Role Of Fibroblast In Thyroid Diseases

Context: As the most abundant stromal cells in human,fibroblast provide supports to the structure integrity of tissue.It refills the tissue to fix the damage via secretion of cytokines,chemokines and adhesion molecules.However,in autoimmune and tumor diseases,fibroblast sustains its activation,leading to consistant infiltration of immune cells,or promotes tumor formation and invasion.Recent findings on fibroblast reveal that it also has an impact on the therapeutical effects of medication.In thyroid diseases,fibroblast is not only the effector cell of Graves’ Ophthalmopathy but also causes desmoplasia in thyroid cancer,yet current researches were limited.Objectives: Explore the role of fibroblast in two kinds of thyroid diseases and their clinical implications.In Graves’ Ophthalmopathy(GO),we investigated in the role of fibroblasts played in glucocorticoids(GC)response and the clinical predictive value of its modulating factors.In benign and malignant thyroid nodules,we explore the role of fibroblasts derived from different histological locations of thyroid nodules in promoting thyroid cancer and provide grounded evidence for clinical treatment.Methods: In GO section,we isolated the ocular fibroblasts(OF)from GO patients to evaluate its sensitivity to dexamethasone(Dex)under inflamed circumstances.We discovered differentially expressed candidate micro RNAs by comparing patients sensitive or resistant to GC and investigated in their roles in modulating OF sensitivity to Dex.Further,we evaluate the micro RNA in a larger cohort as predictive parameter of GC resistance.In thyroid nodule section,we analyzed the correlation of fibroblast immunostaining with malignancy and clinical staging.We isolated fibroblast from benign and malignant nodules and the according peripheral normal tissues to investigate any differences in biomarkers.In vitro indirect co-culture and in vivo direct co-injection of fibroblast and cancer cell line were used to investigate tumor promoting capability of fibroblasts.Results: OF showed direct resistant to Dex treatment under in vitro highly inflamed circumstances(Dex repression rate dropped from 69% to 28%,p<0.01),while miR-885-5p and miR-224-5p can restore its sensitivity(Dex repression rate rose from 28% to 60%,p=0.03).GO patients who resistant to the GC therapy have lower miR-885-5p serum level and narrower lid width,with each parameter as independent risk factor of poor response.A composite marker of baseline serum miR-885-5p,mir-224-5p,TRAb and lid width can effectively predict GC insensitivity(NPV=100%).Malignant thyroid nodules had more staining of fibroblast than benign nodules(11450±1022 VS.3624±871.2,p<0.0001).In papillary thyroid carcinoma,such staining is correlated with clinical stage(stage I/II vs.stage III/IV,p=0.001).In vitro studis showed cancer-associated fibroblast(CAF)and normal-adjacent fibroblast(NAF)had the ability to promote cancer proliferation(2.5-4 folds,p<0.0001),while only NAF was capable to promote invasion(1.5 fold,p<0.01).In vivo studies showed fibroblasts promoted cancer formation(p=0.03)and progress(6/22 vs 2/8),with NAF more potent than CAF and goiter-associated fibroblast(GAF)in promoting tumor formation,invasion and metastasis.Conclusion: Mi R-885-5p and miR-224-5p can restore sensitivity to steroids in GO.Baseline circulating miR-885-5p and miR-224-5p,together with TRAb and lid width could be used as a composite marker to predict therapeutical response in GO patients with negative predictive value of 100%.Fibroblasts participate in the tumorigenesis and progression of thyroid cancer.NAF had a much more potent ability in promoting cancer progression than CAF.Meanwhile,GAF also showed ability to promote cancer.Therefore,this evidence should be considered when deciding surgical procedures.