【摘要】：多發(fā)性骨髓瘤(multiple myeloma, MM)是起源于B細(xì)胞的血液系統(tǒng)惡性腫瘤,以單克隆性漿細(xì)胞的異常增生為主要特征。隨著研究的深入,以新藥如蛋白酶體抑制劑、免疫調(diào)節(jié)劑為基礎(chǔ)的聯(lián)合化療聯(lián)合自體干細(xì)胞移使MM的治療取得了重大的進(jìn)展,但MM目前仍是一種不可治愈的疾病,化療耐藥是治療失敗的主要問題。因此,進(jìn)一步研究MM細(xì)胞耐藥機(jī)制,尋找克服耐藥的方法提高患者的治療效果,是臨床上亟待解決的問題。 我們的前期研究發(fā)現(xiàn),MM患者骨髓(bone marrow, BM)存在巨噬細(xì)胞(MΦs)的大量浸潤并保護(hù)MM細(xì)胞免于化療藥物誘導(dǎo)的凋亡。一些臨床研究也證實(shí)MM患者BM中MOs的浸潤與預(yù)后不良相關(guān)。但MΦs在MM BM中大量浸潤的原因仍不清楚。大多數(shù)研究認(rèn)為,與正常MΦs一樣,MM中的MΦs (multiple myeloma associated macrophages, mMΦs)起源于外周循環(huán)中的單核細(xì)胞(monocytes, MOs),在腫瘤細(xì)胞和/或腫瘤微環(huán)境分泌的趨化因子作用下向組織定向移動進(jìn)而分化、發(fā)育,行使特定的生物學(xué)功能。我們的研究旨在探索MM中調(diào)節(jié)MOs/MΦs募集的關(guān)鍵因子并研究其作用機(jī)制。我們的結(jié)果表明,較之正常供者,趨化因子CCL2,CCL3, CCL14在MMBM中表達(dá)增高。臨床樣本顯示,MM患者BM上清中趨化因子CCL3和CCL14的蛋白表達(dá)水平與MΦs在患者BM中的含量正相關(guān)。通過分析趨化因子的分泌來源,我們發(fā)現(xiàn)MM細(xì)胞與骨髓基質(zhì)細(xì)胞(bone marrow stroma cells, BMSCs)均可表達(dá)趨化因子,而與MM細(xì)胞株共培養(yǎng)的BMSCs可以上調(diào)以上三種趨化因子的表達(dá)。體外實(shí)驗(yàn)進(jìn)一步證明使用上述三種趨化因子中和抗體可以減少M(fèi)Os向MM腫瘤微環(huán)境的遷移。在MM動物模型中,荷瘤小鼠BM較對照組存在MΦs的大量浸潤,且CCL2. CCL3在荷瘤小鼠BM中分泌水平較高。使用趨化因子的中和抗體可以顯著減少M(fèi)Os/MΦs在小鼠BM中浸潤的數(shù)量。因此,我們的研究證實(shí)趨化因子CCL2, CCL3, CCL14在MMBM中表達(dá)增高,并且是調(diào)節(jié)MOs/MΦs在MMBM中浸潤的關(guān)鍵因子。 在一些實(shí)體瘤和代謝性疾病的研究中發(fā)現(xiàn),組織中定植的MΦs具有類似干細(xì)胞“自我更新”的能力發(fā)生增殖,是腫瘤組織中MOs/MΦs浸潤增多的原因之一。我們的研究首次發(fā)現(xiàn)與MM細(xì)胞共培養(yǎng)的MOs/MΦs在體外、體內(nèi)均發(fā)生增殖。除了趨化細(xì)胞的定向移動,越來越多的研究表明趨化因子與腫瘤細(xì)胞的的生長、侵襲與轉(zhuǎn)移相關(guān)。我們發(fā)現(xiàn)趨化因子CCL2, CCL3, CCL14通過活化細(xì)胞增殖相關(guān)的PI3K/Akt及MAPK/Erk信號通路及上調(diào)原癌基因c-myc的表達(dá)促進(jìn)MM中MOs/MOs的增殖與分化。因此,本研究結(jié)果表明趨化因子CCL2, CCL3, CCL14不僅是MM中調(diào)控MOs/MΦs募集的重要因子,更在MOs/MΦs增殖、分化的調(diào)節(jié)中起重要作用。 綜上所述,我們的研究發(fā)現(xiàn)趨化因子CCL2、CCL3、CCL14不僅是介導(dǎo)MOs/MOs在MMBM中募集與定向移動的關(guān)鍵因子,也通過活化PI3K/Akt及MAPK/Erk信號通路及上調(diào)c-myc的表達(dá)促進(jìn)MOs/MΦs在MM中的增殖與分化。MΦs在MM BM中的大量浸潤是MM患者預(yù)后不良的高危因素。因此,研究趨化因子調(diào)控MOs/MΦs在MM BM中募集、增殖與分化中的作用和相關(guān)機(jī)制為MM的診療提供了新的理論依據(jù),針對趨化因子的靶向治療可以減少M(fèi)Φs在MM中的浸潤,是MM治療的新策略。
[Abstract]:Multiple myeloma (MM) is a malignant tumor derived from B-cell blood system, characterized by abnormal proliferation of monoclonal plasma cells. With the in-depth study, the combination chemotherapy combined with new drug, such as proteome inhibitor and immunomodulator, has made MM treatment progress, but MM is still a incurable disease, chemotherapy drug resistance is the main problem of treatment failure. Therefore, it is urgent to