發(fā)布時(shí)間：2018-09-13 10:04

【摘要】：第一部分低氧對(duì)巨噬細(xì)胞M2型極化的選擇性促進(jìn)作用及其機(jī)制研究 目的：巨噬細(xì)胞具有很強(qiáng)的功能可塑性,根據(jù)誘導(dǎo)條件的不同,巨噬細(xì)胞可以極化成兩種主要的功能表型：經(jīng)典活化的巨噬細(xì)胞(M1型)和替代性活化的巨噬細(xì)胞(M2型)。腫瘤組織中的巨噬細(xì)胞被稱為腫瘤相關(guān)巨噬細(xì)胞(TAM),其表型和功能與腫瘤微環(huán)境密切相關(guān)。低氧作為眾多惡性腫瘤發(fā)生發(fā)展過程中所必然經(jīng)歷的微環(huán)境條件之一,已被證實(shí)在TAM的浸潤(rùn)中發(fā)揮著重要作用,但其在TAM極化表型轉(zhuǎn)換中的作用則鮮有研究。本部分研究將以低氧和巨噬細(xì)胞為研究對(duì)象,系統(tǒng)探討低氧對(duì)巨噬細(xì)胞表型極化的影響和相關(guān)作用機(jī)制。 方法：本研究采用小鼠巨噬細(xì)胞系RAW264.7和原代巨噬細(xì)胞BMDM作為研究對(duì)象。(1)流式細(xì)胞術(shù)檢測(cè)RAW264.7細(xì)胞和BMDM細(xì)胞膜表面抗原的表達(dá)；(2)免疫組化及免疫熒光檢測(cè)瘤組織切片相關(guān)蛋白的表達(dá)；(3)RT-PCR檢測(cè)M2型巨噬細(xì)胞相關(guān)mRNA的水平；(4)表達(dá)譜芯片分析相關(guān)差異基因的表達(dá)；(5)Western blot考察相關(guān)信號(hào)通路蛋白的表達(dá)。 結(jié)果：首先,采用免疫熒光技術(shù)對(duì)Lewis肺癌細(xì)胞(LLC)移植瘤組織中M2型巨噬細(xì)胞的表達(dá)及分布進(jìn)行檢測(cè),發(fā)現(xiàn)腫瘤中的巨噬細(xì)胞(F4/80+)大多表現(xiàn)為M2型(CD209+)且主要集中在低氧區(qū)域(PIMO+).這一結(jié)果提示,低氧可能對(duì)巨噬細(xì)胞的M2型極化有一定的調(diào)控作用。通過建立常壓低氧動(dòng)物模型,研究發(fā)現(xiàn)間歇性低氧處理C57BL/6小鼠能明顯促進(jìn)腫瘤組織中巨噬細(xì)胞的浸潤(rùn),同時(shí)伴隨著CD209+巨噬細(xì)胞比例的增加。進(jìn)一步利用體外低氧共培養(yǎng)模型,研究發(fā)現(xiàn)低氧處理RAW264.7細(xì)胞能選擇性地促進(jìn)巨噬細(xì)胞極化因子(LLC-CM、IL6、IL4和IL13)誘導(dǎo)的M2型表面標(biāo)記物CD209和CD206的表達(dá),但對(duì)M1型表面標(biāo)記物CD86的表達(dá)無(wú)明顯影響。此外,RT-PCR結(jié)果顯示低氧能顯著增加IL6誘導(dǎo)的M2型特征性基因Arg1和Yml的mRNA水平。表達(dá)譜基因芯片結(jié)果顯示低氧條件下IL6誘導(dǎo)的巨噬細(xì)胞表達(dá)高水平的M2型基因和低水平的M1型基因。在BMDM的原代巨噬細(xì)胞模型中,同樣發(fā)現(xiàn)低氧能促進(jìn)IL6誘導(dǎo)的CD209的表達(dá)。以上結(jié)果均表明,低氧能選擇性地促進(jìn)IL6誘導(dǎo)的巨噬細(xì)胞M2型極化。在機(jī)制研究方面,結(jié)合特異性抑制劑與分子生物學(xué)手段的應(yīng)用,發(fā)現(xiàn)IL6/STAT3信號(hào)通路及低氧相關(guān)的HIF信號(hào)通路并不直接參與低氧對(duì)巨噬細(xì)胞M2型極化的選擇性促進(jìn)作用。