肝细胞癌的微环境研究进展

越来越多的研究表明,肿瘤细胞与其周围微环境的交互作用是肿瘤发生、上皮间质转化、肿瘤浸润和转移的关键调节因素．肝细胞癌的微环境可以分为细胞组分和非细胞组分．主要的细胞组分包含：肝星形细胞、肿瘤相关的纤维母细胞、免疫细胞和肝窦内皮细胞等．非细胞组分包含：胞外基质蛋白、酶类、各种生长因子和炎症因子等．综述了近年来肝细胞癌的微环境研究进展,分别从细胞组分和非细胞组分及其之间的相互作用角度对肝细胞癌微环境作一介绍．     

Impaired desensitization of a human polymorphic α2B-adrenergic receptor variant enhances its sympatho-inhibitory activity in chromaffin cells

Recent advances in tumor biology have revealed that a detailed analysis of the complex interactions of tumor cells with their adjacent microenvironment (tumor stroma) is mandatory in order to understand the various mechanisms involved in tumor growth and the development of metastasis. The mutual interactions between tumor cells and cellular and non-cellular components (extracellular matrix = ECM) of the tumor microenvironment will eventually lead to a loss of tissue homeostasis and promote tumor development and progression. Thus, interactions of genetically altered tumor cells and the ECM on the one hand and reactive non-neoplastic cells on the other hand essentially control most aspects of tumorigenesis such as epithelial-mesenchymal-transition (EMT), migration, invasion (i.e. migration through connective tissue), metastasis formation, neovascularisation, apoptosis and chemotherapeutic drug resistance. In this mini-review we will focus on these issues that were recently raised by two review articles in CCS.     

Cancer cell invasion is enhanced by applied mechanical stimulation

Metastatic cells migrate from the site of the primary tumor, through the stroma, into the blood and lymphatic vessels, finally colonizing various other tissues to form secondary tumors. Numerous studies have been done to identify the stimuli that drive the metastatic cascade. This has led to the identification of multiple biochemical signals that promote metastasis. However, information on the role of mechanical factors in cancer metastasis has been limited to the affect of compliance. Interestingly, the tumor microenvironment is rich in many cell types including highly contractile cells that are responsible for extensive remodeling and production of the dense extracellular matrix surrounding the cancerous tissue. We hypothesize that the mechanical forces produced by remodeling activities of cells in the tumor microenvironment contribute to the invasion efficiency of metastatic cells. We have discovered a significant difference in the extent of invasion in mechanically stimulated verses non-stimulated cell culture environments. Furthermore, this mechanically enhanced invasion is dependent upon substrate protein composition, and influenced by topography. Finally, we have found that the protein cofilin is needed to sense the mechanical stimuli that enhances invasion. We conclude that other types of mechanical signals in the tumor microenvironment, besides the rigidity, can enhance the invasive abilities of cancer cells in vitro. We further propose that in vivo, non-cancerous cells located within the tumor micro-environment may be capable of providing the necessary mechanical stimulus during the remodeling of the extracellular matrix surrounding the tumor.     

Understanding the role of stromal fibroblasts in cancer progression

The major cellular components of tumor microenvironment, referred to as the cancer stroma, are composed of cancer-associated fibroblasts that support tumor epithelial growth, invasion and therapeutic resistance. Thus when we speak of developing therapies that address tumor heterogeneity it is not only a matter of different mutations within the tumor epithelia. While individual mutations in the stromal compartment are controversial, the heterogeneity in fibroblastic population in a single tumor is not up for debate. Cooperative interaction among heterotypic fibroblasts and tumor cells contribute to cancer progression. Therefore to tackle solid tumors, we need to understand its complex microenvironment. Here we review some seminal developments in the field of tumor microenvironment, mainly focusing on cancer-associated fibroblast.     

Understanding the role of stromal fibroblasts in cancer progression

The major cellular components of tumor microenvironment, referred to as the cancer stroma, are composed of cancer-associated fibroblasts that support tumor epithelial growth, invasion and therapeutic resistance. Thus when we speak of developing therapies that address tumor heterogeneity it is not only a matter of different mutations within the tumor epithelia. While individual mutations in the stromal compartment are controversial, the heterogeneity in fibroblastic population in a single tumor is not up for debate. Cooperative interaction among heterotypic fibroblasts and tumor cells contribute to cancer progression. Therefore to tackle solid tumors, we need to understand its complex microenvironment. Here we review some seminal developments in the field of tumor microenvironment, mainly focusing on cancer-associated fibroblast.     

Impact of the non-cellular tumor microenvironment on metastasis: potential therapeutic and imaging opportunities

Evidence is accumulating that the malignant phenotype of a given tumor is dependent not only on the intrinsic characteristics of tumor cells, but also on the cooperative interactions of non-neoplastic cells, soluble secreted factors and the non-cellular solid-state ECM network that comprise the tumor microenvironment. Given the ability of the tumor microenvironment to regulate the cellular phenotype, recent efforts have focused on understanding the molecular mechanisms by which cells sense, assimilate, interpret, and ultimately respond to their immediate surroundings. Exciting new studies are beginning to unravel the complex interactions between the numerous cell types and regulatory factors within the tumor microenvironment that function cooperatively to control tumor cell invasion and metastasis. Here, we will focus on studies concerning a common theme, which is the central importance of the non-cellular solid-state compartment as a master regulator of the malignant phenotype. We will highlight the non-cellular solid-state compartment as a relatively untapped source of therapeutic and imaging targets and how cellular interactions with these targets may regulate tumor metastasis.     

