstrating that CAP might improve radioiodine avidity through the activation of the TRPV1–Ca2þ/cAMP/PKA/CREB signaling pathway.In addition,our study indicated that CAP might trigger a novel cascade to redifferentiate ATC cells and provide unprecedented opportunities for radioiodine therapy in ATC,bypassing canonical TSH–TSHR pathway.
