肿瘤相关成纤维细胞在结直肠癌中的作用及相关治疗的研究进展

肿瘤相关成纤维细胞（cancer-associated fibroblasts,CAFs）主要来源于肿瘤微环境中被激活的正常成纤维细胞和间充质干细胞。CAFs能够通过分泌多种小分子生物活性物质调控肿瘤细胞的增殖、侵袭、耐药等生物学行为,并通过细胞间相互作用影响微环境中免疫细胞的活性,进而影响肿瘤患者的预后。近年来,关于CAFs的标志物、活化机制、生物作用以及单细胞测序的研究取得一些进展,靶向CAFs治疗也有望成为结直肠癌（colorectal cancer,CRC）新的治疗策略。本文主要对CAFs的来源、活化与募集以及这一细胞亚群在CRC中的研究进展进行综述,为CAFs在CRC中的研究及临床应用提供新的视角。     

肿瘤相关成纤维细胞在肿瘤中作用的研究进展

[摘要] 肿瘤是由肿瘤细胞及其周围基质细胞和非细胞组分构成的复合体,肿瘤的发生发展是肿瘤细胞与其微环境相互促进、共同演化的一个动态过程,肿瘤微环境在肿瘤的生长转移过程中发挥至关重要的作用。肿瘤相关成纤维细胞（cancer associated fibroblasts, CAFs）,作为肿瘤微环境中最主要的组成成分之一,能够分泌多种细胞因子,从而促进肿瘤血管生成,诱导肿瘤细胞发生上皮间质转化,打破组织细胞之间的稳态,使微环境更有利于肿瘤生长。CAFs对乳腺癌、肝癌、胃癌、结直肠癌、卵巢癌、肺癌等多种常见癌有促进作用。本文就近年来CAFs对肿瘤的发生发展、耐药及其他方面的影响及作用机制加以讨论,以期为癌症的治疗提供新的思路。     

肿瘤相关成纤维细胞在胃癌侵袭和转移中的作用研究进展

摘 要：肿瘤相关成纤维细胞（cancer-associated fibroblasts,CAFs）是包括胃癌在内的多种肿瘤的重要组成部分,主要通过细胞外基质沉积、血管形成、代谢重编程和耐药性等方式在肿瘤侵袭和转移过程中发挥关键作用。然而,CAFs在胃癌侵袭和转移中的作用机制尚不明确,相关报道主要集中在考察CAFs中miRNA或细胞因子的变化上。miRNA是一种非编码小RNA分子,不仅在CAFs中控制多个目标基因的表达,而且在肿瘤细胞与CAFs的信号通路中具有重要作用。CAFs分泌的某些细胞活性因子也可促进肿瘤的发生、发展和转移。全文对CAFs中miRNA、细胞因子在胃癌侵袭和转移中的作用以及相关的信号通路进行概述,以期为寻找胃癌治疗的新靶点提供理论依据。     

肿瘤相关成纤维细胞及其在肿瘤发生发展中的作用

肿瘤微环境在肿瘤发生发展中起重要作用,而肿瘤相关成纤维细胞（ cancer-associated fibroblasts, CAFs）是肿瘤微环境的主要基质细胞,越来越多的研究表明CAFs不仅是肿瘤生长的“土壤”,更能通过旁分泌的方式分泌多种可溶性因子,同肿瘤细胞及肿瘤间质中的其他细胞发生相互作用,促进肿瘤的发生、生长、侵袭及转移。因此CAFs有望成为肿瘤治疗的新靶点。     

肿瘤相关成纤维细胞在大肠癌发生发展中的研究进展

肿瘤相关成纤维细胞(Cancer-associated-fibroblasts,CAFs)是肿瘤外部微环境中最重要的细胞成分之一。CAFs可以与肿瘤细胞发生相互作用,分泌多种可溶性因子如生长因子、趋化因子等,并通过调控大肠癌进展过程中发挥关键作用的多条信号通路,参与大肠癌的增殖、侵袭、转移以及耐药等生物学过程。近年研究发现,CAFs相关标记物及基因可作为大肠癌患者预后判断的参考指标,因此,靶向CAFs有望成为大肠癌早期诊断、治疗以及预后判断的关键靶点。本文主要就CAFs的特征、募集与活化过程以及在大肠癌发生发展中的作用进行总结,以期为CAFs在大肠癌中作用机制研究及临床应用提供新的科研方向。     

