摘要
肿瘤微环境是肿瘤周围复杂的细胞生态系统,与肿瘤细胞的生长,迁移,转移和抗药性都有密切关系。胰腺导管腺癌特征性组织病理学改变为间质内大量纤维结缔组织增生,产生这种组织学特征的分子生物学基础是肿瘤微环境内纤维母细胞活化、增生并产生大量细胞外基质。这种纤维母细胞因其对肿瘤细胞的多种支持作用称为肿瘤相关纤维母细胞(CAF)。关于CAF的来源、活化和对肿瘤的支持作用是胰腺导管腺癌肿瘤微环境研究中的重要课题。
本研究从两方面初步探讨了CAF对胰腺导管腺癌细胞的促进作用。
一、探讨了关于间充质干细胞样肿瘤相关纤维母细胞(MSCs-like CAF)对肿瘤细胞干细胞性和迁移力的作用。间充质干细胞(MSCs)是CAF的来源之一,它受到肿瘤细胞或微环境中炎症及缺氧环境释放的化学趋化因子的作用,通过血循环定位到肿瘤间质内,分化成CAF,一些CAF还保留部分间充质干细胞性。已知一些研究利用骨髓或脂肪来源的“正常”MSCs,发现其对肿瘤细胞有多方面作用,而肿瘤间质内的MSC样CAF在肿瘤微环境中作用还未明确。
本研究采用outgrowth法原代培养胰腺导管腺癌CAF,通过检测CK19及CD45抗原表达排除原代培养细胞群中的上皮细胞和免疫细胞,由于考虑到胰腺癌中存在的上皮-间质转化现象,胰腺肿瘤细胞会丢失CK19抗原表达,所以应用肿瘤细胞和肿瘤相关纤维母细胞配对Kras突变检测法,排除原代培养CAF中肿瘤细胞污染。得到的细胞群通过MSCs表面标记物CD90/CD73/CD44/CD49a,利用流式细胞术分选出间充质干细胞样的CAF,证明其具有集落形成能力及向骨、软骨和脂肪的分化能力。
"CD90+/CD73+/CD44+/CD49a+肿瘤相关纤维母细胞群对胰腺癌肿瘤细胞的作用：
1增加肿瘤细胞干细胞性。
在肿瘤细胞和CAF直接共同培养组和与CAF条件培养基间接共同培养组,均发现MSCs-CAF在增加肿瘤细胞干细胞团数量和肿瘤干细胞群CD44+/c-Met+比例方面均强于不具有间充质干细胞性的CAF,其中直接培养组的作用效果更明显。
2增加肿瘤细胞迁移力。
利用3D胶原滴共同培养方法,观察到在直接共同培养组和条件培养基间接共同培养组中,MSCs-CAF在增加肿瘤细胞迁移距离方面均强于不具有间充质干细胞性的CAF,其中直接培养组的作用效果更明显,肿瘤细胞呈现不连续的跳跃式生长,且在一例直接培养组中发现肿瘤细胞出现灶状生长。
3MSCs-CAF分泌特殊的细胞因子。
在检测的36种常见间质细胞分泌细胞因子中发现,MSCs-CAF和不具有间充质干细胞性的CAF均有MIF和Serpin E1分泌,且两组间差异不具统计学意义。CXCL-1,白介素-6(IL-6),白介素-8(IL-8)三种细胞因子在MSCs-CAF中特异表达或表达量高于不具有间充质干细胞性的CAF。粒细胞和巨噬细胞集落刺激因子(GM-CSF)在4例CAF中特异性表达于MSCs-CAF.