進(jìn)一步采用基因芯片技術(shù)分析不同誘導(dǎo)條件下獲得的巨噬細(xì)胞的差異基因,結(jié)果發(fā)現(xiàn)多個(gè)差異基因在MAPK信號(hào)級(jí)聯(lián)中富集。Western blot結(jié)果也顯示低氧能顯著增加巨噬細(xì)胞中p-ERK,p-p38,p-JNK的表達(dá)。通過采用特異性抑制劑,證實(shí)雖然低氧條件下MAPK的三條子信號(hào)通路都被激活,但只有抑制ERK信號(hào)后才能逆轉(zhuǎn)低氧介導(dǎo)的巨噬細(xì)胞M2型極化。 結(jié)論：低氧微環(huán)境可以選擇性地促進(jìn)巨噬細(xì)胞M2型極化,該選擇性促進(jìn)作用與ERK信號(hào)通路的激活密切相關(guān)。 第二部分低氧介導(dǎo)的M2型巨噬細(xì)胞對(duì)腫瘤轉(zhuǎn)移的影響 目的：低氧是包括非小細(xì)胞肺癌(NSCLC)在內(nèi)的多數(shù)實(shí)體瘤發(fā)展過程中所必然經(jīng)歷的微環(huán)境條件。長(zhǎng)期以來(lái),腫瘤低氧研究的重心是其對(duì)腫瘤細(xì)胞本身的影響,而忽視了低氧通過作用于非腫瘤細(xì)胞來(lái)推動(dòng)腫瘤發(fā)生發(fā)展的可能性。TAM作為非腫瘤細(xì)胞的主要成分,被認(rèn)為是腫瘤惡性行為的參與者。第一部分的研究已經(jīng)證實(shí)低氧能選擇性地促進(jìn)巨噬細(xì)胞的M2型極化(將該條件下獲得的M2型巨噬細(xì)胞定義為低氧介導(dǎo)的M2型巨噬細(xì)胞)。在本部分研究中,將以NSCLC為研究對(duì)象,考察低氧介導(dǎo)的M2型巨噬細(xì)胞對(duì)腫瘤轉(zhuǎn)移的影響,進(jìn)而探討低氧對(duì)巨噬細(xì)胞M2型極化的作用與低氧介導(dǎo)的腫瘤惡性行為(轉(zhuǎn)移)之間的相關(guān)性,有助于從新的角度完善腫瘤低氧研究領(lǐng)域,以期為腫瘤治療提供新的理論基礎(chǔ)和可能的治療策略。 方法：(1)免疫組化及免疫熒光檢測(cè)臨床病人樣本和瘤組織切片相關(guān)蛋白的表達(dá)；(2)劃痕修復(fù)和transwell小室法檢測(cè)細(xì)胞的遷移運(yùn)動(dòng)能力；(3)管腔形成實(shí)驗(yàn)考察HUVEC細(xì)胞的管腔形成能力；(4)C57BL/6動(dòng)物模型檢測(cè)Lewis肺癌的肺轉(zhuǎn)移率；(5)SRB染色法評(píng)價(jià)腫瘤細(xì)胞的增殖能力。 結(jié)果：36例人肺組織樣本基因芯片數(shù)據(jù)(GSE1987)分析和55例(其中20例為轉(zhuǎn)移病人)臨床NSCLC病人樣本的免疫組化分析結(jié)果表明M2型TAM與NSCLC的轉(zhuǎn)移密切相關(guān)。在此基礎(chǔ)上,通過體內(nèi)外實(shí)驗(yàn)評(píng)價(jià)第一部分中闡述的低氧介導(dǎo)的M2型巨噬細(xì)胞對(duì)NSCLC轉(zhuǎn)移的影響。體外實(shí)驗(yàn),采用條件培養(yǎng)基與LLC細(xì)胞或HUVEC細(xì)胞共孵育模型,通過細(xì)胞增殖實(shí)驗(yàn)、劃痕修復(fù)實(shí)驗(yàn)、transwell實(shí)驗(yàn)和管腔形成實(shí)驗(yàn)等手段,發(fā)現(xiàn)低氧介導(dǎo)的M2型RAW264.7細(xì)胞上清可增加HUVEC細(xì)胞的管腔形成和LLC細(xì)胞的遷移運(yùn)動(dòng),但對(duì)LLC細(xì)胞的增殖無(wú)影響。