调节性T细胞在结直肠癌发生发展中的作用及相关治疗

调节性T细胞（regulatory T cell,Treg）是肿瘤微环境中重要的免疫抑制性细胞,在维持免疫稳态方面发挥重要的作用。Treg不仅可以通过分泌抑制性细胞因子阻碍有效的抗肿瘤免疫,还可以通过调节细胞因子进而调控结直肠癌（colorectal cancer,CRC）细胞生长,同时直接或间接地促进CRC血管新生,并与患者不良预后有关;但Treg也可能在炎症相关性肿瘤发生的早期,通过抑制炎症反应降低肠道肿瘤发生的风险。近年来,靶向Treg的免疫治疗也成为了研究热点,一些治疗策略已经在临床应用,还有一些正在进行临床前及临床试验。本文就Treg在CRC发生发展中的作用及靶向Treg的免疫治疗策略进行综述,探讨Treg作为治疗靶点的作用机制及临床应用前景。      

肠道菌群与结直肠癌发生及中医药调节作用的研究现状

人类肠道菌群是一个复杂的微生态体系,具有抗炎、抗菌、免疫、神经、营养、代谢等多方面作用。结直肠癌（colorectal cancer,CRC）是人体常见的消化道恶性肿瘤,研究表明,肠道菌群失调与CRC的发生发展密不可分,而中医药作为我国医疗体系中一个特色治疗技术,在通过调节肠道菌群达到抗肿瘤作用方面发挥着显著作用。本文就肠道菌群与CRC的发生关系以及中医药调节作用加以综述,为中医药调节肠道菌群并防治CRC提供依据。     

MicroRNAs在肿瘤相关成纤维细胞促进肿瘤发展进程中的作用

肿瘤相关成纤维细胞（CAFs）是肿瘤微环境（TME）中最主要的细胞组分之一,在肿瘤发生、进展中发挥重要作用。微小RNA（miRNAs）参与CAFs的转化与代谢重编程,并可调控CAFs 的干性及其介导的肿瘤细胞增殖、侵袭和化疗耐药等机制,在CAFs 的形成和CAFs 对肿瘤的促进作用中发挥重要功能;而CAFs 释放的miRNAs 可作为肿瘤的诊断、预后及用药选择的参考指标。因此探索miRNAs 在肿瘤细胞与CAFs 相互作用中的功能,揭示其作用机制,对于理解肿瘤的发生和发展具有重要意义;同时也可为新的肿瘤治疗策略提供研究方向。本文将对miRNAs在CAFs的形成及CAFs对肿瘤细胞调控中的作用加以介绍     

结直肠癌免疫微环境中肿瘤相关巨噬细胞的作用

结直肠癌（colorectal cancer,CRC）的发生、发展不仅与肿瘤细胞本身的特性相关,也与肿瘤微环境（tumor microenvironment,TME）密切相关。肿瘤细胞及其微环境通过分泌多种细胞因子,将循环血液中的单核细胞招募至TME并使其极化为肿瘤相关巨噬细胞（tumor-associated macrophages,TAMs）。作为TME中最丰富的免疫细胞之一,TAMs的功能和特点与M2型巨噬细胞相似,TAMs主要具有刺激肿瘤细胞增殖、血管生成、基质重塑和促进肿瘤细胞侵袭及转移等作用。在多数肿瘤中,TAMs主要发挥促肿瘤作用并与患者的不良预后相关;但在CRC中,TAMs的作用仍存争议。本文主要就CRC免疫微环境中TAMs的作用及其机制进行综述,以展示TAMs对CRC患者的病程进展及预后的影响并探讨TAMs作为CRC免疫治疗靶点的可行性。      