第一部分结果显示胰腺导管腺癌间质中分离的具有间充质干细胞性的肿瘤相关纤维母细胞是一群对肿瘤实质细胞干细胞性和迁移力具有更强作用的细胞,对肿瘤细胞的作用不仅通过直接接触作用,还包括分泌的细胞因子,其分泌的特异性细胞因子可能是其独特作用的分子基础。
二、研究关于维甲酸对CAF的抑制作用。有研究发现正常胰腺间质内纤维母细胞在受到炎症、低氧或肿瘤细胞分泌的多种细胞因子的刺激下,胞浆内Vitamin A脂滴的丢失和CAF活化有关。活化后的CAF对肿瘤细胞的生长和进展发挥多种支持作用。本研究试图应用Vitamin A的小分子亲脂性衍生物—维甲酸(RA)作用胰腺癌CAF,使其活性功能发生静止,探讨CAF对肿瘤细胞迁移力的支持作用以及全反式维甲酸(ATRA)和9-顺式-维甲酸(9-cis-RA)通过静止CAF功能后,对肿瘤细胞迁移力的间接抑制作用。
本部分研究发现1.维甲酸对不同胰腺癌肿瘤细胞系有不同作用。ATRA和9-cis-RA对Aspc-1有增殖抑制作用,并且使肿瘤细胞大部分位于G1期,但对Aspc-1无促凋亡作用；对Panc-1在药物高浓度组(20μM)有促细胞早期凋亡作用,但晚期凋亡率与对照组相比无明显变化,且9-cis-RA比ATRA对Panc-1的促凋亡作用更明显,ATRA和9-cis-RA对Panc-1无增殖抑制作用。
2.RA可以抑制CAF的活性状态。表现为RA作用后,CAF内脂滴增多,CAF活性相关蛋白α-SMA和FAP表达下降,细胞外基质产物collagen Ⅰ、fibronectin和laminin基因水平下降,以及细胞因子IL-6/8表达下降,但是RA对CAF的抑制作用不是通过促其凋亡产生的。
3.RA可以抑制CAF产生的可溶性细胞因子,使其对肿瘤细胞迁移和上皮-间质转化(EMT)的促进作用减弱,所以RA间接抑制了肿瘤细胞的迁移和EMT。表现为RA作用后的CAF的条件培养基抑制了肿瘤细胞在3D胶原模型中的迁移距离和向远处迁移细胞数量,而且在3D模型中诱发的肿瘤细胞EMT现象被抑制,RA的作用减少了CAF条件培养基中IL-6的含量,再加入IL-6可恢复肿瘤细胞EMT表型,但RA对肿瘤细胞的迁移和EMT相关基因表达水平并没有直接作用,说明CAF条件培养基中被抑制的可溶性细胞因子减弱了肿瘤细胞迁移力。
第二部分研究发现RA可以抑制肿瘤相关纤维母细胞的活性状态,表现为CAF相关活化蛋白、相关产物和细胞因子表达水平下降,但并不通过介导CAF的凋亡发挥作用,功能被抑制的CAF对肿瘤细胞的迁移力的支持作用减弱,表现为EMT过程的抑制,而涉及这一过程的是CAF分泌的可溶性细胞因子IL-6。
综上所述,胰腺癌肿瘤微环境中的肿瘤相关纤维母细胞具有异质性,其中具有间充质干细胞性的CAF具有更强的促肿瘤增殖和迁移作用,并有独特的细胞因子分泌,而通过利用维甲酸对CAF的抑制作用研究发现,CAF通过分泌细胞因子促进肿瘤细胞迁移,维甲酸可以阻断这一途径而达到对肿瘤的抑制作用。
Tumor microenvironment is complex cellular ecological system arrounding tumor cells and supports the proliferation, migration, metastasis and drug resistance of tumor cells. The significant pathological characteristic of pancreatic ductal adenocarcinoma is desmoplasia. The molecular biological basis of this phenomenon is that fibroblast cells are activated, grow and produce huge extracellular matrix in tumor microenvironment. As potent supporters of tumor cells, such fibroblast cells are called cancer-associated fibroblast cells. Studies about the origins, activation status and supportive effect of CAFs to tumor cells are of vital importance to the knowledge of tumor microenvironment.
There are two parts about the pro-carcinogenesis function of CAFs.
1. Mesenchymal stem cells like CAFs (MSC-like CAFs) promoted sternness and migration of tumor cells. MSCs is one of origins of CAFs and is induced by chemokines secreted by tumor cells or produced in inflammation or hypoxic background in tumor microenvironment. Then they are recruited through circulation to tumor stroma and differentiated into CAFs. Some CAFs still have some mesenchymal sternness. It is reported that "normal" MSCs came from bone marrow or adipose supported tumor growth in many ways. While, the function of MSCs-like CAFs in tumor microenvironment is not clear yet.
We cultured CAF of human pancreatic ductal adenocarcinoma by outgrowth method. Then the contamination of epithelial cells and immunocytes were excluded by immunohistochemistry stain of CK19and CD45. However, given the thoughts that there might be epithelial cells lost their epithelial antigen during the process of epithelial-mesenchymal transforms, the negative stain of CK19alone couldn't exclude the possibility of tumor parenchymal contamination. So we tested the Kras status in CAF and corresponding tumor tissues to make sure there was no Kras mutation in CAF cell population. Among CAFs, we sorted the cell population CD90+/CD73+/CD44+/CD49a+by flow cytometry, which had the potential to form colony and differentiate into bone, cartilage and adipose.
