癌相关成纤维细胞的分化来源

癌相关成纤维细胞(CAF)是肿瘤微环境重要的组成部分,甚至有研究者提出CAF可能作为抗肿瘤治疗的新靶点.然而研究的难点在于CAF分化来源的多样性,包括宿主成纤维细胞、上皮细胞、内皮细胞、间质细胞和干细胞等,而不同的来源决定了CAF不同的表型和功能.全面了解CAF的分化来源,将为抗肿瘤治疗提供新思路.     

癌相关成纤维细胞促进肿瘤进展机制的研究

肿瘤的发生发展过程与肿瘤微环境密切相关。癌相关成纤维细胞（carcinoma-associated fibroblasts,CAF）是肿瘤微环境中最丰富的细胞成分,并且具有来源、表型和功能异质性，它主要通过产生和分泌各种趋化因子以及促进上皮间充质转化从而在肿瘤的发生、血管生成、耐药性、侵袭和转移中发挥重要作用。近年来许多研究证实CAF在促进肿瘤进展中起重要作用，但其作用机制尚未明确。本文就CAF促进肿瘤进展的潜在机制进行概述，以期发现新的治疗靶点，为肿瘤的诊治提供新的思路。     

癌相关成纤维细胞促进肿瘤进展的复杂分子机制探讨

癌相关成纤维细胞（carcinoma-associated fibroblasts, CAF）是肿瘤微环境中最丰富的细胞成分,具有高度的生物学异质性。近年来许多研究已证实CAF促进肿瘤进展的作用,但是其具体的作用机制尚未明确。本文就CAF促肿瘤作用的潜在分子机制进行总结并分类讨论：CAF分泌丰富的促肿瘤因子直接向邻近的肿瘤细胞传达促增殖、侵袭和转移的信号;CAF参与并促进肿瘤血管生成、细胞外基质重塑及肿瘤相关炎症等有利于肿瘤进展的外源性程序,从而间接发挥其促肿瘤作用。深入理解CAF错综复杂的作用机制,有助于发展新的治疗靶点,为恶性肿瘤的根治带来新的契机。     

间充质干细胞对肿瘤细胞的分子作用机制

间充质干细胞(MSC)不但对肿瘤细胞具有良好的靶向性,而且可以直接抑制肿瘤生长或作为新兴的基因治疗载体在肿瘤局部持续高效地表达外源基因,抑制肿瘤的生长和转移.同时,MSC也可通过促进肿瘤间质重构和肿瘤血管形成、抑制肿瘤局部机体免疫以及改变肿瘤表型而促进肿瘤生长.相反的作用机制可能与MSC的来源、异质性、肿瘤细胞微环境或...     

癌相关成纤维细胞异质性的研究进展

癌相关成纤维细胞(cancer-associated fibroblasts,CAFs)是肿瘤微环境主要的间质成分,在肿瘤生长、进展和转移过程中起到关键性的作用.众多研究显示,不同来源的CAFs可表达不同的标志物并具有一定的异质性.对CAFs进行分类以及其所发挥的生物学效应进行研究,有利于深入了解CAFs对肿瘤进展和转...     

肿瘤相关巨噬细胞的免疫重塑——中药抗肿瘤治疗的新靶点

0 引言 近年来研究表明,肿瘤间质中的巨噬细胞(tumor-associated macrophages,TAM)具有抗肿瘤和促进肿瘤的双向作用,其密度与多数肿瘤的血管生成、肿瘤的发生、发展及预后等相关[1].目前,中医药对TAM表型及功能调节、逆转TAM促肿瘤生长作用等方面研究尚缺乏相关资料,但依据TAM来源及不同活化表型转换的内在机制,中医药对其的免疫重塑过程可能是免疫调节作用的新靶点.     

肿瘤相关巨噬细胞在肿瘤放射治疗中的研究进展

肿瘤相关巨噬细胞（TAM）是肿瘤组织中数量最多的免疫细胞之一。TAM为一个表型可塑的异质性细胞群体,能调控肿瘤增殖、转移及耐药等表型,已成为抗肿瘤治疗的新靶点。放射治疗是恶性肿瘤的基本治疗手段之一,研究发现放射治疗对TAM的表型和功能有显著影响,而TAM也可反过来调控肿瘤放疗疗效。本文就TAM在肿瘤放疗中的研究进展作一综述。     

肿瘤相关成纤维细胞对肿瘤微环境及肿瘤免疫代谢影响的研究进展

肿瘤相关成纤维细胞(CAF)是构成肿瘤微环境(TME)的主要组成部分.与静息的成纤维细胞不同, CAF代谢旺盛,且分泌大量的蛋白组,包括细胞因子、趋化因子和各种蛋白酶等.CAF可由原发灶定居的成纤维细胞激活转化而成,也可从外周招募而来.在肿瘤演进的各个时期,CAF发挥着重要的调节作用.CAF可以直接影响肿瘤细胞,也可以作用于非肿瘤成分,从而调节肿瘤的进展.针对CAF的治疗,或许有望成为新的肿瘤靶向治疗方法.本文从CAF的起源和特点,以及对TME和免疫代谢的研究进展作一综述.     

