细胞外基质与肿瘤相关成纤维细胞

肿瘤的发生发展是一个肿瘤细胞与其微环境相互促进,共同演化的动态过程.实体肿瘤的发生发展过程伴随细胞外基质的过量沉积及其组织形式的异常以及成纤维细胞的活化和富集.细胞外基质与肿瘤相关成纤维细胞不仅是实体肿瘤的重要病理特征,同时也是恶性肿瘤发展的重要驱动力量.细胞外基质与肿瘤相关成纤维细胞通过多种机制促进了肿瘤的发生、发展和转移.针对细胞外基质与肿瘤相关成纤维细胞进行肿瘤治疗,可以为肿瘤的临床治疗提供新的思路.     

肿瘤细胞与肿瘤微环境间的相互作用

在肿瘤组织中,除了肿瘤细胞外还有其他成分包括间质细胞和细胞外基质(ECM),这些共同构成肿瘤微环境。这些间质细胞包括:成纤维细胞、内皮细胞、炎症细胞、脂肪细胞等。间质细胞的分布、细胞外基质的组成和代谢产物在同一肿瘤中明显不同。肿瘤细胞周围的间质细胞状态对肿瘤的转移产生重要影响,甚至可以用来预测肿瘤复发。肿瘤的发生发展包括众多成分之间的相互作用,本文论述了这一复杂网络的各个组成部分。     

结缔组织生成和肿瘤

肿瘤的发生并不只是由肿瘤细胞本身恶化引起的,肿瘤基质也发挥了非常重要的作用,肿瘤发生是肿瘤细胞和围绕它的肿瘤基质相互作用的产物。肿瘤细胞可以通过各种途径激活与其相邻的间质,促进成纤维细胞的增生、细胞外基质的沉积、免疫细胞浸润和血管生成,这种现象被称为结缔组织生成。结缔组织生成形成了一个支持肿瘤发展的微环境,通过多种途径促进了肿瘤的发生、发展和转移。针对结缔组织生成进行肿瘤治疗可以为肿瘤的临床治疗提供新的思路。     

结缔组织生成和肿瘤

肿瘤的发生并不只是由肿瘤细胞本身恶化引起的,肿瘤基质也发挥了非常重要的作用,肿瘤发生是肿瘤细胞和围绕它的肿瘤基质相互作用的产物。肿瘤细胞可以通过各种途径激活与其相邻的间质,促进成纤维细胞的增生、细胞外基质的沉积、免疫细胞浸润和血管生成,这种现象被称为结缔组织生成。结缔组织生成形成了一个支持肿瘤发展的微环境,通过多种途径促进了肿瘤的发生、发展和转移。针对结缔组织生成进行肿瘤治疗可以为肿瘤的临床治疗提供新的思路。     

肿瘤相关成纤维细胞促进肿瘤侵袭转移的作用机制

肿瘤相关成纤维细胞(cancer-associated fibroblasts,CAFs)是肿瘤微环境中最主要的成分之一,在肿瘤的发生发展中发挥着必不可少的作用。骨髓和脂肪的局部组织固有成纤维细胞及间充质干细胞是CAFs来源的主要前体细胞。大量研究表明,CAFs并不作为单独细胞在肿瘤周围存在,而是和肿瘤细胞相互作用,促进肿瘤的生长与存活并维持其恶性倾向。肿瘤细胞可以影响CAFs前体的招募,并诱导正常成纤维细胞活化为CAFs;同时,CAFs可以分泌多种细胞因子、生长因子和细胞外基质蛋白质,促进肿瘤细胞的增殖、耐药及侵袭转移,从而影响肿瘤的预后。CAFs还参与血管淋巴管的生成、细胞外基质重塑、免疫抑制以及肿瘤细胞上皮间质转化等有利于肿瘤发生发展的外源性途径,为肿瘤细胞提供了一个良好的微环境。大量研究显示,研发靶向CAFs的药物可以中断其与肿瘤细胞之间的联系,从而抑制肿瘤的生长和转移。因此,深入了解CAFs促肿瘤的作用机制将有利于肿瘤治疗新靶点的发现。本文将对CAFs促进肿瘤侵袭转移的作用机制加以综述。     

