神經膠質瘤被視為一種極具侵略性的惡性腫瘤。即便目前先進的醫療技術，經過治療後的患者仍呈現極差的預後情形，且容易產生腫瘤復發的狀況。此現象除了腫瘤本身的惡性程度，腫瘤相關免疫細胞與腫瘤間的交互作用也扮演了非常重要的角色，因為這些免疫細胞尤其巨噬細胞容易作為提供腫瘤優良生長環境的幫手。神經纖維蛋白-1 (Neuropilin-1,Nrp1) 是一種具多功能性的膜蛋白。其參與了非常多的生理與病理機制。在腫瘤環境中，因為可以被血管內皮細胞、特定免疫細胞與腫瘤細胞表現，它與血管新生及腫瘤免疫息息相關。然而其功能及參與機制過於廣泛複雜，仍未完全研究透徹。此篇研究目的為探討Nrp1對於神經膠質瘤所扮演的角色及了解腦瘤細胞與腫瘤相關巨噬細胞兩者所表現的Nrp1是否有互相調節之關係存在。有研究指出，Nrp1的表現與人類腦腫瘤的惡性程度呈現正相關趨勢，因為Nrp1能幫助增加腫瘤血管新生及侵襲能力。另外表現Nrp1的巨噬細胞也被指出具抑制免疫反應之功能。於此篇論文，我們利用慢病毒轉染shRNA系統抑制腦癌細胞株ALTS1C1的Nrp1表現 (ALTS1C1_Nrp1kd)，並使用原位腦腫瘤模型探討Nrp1於腦瘤微環境帶來的影響。Nrp1抑制腫瘤細胞及腫瘤模型生長，且Nrp1表現與血管密度具高度相關性。另外我們發現成熟的F4/80巨噬細胞有高度Nrp1表現，雖然在Nrp1kd腫瘤內的數量沒有太大差異，但較多的M2傾向巨噬細胞分布在缺氧區。當腫瘤細胞與骨髓分化巨噬細胞共培養，巨噬細胞的Nrp1大幅增加但腫瘤的Nrp1則被抑制，有趣的是此現象似乎與腫瘤上的Nrp1沒有關聯。綜上所述，Nrp1可作為具潛力的癌症治療策略目標。

Astrocytoma is characterized as one of the most invasive malignancies. After current treatment, the patients sill have poor prognosis. Besides the malignant properties of tumors, the interaction between tumors and stromal immune cells played a critical role in contributing to a tumor-favoring complex microenvironment. Neuropilin-1 (Nrp1) is a transmembrane protein involves in many mechanisms such as angiogenesis and immune reaction during tumor progression. It can be expressed on vascular epithelial cells, immune cells, and specific tumor cells. However, due to the diverse involvement in different process, it is still not fully elucidated. One of the purpose of this study is to clarify the regulation of Nrp1 between interaction of brain tumors and tumor-associated macrophages (TAM). Evidence shows that the malignancy of human astrocytoma is positive correlated to its Nrp1 expression, enhancing the angiogenic and invasive ability of tumors. In addition, Nrp1 expressing TAMs are involved in suppression of anti-tumor immunity. In this study, Nrp1 was suppressed by lentiviral transduction of siRNA to reveal the role of Nrp1 in brain tumor microenvironment with the orthotopic brain tumor model ALTS1C1 (ALTS1C1_Nrp1kd). Inhibition of Nrp1 can delay tumor cell growth and orthotopic tumor progression. Also Nrp1 is closely related to angiogenesis in ALTS1C1 tumors. With higher level of Nrp1, higher vascular density is in the tumor region. In immune microenvironment, F4/80+ TAMs are the main contributors of Nrp1, and the expression level is associated with the maturation state. Although the amount of TAMs in tumor site is not affected in ALTS1C1_Nrp1kd tumors, more M2-type CD206+ TAM is distributed in hypoxia. After interaction of ALTS1C1 tumor cells and bone marrow derived macrophages (BMDM), a counter regulation is observed. The Nrp1 on BMDMs is dramatically elevated; on the opposite, the Nrp1 on the tumor cells is suppressed. Interestingly, the regulation seems to be tumor-expressing Nrp1 independent. Altogether, the targeting of Nrp1 could be a possible candidate for cancer therapeutic research.

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