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                  案例分享

                  色氨酸代謝紊亂相關進展和食管鱗狀細胞癌的轉移

                  發布日期:2017.07.06

                  癌癥,惡性腫瘤中的最為常見的一類。是由于各種致癌因素作用而致使局部組織細胞在基因水平上失去正常生長調控進而導致異常增生并分化形成新的生物,并因為其不受正常機體生理調節,不斷生長,破壞正常組織與器官,對于患者造成嚴重的損傷,并最終極其容易導致患者死亡。
                  食管鱗狀細胞癌(簡稱ESCC,常稱食道癌),排名前10位的癌癥死因,是全球性最為常見的惡性腫瘤之一。大多數ESCC患者的死因是致癌細胞通過淋巴結轉移,我們稱為轉移食管鱗狀細胞癌(簡稱mESCC)。據研究,非轉移的ESCC患者術后5年總生存率約為40%,而
                  mESCC患者的術后5年總生存率僅在10%以下。

                   

                  1519613885963219.jpg

                  文獻解讀

                  目前,對于患者的ESCC或mESCC診斷的幾個主要臨床病例因素如:年齡、腫瘤大小、腫瘤原發部位等。根據總結,這些手段對于一些早期的癥狀診斷十分不足。

                  因此對于臨床診斷或治療來說,提高診斷或預測的準確度,對于ESCC轉移與否的監測建立靈敏的方法,以幫助外科醫生選擇適合的治療方法是十分有必要的。本篇論文,探討早期識別和預測ESCC、mESCC以及闡明疾病的潛在發病機制。對于來自健康人群、ESCC患者和mESCC患者數百例臨床血樣的色氨酸代謝通路相關物質,進行基于超高效液相色譜三重四級桿串聯質譜(UPLC-MS/MS)的靶向代謝組學技術(Target  Metabolomics,譜領生物為本次代謝組學服務提供商)檢測分析。

                  樣本信息:

                  Clinical characteristics of patients and healthy subjects
                   Healthy controlESCC patientsmESCC patients
                  No. of subjects283838
                  Age(mean)586061
                  Gender(male/female)20/827/1136/2

                  最初,研究團隊分析了色氨酸通路中的九種代謝產物:

                  九種代謝物:

                  Tryptophan;3-Hydroxyanthranilic acid;Kynurenine;Kynurenic acid;5-Hydroxytryptophan;5-Hydroxyindole-3-acetic acid;Tryptamine;N-acetylserotonin;5-Hydroxytryptamine.
                  后期,最終選擇其中五個代謝物 (即色氨酸 (TRP)、 犬尿氨酸 (KYN)、 5-羥基色氨酸 (5HTP)、 5-羥基吲哚-3-乙酸 (5HIAA)、 5-羥色胺 (5HT)) 進行定量比較,健康人群、ESCC患者、mESCC患者血樣中這五種代謝物的平均含量如下圖:

                  1519613886712791.png

                  Fig. Scheduled multiple-reaction monitoring (S-MRM) chromatograph of ?ve metabolites in positive ion mode. Full, dash and dot line stand for health control, ESCC patients and mESCC patients respectively.

                  我們可以看到ESCC和mESCC患者與健康人群血樣中這五種代謝物含量都具有差異。使用熱圖分析,我們可以發現,在健康人群和病人之間,這五種代謝物峰面積呈現出了顯著不同,如圖:

                  1519613886777383.png

                  通過熱圖可以看到,相對于正常人群樣本來說,ESCC和 mESCC 患者的色氨酸(TRP)含量下調了,而5-羥色胺 (5HT)上調,而其他三個代謝物則出現動態變化。為了闡明這些差異,研究團隊獎下游代謝產物 (5HT、 5HTP、 5HIAA和KYN) 與上游的前體 (TRP) 的計算比率,進過數據預處理之后,研究團隊使用其他四種代謝物與色氨酸的比值作為指標進行分析。相對于正常人群樣本,研究團隊發現這些比值,ESCC和 mESCC 患者的這些比值都呈現了上調的趨勢。再以此建立兩種診斷模型。研究團隊發現這兩種模式能有效的預測和診斷ESCC和 mESCC。