成纤维细胞激活蛋白α与肿瘤发展进程的研究

肿瘤微环境对肿瘤的发生、发展具有重要的意义。选择性表达于肿瘤微环境重要组成部分——肿瘤相关成纤维细胞（carcinoma associated fibroblasts,CAFs）表面的成纤维细胞激活蛋白α（fibroblast activation protein-α,FAPα）广泛参与了肿瘤的生长、侵袭、转移以及肿瘤细胞外基质重建、血管生成、免疫逃逸等过程,从而促进了肿瘤的发展进程。FAPα具有蛋白水解酶活性,并作用于细胞信号通路,但FAPα在肿瘤微环境中发挥功能的具体分子机制还有待进一步研究。由于FAPα的表达具有肿瘤组织特异性,因此,以FAPα作为肿瘤基质标志物,对肿瘤进行病理诊断和免疫治疗将成为新兴的研究靶点。对FAPα的主要生物学性状进行概述,并综述了其对肿瘤细胞的生长、侵袭、转移以及肿瘤细胞外基质重建、血管生成、免疫逃逸等方面的重要影响。     

肿瘤相关成纤维细胞与肿瘤微环境

肿瘤的发展过程与肿瘤微环境密切相关,而肿瘤相关成纤维细胞(CAFs)是上述微环境中最主要的宿主细胞,CAFs是一类不同细胞源性的细胞群,可来源于多种细胞包括静止的成纤维细胞、上皮细胞、内皮细胞和间质干细胞的分化过程。体内和体外生物学实验均证实,成纤维细胞在肿瘤微环境中并不是被动的对肿瘤发展提供支持,而是发挥了至关重要的作用,所以靶向CAFs有望成为肿瘤治疗的新方向,对CAFs相关分子标记物和分子事件的进一步探索将为抗肿瘤的临床治疗提供新的思路。本文将对CAFs的来源以及CAFs对肿瘤发生发展、转移及VEGF耐受等方面的作用做一综述。     

癌相关成纤维细胞的特性及其调控肿瘤进程的研究进展

肿瘤组织是由恶性上皮细胞及其周围的基质细胞微环境形成的复杂混合体。在肿瘤的发生发展过程中,肿瘤细胞与肿瘤微环境相互作用相互影响,其中癌相关成纤维细胞(CAF)是肿瘤微环境的重要组成部分。CAF不仅促进肿瘤细胞的增殖与转移、肿瘤微血管生成以及耐药性产生,还能抑制机体的抗肿瘤免疫,从而促进肿瘤的恶性进展。本文简要综述癌相关成纤维细胞的特性及其在调控肿瘤发生发展中的作用。     

肿瘤相关成纤维细胞与肿瘤微环境

肿瘤的发展过程与肿瘤微环境密切相关,而肿瘤相关成纤维细胞（CAFs）是上述微环境中最主要的宿主细胞,CAFs是一类不同细胞源性的细胞群,可来源于多种细胞包括静止的成纤维细胞、上皮细胞、内皮细胞和间质干细胞的分化过程。体内和体外生物学实验均证实,成纤维细胞在肿瘤微环境中并不是被动的对肿瘤发展提供支持,而是发挥了至关重要的作用,所以靶向CAFs有望成为肿瘤治疗的新方向,对CAFs相关分子标记物和分子事件的进一步探索将为抗肿瘤的临床治疗提供新的思路。本文将对CAFs的来源以及CAFs对肿瘤发生发展、转移及VEGF耐受等方面的作用做一综述。     