LncRNA与结直肠癌诊断治疗的研究进展

摘 要：结直肠癌（CRC）是常见的恶性肿瘤之一,严重威胁着人类的健康。目前大量的研究表明异常表达的长链非编码RNA（lncRNA）通过影响肿瘤细胞的增殖、凋亡、迁移及侵袭等生物学行为参与了CRC的发生发展,并且发现lncRNA的单核苷酸多态性(SNPs)与CRC的易感性密切相关。因此,针对lncRNA的深入研究有望为CRC的诊断和治疗提供新的手段。     

Exosomal miR-1228 From Cancer-Associated Fibroblasts Promotes Cell Migration and Invasion of Osteosarcoma by Directly Targeting SCAI

Cancer-associated fibroblasts (CAFs) play a predominant role in regulating tumor progression. Understanding how CAFs communicate with osteosarcoma is crucial for developing novel approaches for osteosarcoma therapy. Exosomes are able to transmit messages between cells. In this study, we demonstrated that CAFs transfer exosomes to osteosarcoma cells, which promotes osteosarcoma cell migration and invasion. Using a miRNA microarray analysis, we identified 13 miRNAs that are significantly increased in exosomes derived from cancer-associated fibroblasts (CAFs) and corresponding paracancer fibroblasts (PAFs). In vitro studies further validated that the levels of microRNA-1228 (miR-1228) were increased in CAFs, its secreted exosomes, and in recipient osteosarcoma cells, which can downregulate endogenous SCAI mRNA and protein level in osteosarcoma. Furthermore, our findings demonstrate that SCAI was downregulated in osteosarcoma tissues. Taken together, this study provides evidence that CAF exosomal miR-1228 is able to promote osteosarcoma invasion and migration by targeting SCAI, which may represent a critical therapeutic target for osteosarcoma treatment.     

成纤维细胞在肝癌发生发展中的作用

肝脏发生纤维化及进一步产生的肝硬化是肝癌发生发展的重要因素。成纤维细胞可以使细胞外基质沉积,而细胞外基质沉积也是肝脏纤维化的标志性改变。成纤维细胞有多种来源,主要是由于肝损伤的性质不同。目前认为成纤维细胞主要来源于肝星状细胞(Hepatic stellate cells,HSCs),亦称为Ito细胞。在肝细胞癌(Hepatocellular carcinoma,HCC)的发生发展过程中肝成纤维细胞可以转化为肿瘤相关成纤维细胞(Cancer-associated fibroblasts,CAFs)。活化的肝星状细胞(Activated HSCs,AHSCs)/CAFs在HCC的发生发展中的作用已经被证实。CAFs是HCC中的肿瘤微环境(The tumor microenvironment,TME)中一组具有不同细胞来源和表型的活化成纤维细胞,与肿瘤的发生发展密切相关。CAFs可能通过分泌多种生长因子和细胞因子,促进细胞外基质重塑、增强肝癌细胞的干性、促进肿瘤耐药、促进肝癌的血管生成和血管生成拟态(Vasculogenic mimicry,Vm)来影响肿瘤细胞的增殖、凋亡、迁移、侵袭、血管生成、免疫逃逸和耐药性。由于存在上述特性,CAFs可以作为肿瘤治疗中的理想靶点。在这篇综述中,我们将对HCC中CAFs的最新认识、其细胞起源以及生物学功能进行阐释。     

Automated tracking of tumor-stroma morphology in microtissues identifies functional targets within the tumor microenvironment for therapeutic intervention

Cancer-associated fibroblasts (CAFs) constitute an important part of the tumor microenvironment and promote invasion via paracrine functions and physical impact on the tumor. Although the importance of including CAFs into three-dimensional (3D) cell cultures has been acknowledged, computational support for quantitative live-cell measurements of complex cell cultures has been lacking. Here, we have developed a novel automated pipeline to model tumor-stroma interplay, track motility and quantify morphological changes of 3D co-cultures, in real-time live-cell settings. The platform consists of microtissues from prostate cancer cells, combined with CAFs in extracellular matrix that allows biochemical perturbation. Tracking of fibroblast dynamics revealed that CAFs guided the way for tumor cells to invade and increased the growth and invasiveness of tumor organoids. We utilized the platform to determine the efficacy of inhibitors in prostate cancer and the associated tumor microenvironment as a functional unit. Interestingly, certain inhibitors selectively disrupted tumor-CAF interactions, e.g. focal adhesion kinase (FAK) inhibitors specifically blocked tumor growth and invasion concurrently with fibroblast spreading and motility. This complex phenotype was not detected in other standard in vitro models. These results highlight the advantage of our approach, which recapitulates tumor histology and can significantly improve cancer target validation in vitro.     