人体肿瘤髓系来源抑制性细胞的研究进展

髓系来源抑制性细胞(MDSC)是一群来源于髓系的异质性未分化成熟的细胞;在感染、创伤、败血症,尤其是肿瘤等病理状态下,MDSC在血液、淋巴器官、脾脏及肿瘤等组织中大量聚集;MDSC可以通过多种机制抑制肿瘤免疫,MDSC在患者外周血的数量与肿瘤的分期、负荷、远处转移及患者的预后密切相关.然而关于MDSC的研究结果大部分来自小鼠实验,由于肿瘤患者MDSC的表型比较复杂,其研究进展相对缓慢.     

肿瘤相关成纤维细胞来源外泌体miRNA对结直肠癌发展的促进作用研究进展

肿瘤相关成纤维细胞(CAF)是结直肠癌(CRC)肿瘤微环境的重要组成部分.CAF与肿瘤细胞相互作用分泌各种趋化因子和细胞因子,促进了肿瘤的发生和发展.随着CAF的深入了解,发现CAF所释放的外泌体miRNA在CRC发病机制中发挥重要作用.外泌体miRNA可调控相关靶基因表达,调控肿瘤细胞增殖、干性、转移和治疗抵抗.并且异常表达的miRNA也有望为CRC的诊断及治疗提供参考.本文就CAF外泌体miRNA在肿瘤微环境中对CRC的影响作一综述,以期为深入探究CAF在CRC中的作用提供新的线索.     

Heterogeneity of cancer‐associated fibroblasts: Opportunities for precision medicine

Despite marked development in cancer therapies during recent decades, the prognosis for advanced cancer remains poor. The conventional tumor–cell‐centric view of cancer can only explain part of cancer progression, and thus a thorough understanding of the tumor microenvironment (TME) is crucial. Among cells within the TME, cancer‐associated fibroblasts (CAFs) are attracting attention as a target for cancer therapy. However, CAFs present a heterogeneous population of cells and more detailed classification of CAFs and investigation of functions of each subset is needed to develop novel CAF‐targeted therapies. In this context, application of newly developed approaches to single‐cell analysis has already made an impact on our understanding of the heterogeneity of CAFs. Here, we review the recent literature on CAF heterogeneity and function, and discuss the possibility of novel therapies targeting CAF subsets.     

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。     

In search of definitions: Cancer-associated fibroblasts and their markers

The tumor microenvironment has been identified as one of the driving factors of tumor progression and invasion. Inside this microenvironment, cancer-associated fibroblasts (CAFs), a type of perpetually activated fibroblasts, have been implicated to have a strong tumor-modulating effect and play a key role in areas such as drug resistance. Identification of CAFs has typically been carried based on the expression of various “CAF markers”, such as fibroblast activation protein alpha (FAP) and alpha smooth muscle actin (αSMA), which separates them from the larger pool of fibroblasts present in the body. However, as outlined in this Review, the expression of various commonly used fibroblast markers is extremely heterogeneous and varies strongly between different CAF subpopulations. As such, novel selection methods based on cellular function, as well as further characterizing research, are vital for the standardization of CAF identification in order to improve the cross-applicability of different research studies in the field. The aim of this review is to give a thorough overview of the commonly used fibroblast markers in the field and their various strengths and, more importantly, their weaknesses, as well as to highlight potential future avenues for CAF identification and targeting.     

Human breast cancer-associated fibroblasts (CAFs) show caveolin-1 downregulation and RB tumor suppressor functional inactivation: Implications for the response to hormonal therapy