體內(nèi)實(shí)驗(yàn)發(fā)現(xiàn),將低氧介導(dǎo)的M2型RAW264.7細(xì)胞與LLC細(xì)胞的共接種可增加LLC的肺轉(zhuǎn)移發(fā)生率(從22.6%增加到100%)和移植瘤腫瘤組織中的血管生成。以上結(jié)果表明,低氧介導(dǎo)的M2型巨噬細(xì)胞具有強(qiáng)有力的促進(jìn)腫瘤血管生成和轉(zhuǎn)移的能力。鑒于低氧介導(dǎo)的M2型巨噬細(xì)胞表現(xiàn)出與低氧類似的促進(jìn)腫瘤演進(jìn)的功能,進(jìn)一步考察低氧對(duì)巨噬細(xì)胞M2型極化的促進(jìn)作用與低氧介導(dǎo)的腫瘤惡性行為之間的相關(guān)性。結(jié)果顯示,間歇性低氧處理C57BL/6小鼠可顯著促進(jìn)LLC的肺轉(zhuǎn)移發(fā)生率,從20%增加到60%。免疫熒光實(shí)驗(yàn)結(jié)果表明低氧處理后,腫瘤組織中的M2型巨噬細(xì)胞顯著增加。此外,本研究還發(fā)現(xiàn)ERK特異性抑制劑PD98059可通過靶向巨噬細(xì)胞,(而不是腫瘤細(xì)胞)抑制腫瘤細(xì)胞的遷移運(yùn)動(dòng)。 結(jié)論：低氧介導(dǎo)的M2型巨噬細(xì)胞,在體內(nèi)外均能顯著促進(jìn)腫瘤的轉(zhuǎn)移(遷移)和血管生成。干擾ERK可通過靶向巨噬細(xì)胞,抑制腫瘤細(xì)胞的遷移運(yùn)動(dòng)。 第三部分基于抑制TAMM2型極化的化合物M的發(fā)現(xiàn)及其抗轉(zhuǎn)移作用研究 目的：抑制TAM的M2型極化被認(rèn)為是極具應(yīng)用前景的抗腫瘤轉(zhuǎn)移新策略,但相關(guān)小分子化合物的發(fā)現(xiàn)尚處于起步階段。因此,尋找并發(fā)現(xiàn)特異性抑制TAMM2型極化的小分子化合物是開發(fā)以TAM為中心的治療策略的一個(gè)關(guān)鍵方向。前期研究中,通過篩選發(fā)現(xiàn)了特異性抑制巨噬細(xì)胞M2型極化的化合物M。在本部分研究中,將進(jìn)一步評(píng)價(jià)化合物M對(duì)腫瘤轉(zhuǎn)移的作用并初步探討其作用機(jī)制,確證通過小分子化合物干預(yù)M2型極化實(shí)現(xiàn)抗腫瘤轉(zhuǎn)移的可行性,以期為設(shè)計(jì)全新抗腫瘤轉(zhuǎn)移化合物或干預(yù)手段提供思路及潛在靶點(diǎn)。 方法：(1)SRB染色法評(píng)價(jià)細(xì)胞增殖能力；(2)流式細(xì)胞術(shù)檢測(cè)RAW264.7細(xì)胞和BMDM細(xì)胞膜表面抗原的表達(dá)；(3)免疫熒光檢測(cè)瘤組織切片中相關(guān)蛋白的表達(dá)；(4)RT-PCR檢測(cè)M1、M2型巨噬細(xì)胞特征性mRNA水平；(5) Transwell小室法檢測(cè)腫瘤細(xì)胞的遷移運(yùn)動(dòng)；(6)C57BL/6動(dòng)物模型考察LLC的肺轉(zhuǎn)移情況；(7)HE染色檢測(cè)肺部轉(zhuǎn)移灶點(diǎn)；(8)Western blot考察相關(guān)信號(hào)通路蛋白的表達(dá)。結(jié)果：體外采用經(jīng)典的IL13誘導(dǎo)的M2型巨噬細(xì)胞極化模型,從眾多化合物中篩選得到可抑制巨噬細(xì)胞M2型極化的化合物M。