探討信號轉導及轉錄激活蛋白3於貓注射部位肉瘤之角色

Abstract

貓注射部位肉瘤（Feline injection site sarcomas; FISSs）為組織型態多樣的間質來源惡性腫瘤，最早在1990年代因與含鋁佐劑之狂犬病和貓白血病疫苗之使用有高度相關性而被注意到。目前普遍認為FISS的致病機轉與注射或異物引起之慢性炎症有關。慢性炎症會促進細胞激素及生長因子的分泌與轉錄因子的活化，進而促使纖維母細胞與肌纖維母細胞的增生與腫瘤化。在眾多與慢性炎症相關的轉錄因子中，信號轉導及轉錄激活蛋白3（STAT3）在致腫瘤上扮演了舉足輕重的角色。人類醫學的研究中顯示，有近百分之七十的實質固態腫瘤與血液腫瘤其JAK-STAT3信號傳送路徑呈顯著活化，而STAT3信號傳送路徑可調控腫瘤細胞的增殖、存活及轉移與血管新生。本研究首先以免疫組織化學染色（immunohistochemitry; IHC）探討福馬林固定和石蠟包埋的FISS組織中，STAT3與磷酸化型STAT3之表現情形，結果證實有88.9％（40/45）的樣本呈現腫瘤細胞細胞質內STAT3陽性反應，53.3%（24/45）的樣本呈現磷酸化型STAT3腫瘤細胞細胞核內陽性反應。為了進一步探討STAT3之表現在貓疫苗注射部位肉瘤之角色，本研究使用兩個來自不同貓隻之FISS初代細胞株，並以STAT3抑制劑5-hydroxy-9,10-dioxo-9,10-dihydroanthracene-1-sulfonamide （LLL12）證實在STAT3磷酸化路徑受抑制下，FISS初代細胞之增殖與移行能力具劑量依賴性之顯著下降。由此可知STAT3在FISS之致腫瘤機制中扮演重要角色，在腫瘤的治療策略上，STAT3抑制劑可能具有臨床應用潛力。

Feline injection site sarcomas (FISSs) are malignant mesenchymal tumors of different histotypes and have been correlated with immunization of aluminum adjuvanted rabies and feline leukemia virus (FeLV) vaccines since 1990s. The pathogenesis of FISS has been correlated with chronic inflammation induced by injection or foreign materials, resulting in proliferation and ultimately neoplastic transformation of fibroblasts and myofibroblasts through upregulation of multiple cytokines, growth factors, and transcription factors. Activation of the Janus Kinase (JAK)-signal transducer and activator of transcription 3 (STAT3) has been described in nearly 70% of solid and hematological tumors in humans. The STAT3 signaling has been demonstrated to play a critical role in tumor development by regulating signaling pathways involved in cell proliferation, survival, metastasis, and angiogenesis. To characterize the role of STAT3 in FISS, we first detected STAT3 and phosphorylated STAT3 in formalin-fixed and paraffin- embedded (FFPE) FISS tissues by immunohistochemistry. The STAT3 was detected in 88.9% (40/45) of FISS cases and the phosphorylated STAT3 was detected in 53.3% (24/45) of FISS cases. However, both were not correlated with tumor grading. Two primary cells derived from the FISSs of two cats exhibiting consistent immunophenotypes with their parental FFPE tissues were established. A dose-dependent inhibitory effect on the cell proliferation and cell migration was observed in both primary FISS cells treated with the STAT3 inhibitor, 5-hydroxy-9,10-dioxo-9,10-dihydroanthracene-1-sulfonamide (LLL12). The high expression rate of STAT3 in FISS cases and the dose-dependent inhibitory effect on the growth of FISS primary cells treated with STAT3 inhibitor suggest that STAT3 may play an important role in the tumorigenesis of FISS and be a potential molecular therapeutic target for FISS.