The function of MSCs-CAFs to pancreatic cancer cells:
1.1increase the sternness of tumor cells In groups of direct and indirect co-culture of tumor cells and CAFs, compared with the non-MSCs-CAFs, the MSCs-CAFs had a greater potential to increase the sphere forming number of tumor cells and the ratio of CD44+/c-Met+in tumor cell population. And the direct co-culture group had an even greater effect.
1.2promote migration of tumor cells
In groups of direct and indirect co-culture of tumor cells and CAFs, compared with the non-MSCs-CAFs, the MSCs-CAFs had a greater potential to promote migration of tumor cells in a3D collagen co-culture model. Tumor cells in the direct co-culture group showed discrete growth pattern, and had tumor foci in1case of directly co-culture group.
1.3the distinct cytokines secreted by MSCs-CAFs
We tested36common cytokines reported secreted by CAFs, among which there were some cytokines positively stained in our sample. MIF and Serpin E1secreted by MSCs-CAFs and non-MSCs-CAFs. CXCL-1, IL-6, IL-8were exclusively or predominantly expressed in MSCs-CAFs rather than non-MSCs-CAFs. And the GM-CSF was expressed only in MSCs-CAFs groups.
From the above study, we found that MSCs-CAFs isolated from pancreatic cancer stroma was a cell population showed higher ability to drive stemness and migration of tumor cells. They exerted their function not only through direct contact with tumor cells, but also involved the roles of soluble cytokines they secreted. Those distinct cytokines might be the molecular basis of their special function to tumor cells.
2. Inhibitory effect of retinoic acid to CAFs. Some researchers found that normal fibroblast cells in pancreas stroma were activated by stimulations such as inflammation, hypoxia and cytokines secreted by tumor cells. When they are activated,Vitamin A fat droplets in the plasma are lost, which is related with the activation status of CAFs. Activated CAFs supported tumor initiation and development in many ways. Our research utilized retinoic acid-small molecular lipophilic derivatives to inactivate CAFs, by which to investigate the function of CAFs to migration of tumor cells and the indirect inhibition effect of all-trans retinoic acid (ATRA) and9-cis-RA to pancreatic cancer cells. We found that2.1The effect of RA to different pancreatic cancer cells varied. There were inhibition effect of ATRA and9-cis-RA to proliferation of Aspc-1. And RAs treatment maintained Aspc-1in Gl phase. But there was no proapoptosis effect to Aspc-1. While, to Panc-1, high concentration (20μM) group of RAs promoted early phase of apoptosis, although there was no significant difference of late phase of apoptosis rate between experiment groups and control group. And the effect of9-cis-RA was more evident than that of ATRA to Panc-1. However, RAs didn't show proliferation inhibition of Panc-1.
2.2RA could inactivate CAF. With the treatment of RAs, there were more fat droplets showed in CAFs plasma. And the expression level of CAF activation-related protein α-SMA and FAP were lower than control group, as so to ECM production gene, such as collagen Ⅰ, fibronectin and laminin, and cytokines as IL6/8. However, the inhibition effect of RAs was not through the promotion of apoptosis of CAFs.
2.3RA could inhibit the soluble cytokines of CAFs, which promoted epithelial-mesenchymal transform (EMT) of tumor cells. By such, RA inhibited the migration and EMT of tumor cells indirectly. We found that incubation with the CAFs conditioned media previously treated with RAs, the migration distance and numbers of tumor cells crossing the borderline were less than control groups. And the EMT of tumor cells induced by3D collagen was inhibited, but RAs did no effect on migration and EMT of tumor cells directly. So the cytokines inhibited by RAs treatment in CAFs conditioned media was responsible for the migration of tumor cells.
In this part, we found that RAs could inactivate CAFs, which were related with low level of activation-associated protein, ECM production, cell surface receptor and cytokines. Static CAFs showed weaker support to migration and EMT of tumor cells. Cytokines IL-6secreted by CAFs were involved in the process.
In conclusion, the CAFs in pancreatic cancer microenvironment have a characteristics of heterogeneity, among which, MSCs-like CAFs have more potent ability to drive sternness and migration of tumor cells and secrete special cytokines. While through the study about inhibitory effect of retinoic acid, we found CAFs promote migration of tumor cells by secreting soluble cytokines. And retinoic acid can inhibit tumor migration and EMT by inactivation of CAFs.
引文
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