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。     

肿瘤微环境的组成及其在肿瘤转移中的作用

肿瘤微环境是肿瘤细胞赖以生存的复杂环境,主要是由多种不同的细胞外基质和基质细胞组成。肿瘤微环境的成分与肿瘤细胞之间存在相互刺激作用,从而促进肿瘤进展和肿瘤细胞的转移。研究表明肿瘤细胞和基质细胞通过两种方式共同演变：基质变化导致上皮细胞转化,或者转化的上皮细胞可能以旁分泌方式激活基质细胞。肿瘤细胞引起细胞外基质重建,并参与肿瘤生长,进一步引起肿瘤侵袭和播撒。基因表达谱研究发现肿瘤基质中的动态变化有利于肿瘤细胞转移,以基质变化为标准的肿瘤分类能够预测其临床预后和转移靶器官。     

肿瘤—宿主界面微环境研究进展

肿瘤—宿主界面微环境主要由肿瘤细胞、宿主细胞、细胞外基质、分泌因子等组成,各成分之间的交互作用形成一个庞大而复杂的网络系统，对肿瘤的发生发展具有重要的调控作用。文章对近年来肿瘤一宿主界面微环境的研究进展进行综述。     

分泌模块化钙结合蛋白?鄄2在肿瘤中的研究进展

摘 要：细胞微环境包括细胞外基质、免疫细胞和基质细胞等，肿瘤在其发生、发展过程中受到肿瘤细胞微环境的调控。分泌模块化钙结合蛋白-2（secreted modular calcium binding protein-2，SMOC-2蛋白）是新近发现的基质细胞蛋白，在正常人体组织及多种肿瘤组织内均有表达。SMOC-2蛋白参与调控肿瘤细胞周期进程、血管生成、细胞增殖、细胞附着和迁移，并在原发性肝细胞肝癌、结直肠癌、子宫内膜癌、肺癌等不同肿瘤中表现出不同作用。该文对SMOC-2蛋白的生物学功能及其与原发性肝细胞肝癌、结直肠癌、子宫内膜癌、肺癌等肿瘤的关系进行综述。     

活血化淤中药干预肿瘤乏氧微环境在侵袭转移方面的研究进展

1 传统与现代医学对于肿瘤乏氧的认识 肿瘤的发生和发展是一个多因素、多步骤、多基因共同作用的综合病变过程.特殊的宿主微环境通过种种调节机制影响着肿瘤细胞的生成发展、侵袭转移.特殊的宿主微环境是肿瘤细胞生存、增殖的土壤.肿瘤细胞所处的宿主微环境主要是由基质细胞、基质细胞分泌的不溶性细胞外基质及各种细胞因子和生长凶子构成~([1]).     

基质微环境中的肿瘤相关成纤维细胞促进肿瘤远处转移的研究进展

肿瘤微环境是肿瘤细胞赖以生存、增殖的重要场所,其不仅介导肿瘤细胞对化疗药物产生耐药,而且能够促进肿瘤细胞发生远处转移.肿瘤相关成纤维细胞(cancer-associated fi-broblasts,CAFs)作为肿瘤微环境中的重要组成成分,其可通过重塑细胞外基质、分泌可溶性因子等方式来促进多种肿瘤的恶性进展.近年来,...     

肿瘤微环境中的炎性机制与肿瘤转移

炎性微环境是肿瘤微环境中影响肿瘤复发转移的关键因素之一.肿瘤炎性微环境可以通过调节上皮细胞向间充质细胞转变,启动肿瘤转移;可以通过降解细胞外基质从而破坏细胞外基质膜促进肿瘤细胞的侵袭;同时,炎性微环境促进肿瘤血管的新生为肿瘤的发生发展提供保障.     