在此基礎(chǔ)之上,進(jìn)一步應(yīng)用IL4和IL6誘導(dǎo)的M2型極化模型,也得到了同樣的結(jié)果。另一方面,通過對(duì)IFNy和LPS誘導(dǎo)的M1型巨噬細(xì)胞極化模型的考察,發(fā)現(xiàn)化合物M能選擇性抑制巨噬細(xì)胞M2型極化,而對(duì)M1型極化無(wú)影響。LLC移植瘤組織切片的免疫熒光結(jié)果表明化合物M在體內(nèi)也能抑制巨噬細(xì)胞的M2型極化。進(jìn)一步考察化合物M的體外抗轉(zhuǎn)移作用,研究發(fā)現(xiàn)化合物M可通過抑制巨噬細(xì)胞的M2型極化來(lái)影響腫瘤細(xì)胞的遷移運(yùn)動(dòng)。LLC自發(fā)肺轉(zhuǎn)移動(dòng)物實(shí)驗(yàn)結(jié)果顯示化合物M具有體內(nèi)抗腫瘤轉(zhuǎn)移作用。通過引入巨噬細(xì)胞“清除劑”脂質(zhì)體氯磷酸鹽,研究發(fā)現(xiàn)化合物M對(duì)腫瘤肺轉(zhuǎn)移的抑制作用可能是通過抑制腫瘤組織中巨噬細(xì)胞的M2型極化來(lái)發(fā)揮作用的。免疫熒光結(jié)果證實(shí)化合物M能減少移植瘤腫瘤組織中新生血管的形成。機(jī)制研究證實(shí)化合物M通過激活A(yù)MPK來(lái)發(fā)揮抑制巨噬細(xì)胞M2型極化的作用。 結(jié)論：小分子化合物M能選擇性地抑制巨噬細(xì)胞M2型極化,并基于此發(fā)揮體內(nèi)外抗轉(zhuǎn)移作用。化合物M對(duì)巨噬細(xì)胞M2型極化的選擇性抑制作用依賴于AMPK信號(hào)通路的激活。
[Abstract]:Part one: selective enhancement of hypoxia on macrophage M2 polarization and its mechanism
AIM: Macrophages have strong functional plasticity. According to different induction conditions, macrophages can be polarized into two major functional phenotypes: classically activated macrophages (M1) and alternatively activated macrophages (M2). Macrophages in tumor tissues are called tumor-associated macrophages (TAM), and their phenotypes and functions are known as tumor-associated macrophages (TAM). Hypoxia has been proved to play an important role in the invasion of TAM as one of the necessary microenvironment conditions in the development of many malignant tumors, but its role in the polarization phenotype transition of TAM is rarely studied. Effects of hypoxia on phenotypic polarization of macrophages and related mechanisms were discussed.