MicroRNA-375表达对大肠癌细胞生物学特性的影响

目的:研究构建miRNA-375慢病毒表达载体并转染结直肠癌细胞,探讨其对结直肠癌细胞生物学特性的影响.方法:采用qRT-PCR法检测结直肠癌细胞株中miRNA-375表达水平.构建FUA-ZMCS-EF1-EGFP-miR-375/inhibitor慢病毒表达载体,建立稳定过表达miRNA-375及其抑制剂的HCT-116亚细胞系,体外观察细胞生长速度并绘制生长曲线,流式细胞仪检测细胞凋亡率,划痕实验检测miRNA-375对HCT-116细胞迁移能力的影响,Western blot法检测miRNA-375对细胞内ERK磷酸化水平的影响.结果:结直肠癌细胞株中miRNA-375低表达不但能促进细胞生长、抑制细胞凋亡,而且能促进细胞内ERK磷酸化水平、增加细胞迁移力和侵袭力.结论:结直肠癌miRNA-375发挥抑癌基因的作用,为miRNA-375在结直肠癌基因诊断及治疗中的应用提供了实验依据.     

癌症相关成纤维细胞的异质性及其在靶向治疗中的应用

癌症相关成纤维细胞（cancer-associated fibroblasts,CAFs）是肿瘤微环境中最丰富和最关键的组成部分之一,不仅为肿瘤细胞提供物理支持,也在促进或延缓肿瘤发生发展方面起着关键作用。CAFs是一类高度丰富和异质性明显的间充质细胞系,包含大量不同表型和功能的细胞亚群,针对其异质性的靶向治疗也应运而生。本文阐述CAFs来源、表型和功能相关的异质性,以及在靶向治疗中应用的研究进展,以期提高对恶性肿瘤中CAFs的认识。     

Cancer-associated fibroblasts promote PD-L1 expression in mice cancer cells via secreting CXCL5

Cancer-associated fibroblasts (CAFs) play a key role in orchestrating the tumor malignant biological properties within tumor microenvironment and evidences demonstrate that CAFs are a critical regulator of tumoral immunosuppression of the T cell response. However, the functions and regulation of CAFs in the expression of programmed death-ligand 1 (PD-L1) in melanoma and colorectal carcinoma (CRC) are not completely understood. Herein, by scrutinizing the expression of α-SMA and PD-L1 in melanoma and CRC tissues, we found that CAFs was positive correlated with PD-L1 expression. Further analyses showed that CAFs promoted PD-L1 expression in mice tumor cells. By detecting a majority of cytokines expression in normal mice fibroblasts and CAFs, we determined that CXCL5 was abnormal high expression in CAFs and the immunohistochemistry and in situ hybridization confirmed that were CAFs which were expressing CXCL5. In addition, CXCL5 promoted PD-L1 expression in B16, CT26, A375 and HCT116. The silencing of CXCR2, the receptor of CXCL5, inhibited the PD-L1 expression induced by CAFs in turn. Functionally, CXCL5 derived by CAFs promoted PD-L1 expression in mice tumor cells through activating PI3K/AKT signaling. LY294002, the inhibitor of PI3K, confirmed that CXCL5 forested an immunosuppression microenvironment by promoting PD-L1 expression via PI3K/AKT signaling. Meanwhile, the B16/CT26 xenograft tumor models were used and both CXCR2 and p-AKT were found to be positively correlated with PD-L1 in the xenograft tumor tissues. The immunosuppressive action of CAFs on tumor cells is probably reflective of them being a potential therapeutic biomarker for melanoma and CRC.     