炎性微环境主要组分与肿瘤

以肿瘤细胞、肿瘤相关性成纤维细胞、巨噬细胞及细胞外基质等为主要组分组成的炎性微环境与肿瘤的发生发展、复发转移密切相关。诸多研究表明,炎症不仅可导致肿瘤的发生,同时在肿瘤发展过程中也多伴有炎症的存在。炎性微环境的主要组分与肿瘤细胞之间存在丰富的分子网络对话,阻断或干扰其中的一个或多个环节将有助于阻止肿瘤细胞的恶性表型和预后转归。     

肿瘤微环境与肿瘤转移

肿瘤转移与肿瘤微环境中成纤维细胞、转化生长因子、肿瘤相关巨噬细胞、趋化因子及其受体、凝血酶等多种因素密切相关。成纤维细胞通过促进肿瘤血管生成、促进癌细胞与细胞外基质黏附、促进细胞外基质降解等环节参与肿瘤的转移。TGF-β是由巨噬细胞、间质细胞和肿瘤细胞产生,它能对抗血管内皮的紧密连接和黏附连接,使毛细血管壁完整性受到破坏,从而导致毛细血管通透性增加,使肿瘤细胞从血管中游出进入器官组织中形成种植转移。肿瘤相关性巨噬细胞可合成和分泌EGF等细胞因子,引导肿瘤细胞穿越血管壁,促进肿瘤的转移。趋化因子及其受体对肿瘤细胞的迁移起着决定性的作用。凝血酶能通过影响微环境中其他细胞的行为而为肿瘤转移提供一个相容的环境。明晰肿瘤转移与肿瘤微环境的关系,进而明确在肿瘤发生、发展、转移过程中发挥重要作用的关键分子,寻找其相对应的靶点,对于肿瘤的诊断及治疗具有重要的作用。     

Emerging data supporting stromal cell therapeutic potential in cancer: reprogramming stromal cells of the tumor microenvironment for anti-cancer effects

After more than a decade of controversy on the role of stromal cells in the tumor microenvironment, the emerging data shed light on pro-tumorigenic and potential anti-cancer factors, as well as on the roots of the discrepancies. We discuss the pro-tumorigenic effects of stromal cells, considering the effects of tumor drivers like hypoxia and tumor stiffness on these cells, as well as stromal cell-mediated adiposity and immunosuppression in the tumor microenvironment, and cancer initiating cells’ cellular senescence and adaptive metabolism. We summarize the emerging data supporting stromal cell therapeutic potential in cancer, discuss the possibility to reprogram stromal cells of the tumor microenvironment for anti-cancer effects, and explore some causes of discrepancies on the roles of stromal cells in cancer in the available literature.     

Differentiation and transdifferentiation potentials of cancer stem cells

Tumor cells actively contribute to constructing their own microenvironment during tumorigenesis and tumor progression. The tumor microenvironment contains multiple types of stromal cells that work together with the extracellular matrix and local and systemic factors to coordinately contribute to tumor initiation and progression. Tumor cells and their stromal compartments acquire many genetic and/or epigenetic alternations to facilitate tumor growth and metastasis. The cancer stem cell (CSC) concept has been widely applied to interpreting tumor initiation, growth, metastasis, dormancy and relapse. CSCs have differentiation abilities to generate the original lineage cells that are similar to their normal stem cell counterparts. Interestingly, recent evidence demonstrates that CSCs also have the potential to transdifferentiate into vascular endothelial cells and pericytes, indicating that CSCs can transdifferentiate into other lineage cells for promoting tumor growth and metastasis in some tissue contexts instead of only recruiting stromal cells from local or distant tissues. Although the transdifferentiation of CSCs into tumor stromal cells provides a new dimension that explains tumor heterogeneity, many aspects of CSC transdifferentiation remain elusive. In this review, we summarize the multi-lineage differentiation and transdifferentiation potentials of CSCs as well as discuss their potential contributions to tumor heterogeneity and tumor microenvironment in tumor progression.     

Potential of CXCR4 antagonists for the treatment of metastatic lung cancer

Despite advances in surgery, chemotherapy and radiotherapy over the last decades, the death rate from lung cancer has remained largely unchanged, which is mainly due to metastatic disease. Because of the overall poor prognosis, new treatment strategies for lung cancer patients are urgently needed, and targeting CXCR4 constitutes such a novel, attractive strategy. Tumor cell migration and metastasis share many similarities with leukocyte trafficking, which is critically regulated by chemokine receptors and adhesion molecules. Lung cancer cells express CXCR4 (CD184), a seven-transmembrane G-protein-coupled chemokine receptor. Stromal cells within the tumor microenvironment constitutively secrete stromal cell-derived factor-1 (SDF-1/CXCL12), the ligand for CXCR4. Activation of CXCR4 induces lung cancer cell migration and adhesion to stromal cells, which in turn provides growth- and drug-resistance signals to the tumor cells. CXCR4 antagonists, such as Plerixafor (AMD3100) and T140 analogues (TN14003/BKT140), can disrupt CXCR4-mediated tumor cell adhesion to stromal cells and sensitize lung cancer cells to cytotoxic drugs. Therefore, targeting the CXCR4–CXCL12 axis is a novel, attractive therapeutic approach in small-cell lung cancer and non-small-cell lung cancer. In this article, we summarize data about the cellular and molecular microenvironment in small-cell lung cancer and non-small-cell lung cancer, as well as the role of CXCR4 in tumor–stroma crosstalk. In addition, we review the current status of the preclinical and clinical development of CXCR4 antagonists.     

