研究背景: 腫瘤微環境中的癌細胞與免疫細胞交互作用參與癌症的進程。許多證據顯示Rab small GTPase調控胞吐作用 (exocytosis) 的異常參與癌化過程，本研究室未發表數據顯示T細胞中Rab37調控游離的類幾丁質3 (chitinase 3-like 1, CHI3L1) 的胞吐作用 (exocytosis) 促進肺癌進展。很多種細胞型態的細胞會分泌CHI3L1，像是巨噬細胞、上皮細胞、纖維母細胞及癌細胞。腫瘤微環境中的巨噬細胞在調節腫瘤生長和轉移中起著重要作用；然而，巨噬細胞中的Rab37調控CHI3L1的胞外運輸角色仍然不清楚。
研究目的: 本研究旨在鑑定巨噬細胞是否以Rab37調控CHI3L1的胞吐作用以促進癌症進展，並研究針對以Rab37 / CHI3L1為主軸的治療價值性。
研究結果: 我們的ELISA結果證實，與Rab37野生小鼠組相比，在Rab37剔除小鼠組的骨髓源性巨噬細胞 (bone marrow-derived macrophages, BMDMs)的CHI3L1分泌量都降低。此外，我們透過共聚焦顯微鏡的免疫螢光染色 (immunofluorescence) 結果顯示，Rab37與CHI3L1在巨噬細胞有共定位 (colocalization) 的現象。為了研究Rab37是否參與CHI3L1的胞吐作用，我們檢測了過度表現Rab37野生型、與GTP結合的活化態Q89L和與GDP結合的非活化態T43N的老鼠巨噬細胞株RAW264.7及人類單核球細胞株THP-1細胞培養液中CHI3L1的含量，結果顯示，這些由巨噬細胞收集的培養液證實Rab37以GTPase活性模式調控CHI3L1的分泌。接著我們在RAW264.7和THP-1之囊泡分離 (vesicle isolation) 及全內角反射螢光顯微鏡 (total internal reflection fluorescence microscopy, TIRF) 實驗中，證明CHI3L1的確存在於Rab37所調控的囊泡中，並且觀察到其動態運輸。我們開發了中和CHI3L1的多株抗體及11種全人類單株抗體，以進一步驗證CHI3L1作為治療性靶標。這些抗體抑制了植入MC38小鼠結腸癌細胞或源自KPPC胰腺特異性轉基因係的同種異體移植的免疫正常小鼠，以及MiaPaCa人類胰臟癌異種移植的免疫缺陷小鼠和具有MiaPaCa的人類造血幹細胞（hematopoietic stem cell, HSC）人類化鼠（humanized mice）的腫瘤生長。中和CHI3L1的抗體藥物的治療延長了小鼠的存活，並且沒有血清生化與器官毒性。從機制上講，中和CHI3L1的抗體藥物抑制了癌細胞中AKT/ERK的活化以及巨噬細胞的NF-κB入核。
研究結論： 本研究首次證明巨噬細胞中Rab37調控CHI3L1的分泌，並且抑制Rab37 / CHI3L1軸線的促腫瘤功能具有治療的重要性。

Background: Accumulating evidence indicates implication of Rab small GTPase-mediated exocytosis in tumorigenesis. In our previous study, Rab37-mediated exocytosis of chitinase 3-like 1 (CHI3L1) in T cells to promote lung cancer progression. CHI3L1 is secreted by a variety of cell types including macrophages, fibroblasts, neutrophils and tumor cells. Macrophages in the tumor microenvironment play important roles in modulating tumor growth and metastasis. However, the trafficking mode of CHI3L1 in macrophages remains largely unclear.
Purpose: This study aims to determine whether Rab37-mediated exocytosis of CHI3L1 in macrophages plays a promoting role in cancer progression and to investigate the treatment value of targeting Rab37/CHI3L1 axis.
Results: Our ELISA results confirmed that secreted level of CHI3L1 was decreased in ex vivo isolated mouse bone marrow derived macrophages (BMDMs) from Rab37 knockout (KO) mice compared to wild-type (WT) mice. We found colocalization of Rab37 and CHI3L1 in mouse macrophage cell lines RAW264.7 and BMDMs by confocal microscopy. To investigate whether Rab37 was involved in CHI3L1 exocytosis, we examined the presence of CHI3L1 in the collected conditioned medium (CM) from Rab37-WT, constitutive active GTP-bound Rab37-Q89L and dominant negative GDP-bound Rab37-T43N overexpressing macrophage cell lines RAW264.7 and THP-1. Notably, macrophage cell lines manipulated for Rab37 secreted CHI3L1 to CM via Rab37 in a GTPase-dependent manner. To investigate whether Rab37 was involved in CHI3L1 intracellular trafficking, vesicle isolation and total internal reflection fluorescence microscopy results showed the presence of CHI3L1 in Rab37-specific vesicles with dynamic trafficking moves. Next, we developed polyclonal neutralizing-CHI3L1 antibodies (nAbs) and 11 fully human monoclonal nAbs to further validate CHI3L1 as a therapeutic target. These nAbs suppressed the tumor growth in the immunocompetent mice implanted with MC38 mouse colon cancer or allografts derived from KPPC pancreatic specific transgenic line, immunodeficient mice with MiaPaCa human pancreatic cancer xenograft and human CD45+ hematopoietic stem cells (HSCs) humanized mice with MiaPaCa. The CHI3L1 nAb treatment prolonged survival without serum biochemical and organ toxicity of the treated mice. Mechanistically, CHI3L1 nAb inhibited AKT/ERK activation and NF-κB nuclear translocation in both cancer cells and macrophage cell lines.
Conclusion: These results provide the first evidence that Rab37 mediates CHI3L1 secretion in macrophages and tumor promoting function of Rab37/CHI3L1 axis may possess the therapeutic implications.

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