TrkAIII與人類惡性腫瘤的相關性

論文標題：The oncogenic neurotrophin receptor tropomyosin-related kinase variant, TrkAIII

作者：Antonietta Rosella Farina, Lucia Cappabianca, Pierdomenico Ruggeri, Luciana Gneo, Cristina Pellegrini, Maria-Concetta Fargnoli and Andrew Reay Mackay

數字識別碼：10.1186/s13046-018-0786-3

Antonietta Rosella Farina等作者在Journal of Experimental & Clinical Cancer Research上在線發表了一篇綜述：The oncogenic neurotrophin receptor tropomyosin-related kinase variant, TrkAIII 。在這篇綜述中作者介紹了神經營養因子受體原肌球蛋白相關激酶變體（TrkAIII）的檢測及其與人類惡性腫瘤相關性的研究進展，包括：TrkAIII的檢測、TrkAIII與人類惡性腫瘤的相關性、TrkAIII發揮致癌活性的機制，以及表達TrkAIII的腫瘤種類，尤其介紹了神經母細胞瘤的潛在治療策略。

在許多正常的組織中，神經營養因子受體原肌球蛋白相關激酶A (TrkA) 調節著對神經營養因子NGF和NT3的應答過程。並且TrkA對於神經和免疫系統的正常運轉和發育至關重要。

TrK癌基因是人類第一個TrkA來源的癌基因，在結腸癌中被首次發現。當時定義它是一種新的嵌合物（融合了截短的原肌球蛋白和酪氨酸蛋白激酶序列）。後來，TrKA原癌基因被定義為NGF受體，並且在許多人類癌症中均鑒定出許多TrKA來源的癌基因。現在，普遍認為TrKA是多種人類癌症亞群中的重要驅動因素，因此它是重要的癌症治療靶點。

TrKA除了能驅動腫瘤的形成，最新的一項研究結果表明：TrK家族的抑製劑Larotrectinib對新型TrkA嵌合物所驅動的成人和兒童腫瘤具有顯著、持續的抑制效果。這進一步強調了需要進一步優化由TrkA的致癌基因所驅動的癌症的臨床檢測，從而得以最大限度地發揮這種新型治療方案的潛力。

Antonietta Rosella Farina等人總結了可能由TrkA癌基因所驅動的腫瘤，包括一些表達TrkA剪切變體TrkAIII的兒童神經母細胞瘤（NB）。TrkAIII相較於TrkA，區別在於外顯子6，7的9跳躍，以及細胞外D4 Ig樣結構域的缺失所造成的致癌活性。與此形成對比的是，完全剪切的TrkA在神經母細胞瘤中表現出腫瘤抑制作用，且與良好預後息息相關。而TrkAIII則與晚期轉移性疾病、治療後複發以及不良預後相關，還可誘導NIH-3T3細胞的惡變並在神經母細胞瘤模型中表現出致癌活性（圖1）。

圖1：TrkAlll對絕大多數的癌症功能特質均有影響（例如：TrkAlll下調磷酸化蛋白質組和轉錄組）。

圖源：Andrew Reay Mackay 等

TrkAIII在神經母細胞瘤中的誘發主要受模擬缺氧和干擾內質網的應激調節，這有可能在應激性腫瘤微環境中將TrkA的腫瘤抑制信號轉變為TrkAIII的致癌信號。TrkA主要位於細胞表面，而TrkAIII一旦表達，則重新定位於細胞內高爾基體前膜、中心體和線粒體。在這些細胞器內，TrkAIII會出現非配體依賴的自發性激活，通過多種機制促進腫瘤發生和惡性生物學行為，影響大多數腫瘤特徵（圖2）。

圖2：TrkAIII的腫瘤表現和致癌機制以及針對表達TrkAIII腫瘤的潛在治療因子和其他治療方案。

圖源：Andrew Reay Mackay 等

作者最後指出，對於對TrkAIII的活性、表達、下游信號傳導有潛在抑制效果的治療因子，單獨使用這些治療因子或者與基因毒性應激，氧化應激以及內質網干擾應激所誘導的腫瘤藥物聯合作用，可能對表達TrkAIII的癌症有更好的治療效果。

摘要：Oncogenes derived from the neurotrophin receptor tropomyosin-related kinase TrkA act as drivers in sub-populations of a wide-range of human cancers. This, combined with a recent report that both adult and childhood cancers driven by novel oncogenic TrkA chimeric-fusions exhibit profound, long-lived therapeutic responses to the Trk inhibitor Larotrectinib, highlights the need to improve clinical detection of TrkA oncogene-driven cancers in order to maximise this novel therapeutic potential. Cancers potentially driven by TrkA oncogenes include a proportion of paediatric neuroblastomas (NBs) that express the alternative TrkAsplice variant TrkAIII, which exhibits exon 6, 7 and 9 skipping and oncogenic-activity that depends upon deletion of the extracellular D4 Ig-like domain. In contrast to fully spliced TrkA, which exhibits tumour suppressor activity in NB and associates with good prognosis, TrkAIII associates with advanced stage metastatic disease, post therapeutic relapse and worse prognosis, induces malignant transformation of NIH-3T3 cells and exhibits oncogenic activity in NB models. TrkAIII induction in NB cells is stress-regulated by conditions that mimic hypoxia or perturbate the ER with potential to change TrkA tumour-suppressing signals into oncogenic TrkAIII signals within the stressful tumour microenvironment. In contrast to cell surface TrkA, TrkAIII re-localises to intracellular pre-Golgi membranes, centrosomes and mitochondria, within which it exhibits spontaneous ligand-independent activation, triggering a variety of mechanisms that promote tumorigenicity and malignant behaviour, which impact the majority of cancer hallmarks. In this review, we present updates on TrkAIII detection and association with human malignancies, the multiple ways TrkAIII exerts oncogenic activity and potential therapeutic approaches for TrkAIII expressing cancers, with particular reference to NB.

期刊介紹：Journal of Experimental & Clinical Cancer Research(https://jeccr.biomedcentral.com/) is an online peer-reviewed journal that publishes original research papers, reviews and commentaries in cancer research, from bench to bedside.

2017 Journal Metrics

Citation Impact

6.217 - 2-year Impact Factor

5.280 - 5-year Impact Factor

1.350 - Source Normalized Impact per Paper (SNIP)

2.000 - SCImago Journal Rank (SJR)

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