乳腺癌肿瘤微环境中间质细胞介导的化疗耐药性研究进展

乳腺癌是一种具有异质性的全身性疾病,其微环境主要由肿瘤细胞及多种非肿瘤细胞组成。其中间充质干细胞在肿瘤的发生发展中发挥着重要作用。间充质干细胞可直接通过缝隙连接、膜受体和微管或间接通过可溶性分子与肿瘤细胞及其微环境相互作用。肿瘤相关成纤维细胞来源于癌旁成纤维细胞或间充质干细胞,在肿瘤耐药过程中发挥重要作用。在乳腺癌中,肿瘤干细胞与其所处微环境处于动态平衡状态,其表型受细胞因子的密切调控。间质细胞通过与乳腺癌细胞的相互作用,进而对其生物学特性产生重要影响。另外,间质细胞可改变肿瘤细胞对化疗药物的敏感性,进而使其产生耐药。因此,解决肿瘤间质细胞介导的化疗耐药是成功治疗中晚期乳癌的关键。本文主要阐述了间质细胞在乳腺癌微环境中介导化疗耐药的研究进展。     

Tumor microenvironment characterization identifies two lung adenocarcinoma subtypes with specific immune and metabolic state

The tumor microenvironment (TME) is a vital component of tumor tissue. Increasing evidence suggests their significance in predicting outcomes and guiding therapies. However, no studies have reported a systematic analysis of the clinicopathologic significance of TME in lung adenocarcinoma (LUAD). Here, we inferred tumor stromal cells in 1184 LUAD patients using computational algorithms based on bulk tumor expression data, and evaluated the clinicopathologic significance of stromal cells. We found LUAD patients showed heterogeneous abundance in stromal cells. Infiltration of stromal cells was influenced by clinicopathologic features, such as age, gender, smoking, and TNM stage. By clustering stromal cells, we identified 2 clinically and molecularly distinct LUAD subtypes with immune active and immune repressed features. The immune active subtype is characterized by repressed metabolism and repressed proliferation of tumor cells, while the immune repressed subtype is characterized by active metabolism and active proliferation of tumor cells. Differentially expressed gene analysis of the two LUAD subtypes identified an immune activation signature. To diagnose TME subtypes practically, we constructed a TME score using principal component analysis based on the immune activation signature. The TME score predicted TME subtypes effectively in 3 independent datasets with areas under the receiver operating characteristic curves of 0.960, 0.812, and 0.819, respectively. In conclusion, we proposed 2 clinically and molecularly distinct LUAD subtypes based on tumor microenvironment that could be valuable in predicting clinical outcome and guiding immunotherapy.     

癌症相关成纤维细胞诱导的上皮间质转化增强肿瘤细胞干性的研究进展

在肿瘤细胞干性的获得和维持方面,肿瘤微环境扮演着十分重要的角色。作为其中数量最多的基质细胞,癌症相关成纤维细胞(cancer-associated fibroblasts,CAFs)可通过旁分泌信号和改变基质硬度的方式,诱导邻近的肿瘤细胞发生上皮-间质转化(epithelial-mesenchymal transition,EMT),使上皮来源细胞部分或完全地获得间充质表型。当细胞处于EMT进程中的某个过渡阶段时,即可被诱导表达干细胞表型,促进肿瘤的发生与进展。本文主要回顾了CAFs、EMT和肿瘤细胞干性相互之间的关系以及相关分子机制的研究,并尝试论述CAFs诱导肿瘤细胞的EMT增强其细胞干性。     

