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结直肠癌发生发展中的作用研究进展

肿瘤相关成纤维细胞（CAFs）是间质的主要细胞成分,在结直肠癌（colorectal cancer,CRC）的发生发展中发挥重要作用。CAFs通过细胞与细胞间的直接接触以及旁分泌的方式分泌各种细胞因子、生长因子和趋化因子,通过不同的信号通路促进CRC的发生、生长以及血管生成、侵袭和转移。CAFs还为CRC的早期诊断和治疗提供新的标记和新的靶点,为CRC的综合治疗提供新的思路。本文主要就近年来CAFs在结直肠癌发生发展以及诊治中作用的研究进展作一综述。     

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。     

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。     

癌相关成纤维细胞在非小细胞肺癌进展中的作用

癌相关成纤维细胞(Cancer-associated fibroblasts, CAFs)是基质和相关肿瘤微环境中的主要成分,在非小细胞肺癌(Non-small cell lung cancer, NSCLC)的发生发展过程中发挥重要的作用。研究表明,CAFs通过分泌多种类型的细胞因子、趋化因子、生长因子和细胞外基质蛋白,参与调控癌细胞的增殖、侵袭、转移和对化疗药物的耐药性。本文将从CAFs的来源、活化机制及其在NSCLC发生发展过程中的作用进行综述,以深入了解NSCLC进展机制并为其治疗提供新思路。     

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     

肿瘤相关成纤维细胞对卵巢癌细胞增殖作用影响的研究

目的：探讨肿瘤相关成纤维细胞（cancer-associated fibroblast，CAF）分泌的肝细胞生长因子（hepatocyte growth factor，HGF）对卵巢癌SKOV3细胞增殖作用的影响。方法：选取在本院手术的卵巢癌患者及其他妇科疾病同时切除正常卵巢手术患者，收集卵巢癌组织、癌旁组织和正常组织，免疫组化观察卵巢癌组织、癌旁组织和正常组织中CAF标志蛋白α平滑肌肌动蛋白（α-smooth muscle actin，α-SMA）和Ｉ型胶原蛋白表达情况；用卵巢癌相关成纤维细胞（human endometrial carcinoma-1A cell，HEC-1A）培养48小时后的培养上清，培养卵巢癌细胞SKOV3行细胞计数试剂盒-8（Cell Counting Kit-8,CCK-8）增殖实验、克隆形成实验和倒置显微镜观察检测使用HEC-1A培养上清后SKOV3细胞增殖能力变化；酶联免疫吸附实验（enzyme linked immunosorbent assay,ELISA）检测HEC-1A与SKOV3细胞共培养48小时后的培养上清中HGF的表达。结果：免疫组化结果显示，卵巢癌组织中α-SMA和Ｉ型胶原蛋白的表达要明显高于癌旁组织和正常组织；CCK-8增殖实验和克隆形成实验结果显示HEC-1A培养上清处理后的SKOV3细胞的增殖能力显著增强；细胞形态学和免疫荧光结果提示HEC-1A促进SKOV3上皮样细胞增多；ELISA结果显示HEC-1A与SKOV3细胞共培养48小时后的培养上清中HGF的表达明显升高。结论：肿瘤相关成纤维细胞可能通过分泌HGF诱导因子促进卵巢癌细胞的增殖作用。     

肿瘤相关成纤维细胞中自噬作用的研究进展

肿瘤相关成纤维细胞（cancer-associated fibroblasts，CAFs）是组成肿瘤微环境最主要的基质细胞之一，在肿瘤的生长、转移、耐药和调节肿瘤免疫中起着重要的作用。肿瘤细胞利用自噬来降解代谢过程中的产物，并重新加以利用，以应对环境的变化。自噬将细胞内稳态与影响免疫和新陈代谢的细胞外环境联系起来，其对于癌症的发生、发展和对治疗的反应是至关重要的。本文通过介绍CAFs中自噬的作用和CAFs自噬的调控机制，对CAFs自噬与肿瘤代谢、进展、转移、以及治疗抵抗的研究进展加以阐述。     

外泌体非编码RNA在非小细胞肺癌获得性耐药中的研究进展

非小细胞肺癌(non-small cell lung cancer,NSCLC)是肺癌中最常见的类型,对化疗及靶向药物的获得性耐药严重影响NSCLC患者的生存期,NSCLC获得性耐药机制复杂,确切机制仍不清楚.肿瘤来源或与肿瘤相关的外泌体是参与调控NSCLC获得性耐药的重要机制,可以通过传递核酸、蛋白质等赋予敏感细胞耐...     