CD90+ stromal cells are the major source of IL‐6, which supports cancer stem‐like cells and inflammation in colorectal cancer

IL‐6 is a pleiotropic cytokine increased in CRC and known to directly promote tumor growth. Colonic myofibroblasts/fibroblasts (CMFs or stromal cells) are CD90⁺ innate immune cells representing up to 30% of normal colonic mucosal lamina propria cells. They are expanded in CRC tumor stroma, where they also known as a cancer associated fibroblasts (CAFs). Cells of mesenchymal origin, such as normal myofibroblasts/fibroblasts, are known to secrete IL‐6; however, their contribution to the increase in IL‐6 in CRC and to tumor‐promoting inflammation is not well defined. Using in situ, ex vivo and coculture analyses we have demonstrated that the number of IL‐6 producing CMFs is increased in CRC (C‐CMFs) and they represent the major source of IL‐6 in T2‐T3 CRC tumors. Activity/expression of stem cell markers‐aldehyde dehydrogenase and LGR5‐ was significantly up‐regulated in colon cancer cells (SW480, Caco‐2 or HT29) cultured in the presence of conditioned medium from tumor isolated C‐CMFs in an IL‐6 dependent manner. C‐CMF and its derived condition medium, but not normal CMF isolated from syngeneic normal colons, induced differentiation of tumor promoting inflammatory T helper 17 cells (Th17) cell responses in an IL‐6 dependent manner. Our study suggests that CD90⁺ fibroblasts/myofibroblasts may be the major source of IL‐6 in T2‐T3 CRC tumors, which supports the stemness of tumor cells and induces an immune adaptive inflammatory response (a.k.a. Th17) favoring tumor growth. Taken together our data supports the notion that IL‐6 producing CAFs (a.k.a. C‐CMFs) may provide a useful target for treating or preventing CRCs.     

Carcinoma-associated fibroblasts promotes the proliferation of a lingual carcinoma cell line by secreting keratinocyte growth factor

Carcinoma-associated fibroblasts (CAFs) have been confirmed to play an important role in the occurrence and development of many kinds of tumors. Regarding proliferation as one manifestation of malignance, the objective was to observe the effects of oral CAFs on the proliferation of oral squamous carcinoma cells (OSCC) and to explore the role of keratinocyte growth factor (KGF) in this process. The results showed that oral CAFs secreted a higher level of KGF than oral normal fibroblasts (NFs), and the conditioned medium of CAFs could increase the viability of carcinoma cells and promote more of them into G2 and S phase. However, after blocking with KGF antibody, the viability and cell cycle of Tca8113 cultured with CAFs conditioned medium changed to be similar with NFs control groups. It was concluded that CAFs could promote the proliferation of OSCC through secreting high levels of KGF. These findings support the use of carcinoma-associated fibroblasts as a novel target in anticancer therapy.     

Oral Squamous Cell Carcinoma-Derived ANGPTL3 Induces Cancer Associated Fibroblastic Phenotypes in Surrounding Fibroblasts

Objective: Angiopoietin-like proteins (ANGPTLs) have emerged as both important regulator of lipid and glucose metabolism as well as insulin sensitivity. In particular, ANGPTL3 activity is one of the most important factors in cancer growth and invasion. Although ANGPTL3 have been studied in OSCC, but the role of ANGPTL3 between OSCC and CAFs has yet to be clearly defined. Thus, this study aimed to investigate the roles of ANGPTL3 in the differentiation of CAFs. Methods: For our study, we used hTERT-hNOFs to replace CAFs by coculturing them with oral squamous cell carcinoma (OSCC) cells. We did a microarray dataset analysis to investigate what factors secreted from OSCC cells can induce cancer associated fibroblastic phenotype in surrounding fibroblasts. The secreted factors were confirmed by RT-PCR, real-time PCR, and Western blot. Result: ANGPTL3 has the most secreted factor derived from various oral cancer cells. To investigate the role of ANGPTL3 in CAFs, we treated rhANGPTL3 in hTERT-hNOFs. The fibroblasts showed an increase of tumor-promoting cytokines (IL-6 and IL-8) and myofibroblastic markers, such as α-SMA and FAP. Conclusion: In conclusion, our study reports the first evidence that ANGPTL3 plays a crucial role in tumor microenvironments by inducing CAF. Therefore, targeting ANGPTL3 may be promising treatment strategy for CAF-targeted therapy in CAF-rich tumors.