波动性高糖对肾小管上皮细胞Wnt／β-catenin信号途径的影响

肾脏纤维化分为肾小球硬化和肾小管间质纤维化（tubular interstitial fibrosis,TIF）,而TIF过程与肾损伤具有密切的关系。TIF是由于细胞外基质的过度沉积造成的,肌成纤维细胞是TIF发生发展过程中产生细胞外基质的主要细胞,该过程被成纤维细胞激活,涉及上皮细胞向肌成纤维细胞的转分化^[1-2]。Wnt／β-catenin信号途径涉及细胞增殖、肿瘤发生与转移的调控。β-catenin是Wnt信号途径的关键分子,在细胞的生长与分化过程中起着重要的作用,     

Extracellular vesicle-orchestrated crosstalk between cancer-associated fibroblasts and tumors

Communication networks in the tumor microenvironment (TME) play a crucial role in tumor progression. Cancer-associated fibroblasts (CAFs) are among the most abundant stromal cells in the TME. Bidirectional signal transduction between cancer cells and CAFs within the TME is important for cancer development and treatment responsiveness. Extracellular vesicles (EVs) carrying proteins, miRNAs, and other biomolecules are secreted into the extracellular matrix (ECM), which has been demonstrated to be an important communication medium between tumors and CAFs. Tumors regulate the activation of CAFs by secreting EVs. Conversely, CAFs can also affect tumor proliferation, metastasis, and therapeutic resistance through EVs. Here, we will classify EV cargoes and discuss the role of EV-mediated interactions between CAFs and tumors, reviewing current knowledge in combination with our confirmed results.     

Extracellular vesicle-orchestrated crosstalk between cancer-associated fibroblasts and tumors

Communication networks in the tumor microenvironment (TME) play a crucial role in tumor progression. Cancer-associated fibroblasts (CAFs) are among the most abundant stromal cells in the TME. Bidirectional signal transduction between cancer cells and CAFs within the TME is important for cancer development and treatment responsiveness. Extracellular vesicles (EVs) carrying proteins, miRNAs, and other biomolecules are secreted into the extracellular matrix (ECM), which has been demonstrated to be an important communication medium between tumors and CAFs. Tumors regulate the activation of CAFs by secreting EVs. Conversely, CAFs can also affect tumor proliferation, metastasis, and therapeutic resistance through EVs. Here, we will classify EV cargoes and discuss the role of EV-mediated interactions between CAFs and tumors, reviewing current knowledge in combination with our confirmed results.     

Three-dimensional Co-culture Model for Tumor-stromal Interaction

Cancer progression (initiation, growth, invasion and metastasis) occurs through interactions between malignant cells and the surrounding tumor stromal cells. The tumor microenvironment is comprised of a variety of cell types, such as fibroblasts, immune cells, vascular endothelial cells, pericytes and bone-marrow-derived cells, embedded in the extracellular matrix (ECM). Cancer-associated fibroblasts (CAFs) have a pro-tumorigenic role through the secretion of soluble factors, angiogenesis and ECM remodeling. The experimental models for cancer cell survival, proliferation, migration, and invasion have mostly relied on two-dimensional monocellular and monolayer tissue cultures or Boyden chamber assays. However, these experiments do not precisely reflect the physiological or pathological conditions in a diseased organ. To gain a better understanding of tumor stromal or tumor matrix interactions, multicellular and three-dimensional cultures provide more powerful tools for investigating intercellular communication and ECM-dependent modulation of cancer cell behavior. As a platform for this type of study, we present an experimental model in which cancer cells are cultured on collagen gels embedded with primary cultures of CAFs.     

The functional cross talk between cancer cells and cancer associated fibroblasts from a cancer mechanics perspective