Role of circular RNAs in the diagnosis,regulation of drug resistance and prognosis of lung cancer

Lung cancer is one of the most common malignant tumors in China and is the highest cause of mortality among male and female patients, both in urban and rural areas. A subset of patients with lung cancer only display chest tightness without any other obvious symptoms. This is because most symptoms do not manifest during the early stages of disease development. Consequently, most patients with lung cancer are diagnosed when the disease is in the advanced stages, when they are already unfit for surgical treatment. Furthermore, the prognosis of patients with lung cancer is poor. The 5-year survival rate of patients with stage IA lung cancer is 85%, compared with 6% in those with stage IV. This requires the development of strategies for early diagnosis, treatment and prognosis to improve the management of lung cancer. Circular RNAs (circRNAs) belong to a class of closed circular non-coding RNAs formed by reverse splicing of a precursor mRNA. These RNAs are highly stable, ubiquitously expressed, conserved, and show high specificity. CircRNAs regulate biological processes, such as the proliferation, differentiation and invasion of lung cancer cells. Therefore, they can be used as biomarkers for the early diagnosis and prognosis prediction of lung cancer, as well as novel targets for therapy design. In the present review, the biological characteristics and functions of circRNAs, as well as their application in the diagnosis, control of drug resistance and effect on the prognosis of patients with lung cancer, will be discussed.     

Role of caveolin-1 in etoposide resistance development in A549 lung cancer cells

Caveolin 1 expression is downregulated in various cancer cell lines. Interestingly, in several drug-resistant cancer cells, a strong induction of caveolin 1 expression has been reported suggesting a role for caveolin 1 in the acquisition and/or the maintenance of multidrug resistance phenotype. In addition, it was reported that p-glycoprotein localized to caveolin-rich membrane domains in these cells. In this study, we progressively exposed A549 lung adenocarcinoma cells to increasing doses of etoposide. Both R1 and R2 cell lines had greatly increased levels of p-glycoprotein expression while mrp expression levels were moderately increased but only R2 cells had raised caveolin levels compared to control A549 cells. Both caveolin-1 and p-glycoprotein colocalize in Triton-insoluble membrane domains in all our cell lines but only caveolins-1 was solubilized by the addition of octylglucoside at 4C suggesting that these two proteins are located in different membrane domains. Using an anti-caveolin-1 antibody, we did not succeed to immunoprecipitate p-glycoprotein. Interestingly, total cellular cholesterol (the major lipid component of caveolae and triton-insoluble domains) was greatly increased in both R1 and R2 cell lines compared to naive A549 cells.     

Reverse of non‐small cell lung cancer drug resistance induced by cancer‐associated fibroblasts via a paracrine pathway

The tumor microenvironment orchestrates the sustained growth, metastasis and recurrence of cancer. As an indispensable component of the tumor microenvironment, cancer‐associated fibroblasts (CAF) are considered as an essential synthetic machine producing various tumor components, leading to cancer sustained stemness, drug resistance and tumor recurrence. Here, we developed a sustainable primary culture of lung cancer cells fed with lung cancer‐associated fibroblasts, resulting in enrichment and acquisition of drug resistance in cancer cells. Moreover, IGF2/AKT/Sox2/ABCB1 signaling activation in cancer cells was observed in the presence of CAF, which induces upregulation of P‐glycoprotein expression and the drug resistance of non‐small cell lung cancer cells. Our results demonstrated that CAF cells constitute a mechanism for cancer drug resistance. Thus, traditional chemotherapy combined with insulin‐like growth factor 2 (IGF2) signaling inhibitor may present an innovative therapeutic strategy for non‐small cell lung cancer therapy.     

Role of concomitant resistance in the development of murine lung metastases

An attempt was made to explain the distinct lung metastatic patterns of 2 mammary adenocarcinomas with a common BALB/c origin: M3, which does not induce spontaneous metastases, and MM3 with an almost 100% incidence. No difference between the 2 tumors was detected with respect to host mononuclear cell content, degree of immunogenicity or lung-colony-forming ability. Conversely, there was a marked difference in the capacity to induce concomitant resistance: M3-bearing mice induced stronger and earlier resistance against i.v. challenge of both M3 and MM3 tumor cells than MM3-bearing mice; this resistance was expressed as lower number of lung metastases and lower tumor-cell proliferation in metastatic nodules. M3 was also able to control the development of spontaneous metastases: metastases developed in all M3-excised mice, compared with none in M3-bearing mice, while MM3-bearing mice also bearing a secondary M3 tumor developed fewer metastases than mice bearing MM3 only. This anti-metastatic effect does not appear to depend on classical immunological mechanisms since no difference could be detected between the 2 tumors in response to T cells, NK, macrophages or antibodies.     

