摘要：甲狀腺癌之未分化腫瘤細胞增殖迅速且易轉移，此類細胞失去凋亡調控機制而且迅速的去分化(De-differentaition)，病人因癌細胞迅速增生轉移而致命。我們於1999年開始甲狀腺癌研究，TNF-α 可以誘導甲狀腺癌細胞產生型態學上的分化現象。2001年，以降膽固醇藥物史達汀 (Lovastatin)的實驗，低濃度(25μM)誘導癌細胞產生再分化，高濃度(50 μM)，導致癌細胞凋亡。2006年裸鼠模型，使用5及10 mg/kg/day 時，明顯使腫瘤萎縮，但是使用1 mg/kg/day時，腫瘤明顯加速成長的現象，為Duality effects。2012年發現閥蛋白(FLOT1)及轉酮脢(Transketolase, TKT)為甲狀腺未分化癌細胞再分化及癌細胞增殖的控制因子。目前研究Dipeptidyl peptidase-4 (CD26)的抑制劑明顯影響癌細胞。細胞外泌體(Exosome)具預測癌症治療之生物標記，外泌體以小分子傳送細胞間的訊息。我們發現，Vildagliptin (DPP-4抑制劑)和Lovastatin均會影響ARO細胞外泌體蛋白質之表現及影響細胞存活。而尿液的取得，於甲狀腺癌病患，不具侵襲性，尿液中細胞外泌體(Exosome)可為癌症預後指標及治療標的。我們在繼續細胞實驗的基礎下，進行人體的分析，預計收集30位甲狀腺乳突癌、濾泡癌或未分化癌之患者，在手術前及術後進行進一步治療時，在術前，及術後、術後3、6、12個月，收集尿液，進行尿液細胞外泌體生物標記分析，以前瞻性研究，找出病患預後因子，分析其治療療效或發展新型藥物之可能。
Abstract: Although papillary and follicular thyroid cancers are low-grade endocrine malignancy, they were fatal if the cancer cells were poorly-differentiated or anaplastic change. Prior researches indicated that one-third well-differentiated thyroid cancers could transform to poorly-differentiated patterns, even to be anaplastic thyroid cancer (ATC), a fatal malignancy, and no effective therapeutic strategies was noted, including surgical intervention, chemotherapy and radiotherapy. The poorly-differentiated or anaplstic change of thyroid cancer cells proliferates rapidly and always invades local tissues with distant metastasis. Cellular de-differentiation is the most pivotal cause for malignant transformation and invasion. De-differentiation usually in papillary thyroid cancer and follicular thyroid cancer, and definitely in ATC.The Poorly-differentiated thyroid cancer cell will rapidly proliferate and metastasize. The poorly-differentiated tumor cells lost apoptotic mechanism with de-differentiation, and such phenomenon is fatal for such patients. We started research of thyroid cancer since 1999, and we initially found TNF-α could induce cyto-morphological re-differentiation of thyroid cancer cells. Later, we further found Lovastatin could induce re-differentiation of anaplastic thyroid cancer (ATC) cells in 25μM, but induce apoptosis in 50μM, in 2001. In 2006, we designed nude mice model, and found tumor will shrink via treatment of Lovastatin in 5 or 10 mg/kg/day, but tumor will proliferate significantly in 1 mg/kg/day. We called this phenomenon as “Duality effects” of statins. In 2012, we found FLOT1 and transketolase (TKT) as important regulatory factor of re-differentiation and proliferation in ATC cells, respectively. We also found that inhibition of Dipeptidyl peptidase-4 (CD26) will influence proliferation of ATC cells. Exosomes are nanovesicels secrted into extracellular environments. A growing evidence suggests theat exosomes could be used as biomarkers to be the diagnosis and prognosis of malignant tumors. Exosomes are 50-100 nm diameters, and correspond to the intrluminal vesicles of endosomal multivesicular bodies. Because of their cellular orgins, exosomes have specific protein markers, like CD63, CD9, CD81 and heat shock protein (HSP). Urine was used to be the biosamples in the past five years in baldder cancer, prostate cancer, breast cancer and ovarian cancer. Urine sample is usually easy to obtain and non-invasive. Exosomes secreted by cells could micro-molecularly transfer messages between cells and to be biological markers of cancer. We now found Vildagliptin and Lovastatin could influence tumor cells survival via exosomal proteins. For patients of thyroid cancer, we could obtain the urine samples without invasive procedures. Furthermore, we could find the biological markers and therapeutic targets via the exosomal expression in urine. On the continuing basis of ATC cells culture experiments, we expected to enroll 30 patients with papillary, follicular or anaplastic thyroid cancer, and collect their urine samples before operation, immediately after operation, post-operative 3, 6 12 months. We will analyze the urine exosomal proteins and probable biological markers. We hope to find the prognostic biological markers via this prospective study. We further hope to find newly therapeutic mechanism and medications for such patients with poorly-differentiated or anaplastic thyroid cancer.