METHODS: Mouse macrophage line RAW264.7 and primary macrophage BMDM were used as the research objects. (1) The expression of membrane surface antigen in RAW264.7 and BMDM cells was detected by flow cytometry; (2) The expression of tumor slice-related protein was detected by immunohistochemistry and immunofluorescence; (3) The expression of M 2 macrophage-related mRNA was detected by RT-PCR. Ping; (4) Expression profiles were used to analyze the expression of related differentially expressed genes; (5) Western blot was used to investigate the expression of related signaling pathway proteins.
Results: Immunofluorescence technique was used to detect the expression and distribution of M2 macrophages in Lewis lung cancer cell (LLC) transplanted tumor tissues. It was found that most of the macrophages (F4/80+) in the tumor were M2 (CD209+) and mainly concentrated in the hypoxic region (PIMO+). The results suggested that hypoxia might polarize M2 of macrophages. It was found that intermittent hypoxia treatment of C57BL/6 mice could significantly promote the infiltration of macrophages in tumor tissues, accompanied by an increase in the proportion of CD209 + macrophages. In addition, RT-PCR showed that hypoxia significantly increased the mRNA levels of IL-6-induced M2 specific genes Arg1 and Yml. Gene chip analysis showed that hypoxia significantly increased the expression of IL-6-induced M2 specific genes Arg1 and Yml. In the primary macrophage model of BMDM, hypoxia can also promote the expression of CD209 induced by IL 6. These results suggest that hypoxia can selectively promote IL 6-induced M2 polarization in macrophages. It was found that IL-6/STAT3 signaling pathway and hypoxia-related HIF signaling pathway were not directly involved in the selective promotion of hypoxia on the polarization of macrophage M2. The differentially expressed genes of macrophages under different induction conditions were further analyzed by gene chip technique. Western blot also showed that hypoxia significantly increased the expression of p-ERK, p-p38, p-JNK in macrophages. Specific inhibitors were used to confirm that although all three MAPK signaling pathways were activated under hypoxia, hypoxia-mediated macrophage fineness could only be reversed by inhibiting ERK signaling. Cell type M2 polarization.
Conclusion: Hypoxic microenvironment can selectively promote the polarization of M2 in macrophages, which is closely related to the activation of ERK signaling pathway.
The second part is the effect of hypoxia mediated M2 macrophages on tumor metastasis.
OBJECTIVE: Hypoxia is an essential microenvironment in the development of most solid tumors, including non-small cell lung cancer (NSCLC). For a long time, the focus of tumor hypoxia research has been on the effect of hypoxia on tumor cells themselves, ignoring the possibility of hypoxia promoting tumor development by acting on non-tumor cells. The first part of this study has demonstrated that hypoxia selectively promotes the M2 polarization of macrophages (defined as hypoxia-mediated M2 macrophages). The effect of hypoxia-mediated M2 macrophages on tumor metastasis and the correlation between hypoxia-mediated M2 polarization and hypoxia-mediated malignant behavior (metastasis) of tumor are discussed. It is helpful to perfect the research field of tumor hypoxia from a new perspective and provide a new theoretical basis and possible therapeutic strategies for tumor therapy.
Methods: (1) Immunohistochemistry and immunofluorescence were used to detect the expression of tumor-related proteins in clinical samples and tumor tissues; (2) Scratch repair and Transwell chamber were used to detect the migration and motility of HUVEC cells; (3) lumen formation test was used to investigate the lumen formation ability of HUVEC cells; (4) C57BL/6 animal model was used to detect the lung metastasis rate of Lewis lung cancer; (5) The proliferation ability of tumor cells was evaluated by SRB staining.