子宫内膜癌微环境中间质细胞相关信号通路的研究进展

和子宫内膜癌上皮细胞相似，肿瘤微环境中主要细胞的间质细胞也表达雌激素受体（ER），同样也受到雌激素的调控。在雌激素和抑癌基因的作用下，间质细胞与肿瘤细胞的增殖、侵袭和转移等密切相关。间质细胞相关信号通路的研究，为探索雌、孕激素失衡的发病机制、肿瘤复发和化疗耐药等机制提供新的依据。     

Cell-to-cell contact-mediated regulation of tumor behavior in the tumor microenvironment

Tumor growth and progression are complex processes mediated by mutual interactions between cancer cells and their surrounding stroma that include diverse cell types and acellular components, which form the tumor microenvironment. In this environment, direct intercellular communications play important roles in the regulation of the biological behaviors of tumors. However, the underlying molecular mechanisms are insufficiently defined. We used an in vitro coculture system to identify genes that were specifically expressed at higher levels in cancer cells associated with stromal cells. Major examples included epithelial membrane protein 1 (EMP1) and stomatin, which positively and negatively regulate tumor progression, respectively. EMP1 promotes tumor cell migration and metastasis via activation of the small GTPase Rac1, while stomatin strongly suppresses cell proliferation and induces apoptosis of cancer cells via inhibition of Akt signaling. Here we highlight important aspects of EMP1, stomatin, and their family members in cancer biology. Furthermore, we consider the molecules that participate in intercellular communications and signaling transduction between cancer cells and stromal cells, which may affect the phenotypes of cancer cells in the tumor microenvironment.     

肿瘤相关纤维母细胞的研究进展

肿瘤的生物学特性不仅是由癌基因和抑癌基因来调控的,还依赖于由其间质等构成的微环境。基膜、免疫细胞、毛细血管、纤维母细胞和细胞外基质(extracellular matrix,ECM)共同构成肿瘤间质,与创伤愈合过程中的间质相似,肿瘤间质亦为活化的间质(reactive stroma)。而纤维母细胞是活化间质中的主要功能细胞,其与肿瘤的发生发展的关系日益成为研究的热点。本文旨在探讨肿瘤相关纤维母细胞(carcinoma-associated fibroblasts,CAF)的生物学特点及研究进展及方向。     

Changes in the gene expression of co-cultured human fibroblast cells and osteosarcoma cells: the role of microenvironment

Background

The progression of malignant tumors does not depend exclusively on the autonomous properties of cancer cells; it is also influenced by tumor stroma reactivity and is under strict microenvironmental control. By themselves, stromal cells are not malignant, and they maintain normal tissue structure and function. However, through intercellular interactions or by paracrine secretions from cancer cells, normal stromal cells acquire abnormal phenotypes that sustain cancer cell growth and tumor progression. In their dysfunctional state, fibroblast and immune cells produce chemokines and growth factors that stimulate cancer cell growth and invasion. In our previous work, we established an in vitro model based on a monolayer co-culture system of healthy human fibroblasts (HFs) and human osteosarcoma cells (the MG-63 cell line) that simulates the microenvironment of tumor cells and healthy cells. The coexistence between MG-63 cells and HFs allowed us to identify the YKL-40 protein as the main marker for verifying the influence of tumor cells grown in contact with healthy cells.

Methods

In this study, we evaluated the interactions of HFs and MG-63 cells in a transwell co-culture system over 24 h, 48 h, 72 h, and 96 h. We analyzed the contributions of these populations to the tumor microenvironment during cancer progression, as measured by multiple markers. We examined the effect of siRNA knockdown of YKL-40 by tracking the subsequent changes in gene expression within the co-culture. We validated the expression of several genes, focusing on those involved in cancer cell invasion, inflammatory responses, and angiogenesis: TNF alpha, IL-6, MMP-1, MMP-9, and VEGF. We compared the results to those from a transwell co-culture without the YKL-40 knockdown.

Results

In a pro-inflammatory environment promoted by TNF alpha and IL-6, siRNA knockdown of YKL-40 caused a down-regulation of VEGF and MMP-1 expression in HFs.

Conclusions

These findings demonstrated that the tumor microenvironment has an influence on the gene expression of healthy surrounding tissues and on the process of tumorigenicity and it is emerging as attractive targets for therapeutic strategies.