趋化因子CCL2、CCL3、CCL14调节巨噬细胞在多发性骨髓瘤归巢、增殖与分化中的作用及机制研究
发布时间：2018-10-22 10:00
【摘要】：多发性骨髓瘤(multiple myeloma, MM)是起源于B细胞的血液系统恶性肿瘤,以单克隆性浆细胞的异常增生为主要特征。随着研究的深入,以新药如蛋白酶体抑制剂、免疫调节剂为基础的联合化疗联合自体干细胞移使MM的治疗取得了重大的进展,但MM目前仍是一种不可治愈的疾病,化疗耐药是治疗失败的主要问题。因此,进一步研究MM细胞耐药机制,寻找克服耐药的方法提高患者的治疗效果,是临床上亟待解决的问题。 我们的前期研究发现,MM患者骨髓(bone marrow, BM)存在巨噬细胞(MΦs)的大量浸润并保护MM细胞免于化疗药物诱导的凋亡。一些临床研究也证实MM患者BM中MOs的浸润与预后不良相关。但MΦs在MM BM中大量浸润的原因仍不清楚。大多数研究认为,与正常MΦs一样,MM中的MΦs (multiple myeloma associated macrophages, mMΦs)起源于外周循环中的单核细胞(monocytes, MOs),在肿瘤细胞和/或肿瘤微环境分泌的趋化因子作用下向组织定向移动进而分化、发育,行使特定的生物学功能。我们的研究旨在探索MM中调节MOs/MΦs募集的关键因子并研究其作用机制。我们的结果表明,较之正常供者,趋化因子CCL2,CCL3, CCL14在MMBM中表达增高。临床样本显示,MM患者BM上清中趋化因子CCL3和CCL14的蛋白表达水平与MΦs在患者BM中的含量正相关。通过分析趋化因子的分泌来源,我们发现MM细胞与骨髓基质细胞(bone marrow stroma cells, BMSCs)均可表达趋化因子,而与MM细胞株共培养的BMSCs可以上调以上三种趋化因子的表达。体外实验进一步证明使用上述三种趋化因子中和抗体可以减少MOs向MM肿瘤微环境的迁移。在MM动物模型中,荷瘤小鼠BM较对照组存在MΦs的大量浸润,且CCL2. CCL3在荷瘤小鼠BM中分泌水平较高。使用趋化因子的中和抗体可以显著减少MOs/MΦs在小鼠BM中浸润的数量。因此,我们的研究证实趋化因子CCL2, CCL3, CCL14在MMBM中表达增高,并且是调节MOs/MΦs在MMBM中浸润的关键因子。 在一些实体瘤和代谢性疾病的研究中发现,组织中定植的MΦs具有类似干细胞“自我更新”的能力发生增殖,是肿瘤组织中MOs/MΦs浸润增多的原因之一。我们的研究首次发现与MM细胞共培养的MOs/MΦs在体外、体内均发生增殖。除了趋化细胞的定向移动,越来越多的研究表明趋化因子与肿瘤细胞的的生长、侵袭与转移相关。我们发现趋化因子CCL2, CCL3, CCL14通过活化细胞增殖相关的PI3K/Akt及MAPK/Erk信号通路及上调原癌基因c-myc的表达促进MM中MOs/MOs的增殖与分化。因此,本研究结果表明趋化因子CCL2, CCL3, CCL14不仅是MM中调控MOs/MΦs募集的重要因子,更在MOs/MΦs增殖、分化的调节中起重要作用。 综上所述,我们的研究发现趋化因子CCL2、CCL3、CCL14不仅是介导MOs/MOs在MMBM中募集与定向移动的关键因子,也通过活化PI3K/Akt及MAPK/Erk信号通路及上调c-myc的表达促进MOs/MΦs在MM中的增殖与分化。MΦs在MM BM中的大量浸润是MM患者预后不良的高危因素。因此,研究趋化因子调控MOs/MΦs在MM BM中募集、增殖与分化中的作用和相关机制为MM的诊疗提供了新的理论依据,针对趋化因子的靶向治疗可以减少MΦs在MM中的浸润,是MM治疗的新策略。
[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，
本文编号：2286852
[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，
本文编号：2286852
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