RESULTS: Gene chip data of 36 human lung tissue samples (GSE1987) and immunohistochemical analysis of 55 clinical NSCLC patients (20 of whom were metastatic) showed that M2 TAM was closely related to the metastasis of NSCLC. On this basis, hypoxia-mediated M2 macrophages were evaluated in vitro and in vivo. In vitro experiments, conditioned medium was used to co-incubate with LLC cells or HUVEC cells. By means of cell proliferation, scratch repair, Transwell and lumen formation, hypoxia-mediated supernatant of M2 RAW264.7 cells was found to increase lumen formation and migration of LLC cells. In vivo experiments showed that hypoxia-mediated co-inoculation of M 2 RAW264.7 cells with LLC cells increased the incidence of lung metastasis (from 22.6% to 100%) and angiogenesis in transplanted tumor tissues. The ability of hypoxia-mediated M2 macrophages to promote tumor progression was similar to hypoxia. The relationship between hypoxia-mediated M2 polarization and hypoxia-mediated malignant behavior was further investigated. The results showed that intermittent hypoxia treatment could significantly promote LL in C57BL/6 mice. The incidence of lung metastasis of C increased from 20% to 60%. Immunofluorescence assay showed that M2 macrophages in tumor tissues were significantly increased after hypoxia treatment. In addition, this study also found that ERK-specific inhibitor PD98059 could inhibit the migration of tumor cells by targeting macrophages rather than tumor cells.
Conclusion: Hypoxia-mediated M2 macrophages can significantly promote tumor metastasis (migration) and angiogenesis in vivo and in vitro. Interference with ERK can inhibit the migration of tumor cells by targeting macrophages.
The third part is based on the discovery of compound M which inhibits TAMM2 polarization and its anti metastasis effect.
OBJECTIVE: Inhibition of TAM-2 polarization is considered to be a promising new strategy for tumor metastasis, but the discovery of related small molecule compounds is still in its infancy. In this part, we will further evaluate the effect of compound M on tumor metastasis and explore its mechanism, confirm the feasibility of anti-tumor metastasis through small molecule compounds interfering with M2 polarization, in order to design a new anti-tumor metastasis. Combination or intervention provides ideas and potential targets.
Methods: (1) SRB staining was used to evaluate cell proliferation; (2) Flow cytometry was used to detect the expression of membrane antigens on RAW264.7 cells and BMDM cells; (3) immunofluorescence was used to detect the expression of related proteins in tumor tissue slices; (4) RT-PCR was used to detect the characteristic mRNA level of M1 and M 2 macrophages; (5) Transwell chamber was used to detect the migration of tumor cells. Exercise; (6) C57BL/6 animal model to investigate the lung metastasis of LLC; (7) HE staining to detect the lung metastasis site; (8) Western blot to investigate the expression of related signal pathway proteins. Results: The classical IL 13-induced polarization model of M2 macrophages was used in vitro, and the compounds were screened from a number of compounds to inhibit the polarization of M2 macrophages. On the other hand, the polarization model of M1 macrophages induced by IFNy and LPS was investigated. It was found that compound M selectively inhibited the polarization of M2 macrophages, but had no effect on the polarization of M1 macrophages. Immunofluorescence assay showed that compound M could also inhibit the M2 polarization of macrophages in vivo. Further investigation of the anti-metastasis effect of compound M in vitro showed that compound M could affect the migration of tumor cells by inhibiting the M2 polarization of macrophages. Tumor metastasis. By introducing macrophage scavenger liposome chlorophosphate, it was found that the inhibitory effect of compound M on tumor lung metastasis may be mediated by inhibiting the M2 polarization of macrophages in tumor tissues. Immunofluorescence results showed that compound M could reduce neovascularization in tumor tissues. Mechanism study confirmed that compound M could inhibit macrophage M2 polarization by activating AMPK.
Conclusion: Small molecule compound M can selectively inhibit the polarization of macrophage M2 and exert its anti-metastasis effect in vitro and in vivo. The selective inhibition of compound M on the polarization of macrophage M2 depends on the activation of AMPK signaling pathway.
【學(xué)位授予單位】：浙江大學(xué)
【學(xué)位級(jí)別】：博士
【學(xué)位授予年份】：2014
【分類號(hào)】：R965

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