further study the mechanism of MM cell resistance and find ways to overcome the drug resistance. Our previous studies have found that bone marrow (BM) in MM patients has a large infiltration of macrophages (M/ s) and protects MM cells from chemotherapy drug-induced Apoptosis. Some clinical studies also confirmed that the infiltration and prognosis of MMPs in MM patients were poor. Correlate. However, the reason for the large infiltration of MMPs in MM BM is still not It is clear that the majority of the studies suggest that, as in normal M\ s\ s\ s\ x {\ expndtw-1 M\ x {\ expndtw-1 M\ s\ x {\ expndtw-1 M\ s} {\ expndtw-1\ x {\ expndtw-1\ cf1 as in normal M\ x {\ expndtw-1\ x {\ expndtw-1 M\ x {\ expndtw-1 M\ x {\ expndtw-1 M\ x {\ expndtw-1 M\ x {\ expndtw-1\ x {\ expndtw-1\ expndtw-1\ cf1\ cf1 As with normal M\ {\ expndtw-1\ x {\ expndtw-1\ x {\ expndtw-1 M\ x {\ expndtw-1\ x {\ expndtw-1\ expndtw-1\ cf1\ x {\ expndtw-1\ cf1\ f2} {\ expndtw-1\ cf1\ f2} {\ fs22\ expndtw-1\ cf1\ cf1\ f2} {\ fs22\ expndtw-To develop and exercise specific biology. Function. Our study aims to explore the key factors in MM's regulation of MOs/ M Wells and study its role The results showed that CCL2, CCL3 and CCL14 were expressed in MMBM than normal donors. The clinical samples showed that the levels of protein expression levels of CCL3 and CCL14 and the content of MMPs in BM were positive in MM patients. Correlation. We found that MM cells and bone marrow stromal cells (BMSCs) can express chemokine, while BMSCs co-cultured with MM cell strain can upregulate the above three chemotactic factors. In vitro experiments further demonstrate that the use of the above three chemotactic factors and antibodies can reduce the MMPs to MM tumor microenvironment Migration. In MM animal model, BM of tumor-bearing mice had a large infiltration of M% s in the control group, and CC L2. CCL3 secretion level in BM of tumor-bearing mice Higher levels. Neutralizing antibodies using chemotactic factors can significantly reduce the infiltration of MOs/ M/ s in mouse BM Therefore, our studies confirm that the expression of chemokine CCL2, CCL3 and CCL14 in MMBM is increased, and it is the key to regulate the infiltration of MMPs/ MMPs in MMBM. Factor. In some studies of solid tumors and metabolic diseases, M/ s planted in tissue has the ability to proliferate similar to the 鈥渟elf-renewal鈥，

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