It is becoming increasingly apparent that the tumor microenvironment plays a critical role in human breast cancer onset and progression. Therefore, we isolated cancer-associated fibroblasts (CAFs) from human breast cancer lesions and studied their properties, as compared with normal mammary fibroblasts (NFs) isolated from the same patient. Here, we demonstrate that 8 out of 11 CAFs show dramatic downregulation of caveolin-1 (Cav-1) protein expression; Cav-1 is a well-established marker that is normally decreased during the oncogenic transformation of fibroblasts. Next, we performed gene expression profiling studies (DNA microarray) and established a CAF gene expression signature. Interestingly, the expression signature associated with CAFs encompasses a large number of genes that are regulated via the RB-pathway. The CAF gene signature is also predictive of poor clinical outcome in breast cancer patients that were treated with tamoxifen mono-therapy, indicating that CAFs may be useful for predicting the response to hormonal therapy. Finally, we show that replacement of Cav-1 expression in CAFs (using a cell-permeable peptide approach) is sufficient to revert their hyper-proliferative phenotype and prevent RB hyper-phosphorylation. Taken together, these studies highlight the critical role of Cav-1 downregulation in maintaining the abnormal phenotype of human breast cancer-associated fibroblasts.     

Cancer associated fibroblasts stimulated by transforming growth factor beta1 (TGF-β1) increase invasion rate of tumor cells: a population study

Cancer associated fibroblasts (CAFs) are believed to promote tumor growth and progression. Our objective was to measure the effect of TGF-beta1 on fibroblasts isolated from invasive breast cancer patients. Fibroblasts were isolated from tissue obtained at surgery from patients with invasive breast cancer (CAF; n = 28) or normal reduction mammoplasty patients (normal; n = 10). Myofibroblast activation was measured by counting cells immunostained for smooth muscle alpha actin (ACTA2) in cultures +/- TGF-beta 1. Conditioned media (CM) was collected for invasion assays and RNA was isolated from cultures incubated in media +/- TGF-beta1 for 24 h. Q-PCR was used to measure expression of cyclin D1, fibronectin, laminin, collagen I, urokinase, stromelysin-1, and ACTA2 genes. Invasion rate was measured in chambers plated with MDA-MB-231 cells and exposed to CM in the bottom chamber; the number of cells that invaded into the bottom chamber was counted. Wilcox Rank Sum tests were used to evaluate differences in CAFs and normal fibroblasts and the effect of TGF-beta 1. There was no difference in percent myofibroblasts or invasion rate between normal and CAF cultures. However, TGF-beta1 significantly increased the percent of myofibroblasts (P < 0.01) and invasion rate (P = 0.02) in CAF cultures. Stromelysin-1 expression was significantly higher in normal versus CAF cultures (P < 0.01). TGF-beta 1 significantly increased ACTA2 expression in both normal and CAF cultures (P < 0.01). Expression of fibronectin and laminin was significantly increased by TGF-beta in CAF cultures (P < 0.01). CAFs were measurably different from normal fibroblasts in response to TGF-beta 1, suggesting that TGF-beta stimulates changes in CAFs that foster tumor invasion.     

The interplay between cancer associated fibroblasts and immune cells in the context of radiation therapy

Fibroblasts are a key component of the tumor microenvironment (TME) that can serve as a scaffold for tumor cell migration and augment the tumor's ability to withstand harsh conditions. When activated by external or endogenous stimuli, normal fibroblasts become cancer associated fibroblasts (CAFs), a heterogeneous group of stromal cells in the tumor that are phenotypically and epigenetically different from normal fibroblasts. Dynamic crosstalk between cancer cells, immune cells, and CAFs through chemokines and surface signaling makes the TME conducive to tumor growth. When activated, CAFs promote tumorigenesis and metastasis through several phenomena including regulation of tumor immunity, metabolic reprogramming of the TME, extracellular matrix remodeling and contraction, and induction of therapeutic resistance. Ionizing radiation (radiation theraphy [RT]) is a potent immunological stimulant that has been shown to increase cytotoxic Teff infiltration and IFN-I stimulated genes. RT, however, is unable to overcome the infiltration and activation of immunosuppressive cells which can contribute to tumor progression. Another paradox of RT is that, while very effective at killing cancer cells, it can contribute to the formation of CAFs. This review examines how the interplay between CAFs and immune cells during RT contributes to organ fibrosis, immunosuppression, and tumor growth. We focus on targeting mechanistic pathways of CAF formation as a potentially effective strategy not only for preventing organ fibrosis, but also in hampering tumor progression in response to RT.     

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.     

Targeting cancer associated fibroblasts to enhance immunotherapy: emerging strategies and future perspectives

Cancer associated fibroblasts are a prominent component of the tumour microenvironment in most solid cancers. This heterogeneous population of cells are known to play an important role in tumour progression and recent studies have demonstrated that CAFs may confer resistance to checkpoint immunotherapy, suggesting that targeting these cells could improve response rates. However, effective clinical strategies for CAF targeting have yet to be identified. In this editorial, we highlight current limitations in our understanding of CAF heterogeneity, and discuss the potential and possible approaches for CAF-directed therapy.