Role of cancer-associated fibroblasts in the resistance to antitumor therapy,and their potential therapeutic mechanisms in non-small cell lung cancer

Non-small cell lung cancer (NSCLC) is a malignant tumor with high morbidity and mortality rates, which seriously endangers human health. Although treatment methods continue to evolve, the emergence of drug resistance is inevitable and seriously hinders the treatment of NSCLC. The tumor microenvironment (TME) protects tumor cells from the effects of chemotherapeutic drugs, which can lead to drug resistance. Cancer-associated fibroblasts (CAFs) are an important component of the TME, and various studies have demonstrated that CAFs play a crucial role in drug resistance in NSCLC. However, the drug resistance mechanism of CAFs and whether CAFs can be used as a target to reverse the resistance of tumor cells remain unclear. The present review discusses this issue and describes the heterogeneity of CAF markers, as well as their origins and resident organs, and the role and mechanism of this heterogeneity in NSCLC progression. Furthermore, the mechanism of CAF-mediated NSCLC resistance to chemotherapy, targeted therapy and immunotherapy is introduced, and strategies to reverse this resistance are described.     

环氧合酶-2及其抑制剂与肺癌耐药的研究进展

环氧合酶-2（COX-2）是环氧合酶的可诱导形式,在非小细胞肺癌尤其是腺癌中过度表达,并参与肺癌耐药性的产生,降低肿瘤细胞对化疗药物的敏感性。COX-2抑制剂有抗肿瘤并预防肿瘤形成的作用,因此,为逆转肺癌的耐药性,提高肺癌患者的生存率并改善其预后,将COX-2抑制剂作为辅助化疗药物并与化疗药物联合的应用成为了肺癌治疗的新方向。     

Role of LKB1 in lung cancer development

Three phenotypically related genetic syndromes and their lesions (LKB1, PTEN, and TSC1/2) are identified as frequently altered in lung cancer. LKB1, a kinase inactivated in 30% of lung cancers, is discussed in this review. Loss of LKB1 regulation often coincident with KRAS activation allows for unchecked growth and the metabolic capacity to accommodate the proliferation.     

长链非编码RNA在肿瘤耐药中的研究进展

化疗药物耐药性仍然是目前肿瘤有效化疗的主要障碍。尽管肿瘤耐药机制受到了广泛的探索,但至今尚未被完全阐明。长链非编码RNA是近年来的研究热点,参与了基因组功能的许多方面包括基因转录、剪接、表观遗传学以及细胞周期、细胞分化、发育和多能性等过程。在肿瘤耐药中lncRNA可能通过促进DNA修复、改变药物代谢和细胞膜流出、调节细胞凋亡率和影响上皮细胞-间充质转化等过程,调节化疗敏感性。同时,lncRNA表达谱与肿瘤耐药的演变有密切关系。因此,发现新的lncRNA在肿瘤耐药中的机制对于制定新的治疗策略以克服耐药性具有积极意义。     

Cancer‐associated fibroblasts contribute to cisplatin resistance by modulating ANXA3 in lung cancer cells

Cancer tissues consist of cancer cells, surrounding stromal cells and the extracellular matrix. Cancer‐associated fibroblasts (CAF) are one of the key components of stromal cells. CAF have a great impact on the behavior of cancer cells, including proliferation, invasion, metastasis and chemoresistance in many ways. However, the underlying mechanism had not been fully elucidated. In this study, we investigated the role of CAF in cisplatin resistance of lung cancer cells. By using conditioned medium from CAF (CAF‐CM), we found that CAF decreased the sensitivity of lung cancer cells to cisplatin. RNA sequencing results showed that CAF expressed a higher level of Annexin A3 (ANXA3) than normal fibroblasts (NF), and CAF‐CM incubation increased the ANXA3 level in lung cancer cells. Overexpression of ANXA3 in lung cancer cells increased cisplatin resistance and activated c‐jun N‐terminal kinase (JNK), whereas knockdown of ANXA3 increased cisplatin sensitivity. Further study showed that CAF‐CM enhanced cisplatin resistance by inhibiting cisplatin‐induced apoptosis, determined by repression of caspase‐3 and caspase‐8, through activation of the ANXA3/JNK pathway. Conversely, suppression of JNK activation by specific inhibitor retarded the effect of CAF‐CM and ANXA3 on cisplatin sensitivity. Taken together, our study demonstrated that CAF potentiated chemoresistance of lung cancer cells through a novel ANXA3/JNK pathway both in vitro and in vivo, suggesting ANXA3 could be a potential therapeutic target for the treatment of chemoresistant cancer.