The function of biological tissues in health and disease is regulated at cellular level and is highly influenced by the physical microenvironment, through the interaction of forces between cells and ECM, which are perceived through mechanosensing pathways. In cancer, both chemical and physical signaling cascades and their interactions are involved during cell-cell and cell-ECM communications to meet requirements of tumor growth. Among stroma cells, cancer associated fibroblasts (CAFs) play key role in tumor growth and pave the way for cancer cells to initiate metastasis and invasion to other tissues, and without recruitment of CAFs, the process of cancer invasion is dysfunctional. This is through an intense chemical and physical cross talks with tumor cells, and interactive remodeling of ECM. During such interaction CAFs apply traction forces and depending on the mechanical properties, deform ECM and in return receive physical signals from the micromechanical environment. Such interaction leads to ECM remodeling by manipulating ECM structure and its mechanical properties. The results are in form of deposition of extra fibers, stiffening, rearrangement and reorganization of fibrous structure, and degradation which are due to a complex secretion and expression of different markers triggered by mechanosensing of tumor cells, specially CAFs. Such events define cancer progress and invasion of cancer cells.A systemic knowledge of chemical and physical factors provides a holistic view of how cancer process and enhances the current treatment methods to provide more diversity among targets that involves tumor cells and ECM structure.     

Stromal miR-200s contribute to breast cancer cell invasion through CAF activation and ECM remodeling

The activation of cancer-associated fibroblasts (CAFs) is a key event in tumor progression, and alternative extracellular matrix (ECM) proteins derived from CAFs induce ECM remodeling and cancer cell invasion. Here we found that miR-200 s, which are generally downregulated in activated CAFs in breast cancer tissues and in normal fibroblasts (NFs) activated by breast cancer cells, are direct mediators of NF reprogramming into CAFs and of ECM remodeling. NFs with downregulated miR-200 s displayed the traits of activated CAFs, including accelerated migration and invasion. Ectopic expression of miR-200 s in CAFs at least partially restored the phenotypes of NFs. CAF activation may be governed by the targets of miR-200 s, Fli-1 and TCF12, which are responsible for cell development and differentiation; Fli-1 and TCF12 were obviously elevated in CAFs. Furthermore, miR-200 s and their targets influenced collagen contraction by CAFs. The upregulation of fibronectin and lysyl oxidase directly by miR-200 or indirectly through Fli-1 or TCF12 contributed to ECM remodeling, triggering the invasion and metastasis of breast cancer cells both in vitro and vivo. Thus, these data provide important and novel insights into breast CAF activation and ECM remodeling, which trigger tumor cell invasion.It has been well established that a reactive microenvironment induces cancer cells to proliferate, migrate and become invasive. Cancer-associated fibroblasts (CAFs) are thought to be the main players among the cohabitating stromal cell types, and they favor tumor progression. The cancer-promoting ability of CAFs is dependent on their activation; however, this process has not been fully explored.The extracellular matrix (ECM) is a complex mixture of structural proteins, proteoglycans and glycoproteins that exerts biochemical and mechanical effects on cells. An increasing body of evidence suggests that ECM remodeling has an important role in cell morphogenesis,¹ survival,² migration and invasion.³ CAFs can deposit certain ECM components and facilitate the directional migration and invasion of carcinoma cells through mechanotransduction-triggered architectural remodeling of the microenvironment.^{4, 5} However, the mechanism by which activated CAFs stimulate the dysregulation of ECM proteins, thus influencing cancer cell invasion, is not well understood.Previously, our team identified a set of dysregulated miRNAs in breast CAFs using a miRNA microarray, and it was found that the levels of miR-200 family members were noticeably suppressed,⁶ indicating their importance in CAF function. Whether these downregulated miR-200 s in the stroma drive the activated phenotype of CAFs as well as aberrant ECM protein expression to promote cancer cell invasion is an intriguing question.The miR-200 s family can be functionally divided into cluster 1 (miR-200a and miR-141) and cluster 2 (miR-200b and miR-200c) according to their ''seed'' region for binding to mRNA. The effects of the miR-200 s on fibrosis, epithelial cell characteristics, cell differentiation and tumor progression have been discussed. For example, miR-200b is essential for the regulation of renal fibrogenesis⁷ and the intestinal fibrosis of Crohn''s disease.⁸ In aggressive carcinoma cells, the maintenance of EMT,⁹ tumor growth,¹⁰ migration,¹¹ invasion,⁹ anoikis resistance¹² and poor response to chemotherapy¹³ are enhanced by the reduced expression of miR-200 s. Furthermore, miR-200 s are upregulated during mammary differentiation¹⁴ but are downregulated in breast cancer stem cells,¹⁵ and these molecules support the maintenance of pluripotent stem cells.¹⁶ These previous reports indicate that miR-200 s may have a significant role in CAF activation.In the current work, we first determined that miR-200 s were commonly downregulated in breast CAFs, and this result was also demonstrated in normal fibroblasts (NFs) co-cultured with breast cancer cells. miR-200 s induced the conversion of NFs into CAFs by targeting Fli-1 and TCF12. Re-expression of miR-200 s in CAFs attenuated the activation-associated CAF phenotype. In particular, miR-200 s and their targets all contributed to CAF-associated ECM remodeling through two key ECM remodeling proteins, fibronectin (FN) and lysyl oxidase, further fueling cancer cell invasion and metastasis. Therefore, our data provide new information regarding the role of CAF activation and function in the promotion of cancer cell invasion through ECM remodeling and provide a considerable amount of information that will be useful for the development of stromal therapeutic targets.     