                  作者在最后討論部分,對此也進行了討論。小編覺得原話很精彩,這里抄錄獻給大家:
                  In mammals, tryptophan metabolism is a physiological means of preserving immune homeostasis, which avoids acute and chronic hyper-in?ammatory reactions. Recently, some studies report that immune homeostasis is important in cancer progression and the disturbed tryptophan metabolism is correlated to tumorigenesis and metastasis. In this study, a targeted metabolomics approach was conducted to explore variations of tryptophan metabolism in ESCC patients.
                  In procedure of tryptophan metabolism, tryptophan can be degraded in different pathways , in which some physiologically important metabolites are produced, including 5HTP, 5HT, TRA and KYN: (1)TRP is catalyzed by the 5-monooxygenase and converted into 5HTP, which is subsequently converted into 5HT through decarboxylation reaction, and 5HT is converted into 5HIAA ?nally; (2)TRP can be degraded into KYN through the kynurenine pathway, and KYN can be transformed to 3HAA and KYA; (3) TRP can be transformed to TRA by the aromatic-L-amino-acid decarboxylase.
                  TRP is the precursor of 5HTP, 5HT, and 5HIAA. In this study, concentration of TRP was decreased signi?cantly both in ESCC and mESCC patients, which was in consistent with some previous cancer studies. Decreased tryptophan leads to biostatic starvation and thus limits lymphocyte expansion, which has a close correlation with tumorigenesis. In this study, serum 5HTP was down-regulated in ESCC patients due to decreased concentration of TRP and enhanced activity of aromatic-L-aminoacid decarboxylase. 5HT, degraded from the 5HTP by decarboxylation reaction, was upregulated both in non-metastatic and metastatic patients. It has been reported that 5HT is a mitogenic factor and high concentration of 5HT promotes progress of caners. On the other hand, TRP can be converted into N-formylkynurenine and then hydrolyzed to KYN through the kynurenine pathway, in which the downstream metabolites, KYA and 3HAA, are produced.
                  The ratio of KYN to TRP is a widely accepted indicator presenting the enzyme activity involved in the kynurenine pathway. Variation of this ratio in health controls, ESCC, and mESCC patients was showed in. We found that the ratios of KYN/TRP, 5HTP/ TRP, 5HIAA/TRP and 5HT/TRP were increased when compared the ESCC and mESCC patients to healthy controls. Moreover, the increased trends of these ratios of metabolite to tryptophan were in accordance with malignant transformation of ESCC. These results implied that there was a higher enzyme activity in ESCC and mESCC patients compared to healthy controls. The higher enzyme activity has been observed in several types of human solid tumors, including colorectal, breast, ovarian, lung cancers and melanoma. It is worth noting that high enzyme activity of kynurenine pathway is associated with immune escape, which is a trigger factor of tumor progression and migration. The incensement of KYN can inhibit T-cell proliferation and induce T-cell apoptosis, which leads to immune tolerance, thus providing a microenvironment for tumor progression and migration.
                  總結如下圖:

                  1519613885241551.jpg

                  如果大家嫌內容太多看不下去,小編這里總結一下,大體就是說對于哺乳動物來說,免疫系統的穩態對于癌癥的發展有重要作用,色氨酸代謝紊亂與相關腫瘤的發展和轉移有關。色氨酸代謝是維持免疫平衡,避免記性和慢性超炎性反應的生理手段。
                  在色氨酸代謝的過程中,色氨酸可以在不同的路徑被降解,其中會產生一些具有重要生理學作用的代謝物,包括 5HTP,5HT,TRA和KYN: (1) TRP是由 5-單加氧酶催化和轉換成 5HTP,隨后通過脫羧反應被轉化為 5HT,最終5HT 轉換成 5HIAA;(2)TRP可以通過犬尿氨酸通路,降解成KYN,KYN可以再轉化為 3HAA 和KYA;(3) TRP可以被芳香-L-氨基酸脫羧酶轉化成 TRA .
                  TRP是 5HTP、 5HT 和 5HIAA 的先導。在此研究中,在ESCC和 mESCC 患者中,色氨酸濃度顯著下降,符合一些以前癌癥研究。色氨酸降低可以餓死腫瘤細胞從而限制了淋巴細胞擴張,這與腫瘤轉移密切相關。在本研究中, ESCC患者血清中5HTP 下調是由于色氨酸濃度降低,芳香-L-氨基酸脫羧酶的活性增強。5HTP通過脫羧反應降解成5HT,而5HT在非轉移和遠處轉移的患者中表達上調。據報 5HT 是一種有絲分裂因子,高濃度的 5HT 促進了癌癥的發展。另一方面,TRP可以轉化為 N-甲酰犬尿氨酸,然后通過犬尿氨酸途徑,水解成KYN,再產生的下游的代謝產物KYA和 3HAA.
                  對于呈現酶參與的犬尿氨酸途徑,KYN/TRP的值是一個被廣泛接受的指標。這一比率在健康組、 ESCC和 mESCC 患者的變化如圖 3 。我們發現,與健康對照組相比,在ESCC和 mESCC 患者中,KYN/TRP,5HTP / TRP,5HIAA/TRP和 5HT/TRP的比例都增加了。此外,這些色氨酸代謝產物的比值的增加的趨勢與ESCC惡性轉化吻合。這些結果暗示ESCC和 mESCC 患者與健康對照組相比,具有更高的酶活性。包括結直腸癌、 乳腺癌、 卵巢癌、 肺癌和黑色素瘤,過幾種類型的人類腫瘤患者中都觀測到較高的酶活性。值得注意的是犬尿氨酸途徑的高酶活性與免疫逃逸有關,免疫逃逸是腫瘤的生長和遷移觸發因素。KYN的刺激可以抑制 T 細胞增殖并誘導 T 細胞凋亡,從而導致免疫耐受,從而為腫瘤的生長和遷移提供一個微環境。

                  文獻內容

                  Title:Disturbed tryptophan metabolism correlating to progression and metastasis of esophageal squamous cell carcinoma.

                  Author:Jing Cheng , Hai Jin , Xiaobei Hou , Jie Lv , Xianfu Gao *, Guangyong Zheng ** .

                  Journal: Biochemical and Biophysical Research Communications.

                  Keywords: Tryptophan metabolism,Esophageal squamous cell carcinoma Lymph node metastasis,Liquid chromatography Tandem mass spectrometry.

                  Abstract:

                  Esophageal squamous cell carcinoma (ESCC) is one of the most frequent malignancies worldwide. Lymph node metastasis is the leading cause of death in ESCC patients. To identify early diagnostic and prognostic biomarkers of ESCC and elucidate underlying pathogenesis of the disease, a targeted metabolomics strategy based on liquid chromatography combined with tandem mass spectrometry was applied to explore tryptophan metabolism between ESCC patients, metastatic ESCC patients (mESCC), and healthy controls. Statistical analysis on metabolite expression abundance and compound concentration ratio was conducted to discriminate patients from healthy controls. The concentration ratio of kynurenine, 5-hydroxytryptophan, 5-hydroxyindole-3-acetic acid, 5-hydroxytryptamine to their precursor tryptophan were identi?ed as potential biomarkers, presenting high diagnostic capacity for distinguishing ESCC and mESCC patients from healthy controls. Moreover, a prognostic prediction model was also built on these ratios to distinguish metastasis patients from non-metastasis patients successfully. The high performance of ESCC prediction models suggest that concentration ratios of compounds may be used as biomarkers for early diagnosis and prognosis of the disease. In addition, concentration ratios of compounds show a progressively increased trend from non-metastasis to metastasis patients compared with healthy controls, which is in accordance with process of malignant transformation of ESCC. This interested ?nding suggests that disturbed tryptophan metabolism is correlated to progression and metastasis of ESCC since concentration ratios of compounds re?ect activity of enzymes involved in tryptophan metabolism. This study reveals the impact of tryptophan metabolism to tumorigenesis and metastasis of ESCC, which help biologists investigate mechanism of the disease.

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