Extracellular matrix (ECM) stiffness and degradation as cancer drivers

Alteration in the density and composition of extracellular matrix (ECM) occurs in tumors. The alterations toward both stiffness and degradation are contributed to tumor growth and progression. Cancer-associated fibroblasts (CAFs) are the main contributors to ECM stiffness and degradation. The cells interact with almost all cells within the tumor microenvironment (TME) that could enable them to modulate ECM components for tumorigenic purposes. Cross-talks between CAFs with cancer cells and macrophage type 2 (M2) cells are pivotal for ECM stiffness and degradation. CAFs induce hypoxia within the TME, which is one of the key inducers of both stiffness and degradation. Cancer cell modulatory roles in integrin receptors are key for adjusting ECM constituents to either fates. Cancer cell proliferation, migration, and invasion as well as angiogenesis are consequences of ECM stiffness and degradation. ECM stiffness in a transforming growth factor-β (TGF-β) related pathway could make a bridge in the basement membrane, and ECM degradation in a matrix metalloproteinase (MMP)-related pathway could make a path in the TME, both of which contribute to cancer cell invasion. ECM stiffness is also obstructive for drug penetration to the tumor site. Therefore, it would be a promising strategy to make a homeostasis in ECM for easy penetration of chemotherapeutic drugs and increasing the efficacy of antitumor approaches. MMP and TGF-β inhibitors, CAF and M2 reprogramming toward their normal counterparts, reduction of TME hypoxia and hampering integrin signaling are among the promising approaches for the modulation of ECM in favor of tumor regression.     

Reconstitution of a metastatic-resistant tumor microenvironment with cancer-associated fibroblasts enables metastasis

The tumor microenvironment is critical for metastasis to occur. Subcutaneous xenografts of tumors in immunodeficient mice are usually encapsulated and rarely metastasize as opposed to orthotopic tumors which metastasize if the original tumor was metastatic. In the present report, we were able to reconstitute a metastatic tumor microenvironment by subcutaneously co-transplanting a human cervical cancer cell line and human cervical cancer-associated fibroblasts (CAFs), in athymic mice, which resulted in lymph node metastasis in 40% of the animals. In contrast, no metastasis occurred from the cervical cancer without CAFs. These results suggest that CAFs can overcome an anti-metastatic tumor environment and are a potential target to prevent metastasis.     

MicroRNA regulation in cancer-associated fibroblasts

The microenvironment of cancer cells has proven to be a critical component of tumors that strongly influences cancer development and progression into invasive and metastatic disease. Compared to normal tissue, dramatic differences in gene expression occur in multiple cell types that constitute the tumor microenvironment including cancer-associated fibroblasts (CAFs) that are important stromal components of growing tumors. In this review, we present recent advances in understanding how microRNAs are deregulated in cancer-associated fibroblasts (CAFs) and how this affects tumor biology. The microRNA signature of CAFs is discussed with respect to their functional relevance to tumor cells as well as other cell types involved in tumor homeostasis.