Emerging roles of the tumor-associated stroma in promoting tumor metastasis

The stroma in human carcinomas consists of extracellular matrix and various types of non-carcinoma cells, mainly leukocytes, endothelial cells, fibroblasts, myofibroblasts and bone marrow-derived progenitors. The tumor-associated stroma actively supports tumor growth by stimulating neo-angiogenesis, as well as proliferation and invasion of apposed carcinoma cells. It has long been accepted that alterations within carcinoma cells mediate metastasis in a cell-autonomous fashion. Recent studies have, however, suggested an additional notion that cancer cells instigate local and systemic changes in the tumor microenvironment and contribute to niche formation for metastasis. Research, aiming to establish the roles of the tumor-associated stroma in facilitating the spread of carcinoma cells into distant organs, has provided an abundance of data and greater knowledge of the biology of metastatic carcinoma cells and associated stromal cells. This has stimulated further advances in the development of novel therapeutic approaches targeting tumor metastasis.     

免疫细胞与肿瘤微环境

肿瘤细胞和免疫细胞间的相互作用一直是肿瘤生物学关注的热点.流行病学与临床研究均表明,炎症反应与肿瘤的发生发展存在密切关联,但是其中的分子作用机理和遗传学机制尚未完全阐明.研究显示,T淋巴细胞、巨噬细胞、树突状细胞、巨大细胞等多种免疫细胞会浸润到肿瘤微环境中,协同调控肿瘤生长、免疫逃逸和侵袭转移.本文就近年对肿瘤微环境中免疫细胞功能研究的进展进行综述.正确认识这些免疫细胞在肿瘤发生发展中的作用,对于发展更优的肿瘤免疫治疗手段具有十分重要意义.     

The dynamic interactions between the stroma,pancreatic stellate cells and pancreatic tumor development: Novel therapeutic targets

The stroma is a main driver of metastasis and aggressiveness in pancreatic cancer (PC), one of the deadliest malignancies worldwide. Pancreatic stellate cells (PSCs) form approximately 50% of the pancreatic tumor stroma, causing desmoplasia, extracellular matrix (ECM) deposition, epithelial-to-mesenchymal transition (EMT) and metastatic spread. Furthermore, activated PSCs can remodel the pancreatic tumor microenvironment (TME) via dynamic and complex interactions and feedback loops with PC cells, thus facilitating tumor growth through various signalling and immune pathways. Hence, increased understanding of these cellular cross-talks and how they shape the TME in PC might guide the development of novel treatment approaches against this stubborn and deadly malignancy that has so far resisted therapeutic advances. In this review, we will explore the role of the stroma and PSCs in PC development, invasion and metastasis, examine their interaction with PC cells and discuss potential treatment approaches aimed at targeting PSCs in order to reprogram the pancreatic tumor environment.     

Regulation of invadopodia by the tumor microenvironment

The tumor microenvironment consists of stromal cells, extracellular matrix (ECM), and signaling molecules that communicate with cancer cells. As tumors grow and develop, the tumor microenvironment changes. In addition, the tumor microenvironment is not only influenced by signals from tumor cells, but also stromal components contribute to tumor progression and metastasis by affecting cancer cell function. One of the mechanisms that cancer cells use to invade and metastasize is mediated by actin-rich, proteolytic structures called invadopodia. Here, we discuss how signals from the tumor environment, including growth factors, hypoxia, pH, metabolism, and stromal cell interactions, affect the formation and function of invadopodia to regulate cancer cell invasion and metastasis. Understanding how the tumor microenvironment affects invadopodia biology could aid in the development of effective therapeutics to target cancer cell invasion and metastasis.     

A prototypic matricellular protein in the tumor microenvironment--where there's SPARC, there's fire

Within the tumor microenvironment is a dynamic exchange between cancer cells and their surrounding stroma. This complex biologic system requires carefully designed models to understand the role of its stromal components in carcinogenesis, tumor progression, invasion, and metastasis. Secreted protein acidic and rich in cysteine (SPARC) is a prototypic matricellular protein at the center of this exchange. Two decades of basic science research combined with recent whole genome analyses indicate that SPARC is an important player in vertebrate evolution, normal development, and maintenance of normal tissue homeostasis. Therefore, SPARC might also play an important role in the tumor microenvironment. Clinical evidence indicates that SPARC expression correlates with tumor progression, but tightly controlled animal models have shown that the role of SPARC in tumor progression is dependent on tissue and tumor cell type. In this Prospectus, we review the current understanding of SPARC in the tumor microenvironment and discuss current and future investigations of SPARC and tumor-stromal interactions that require careful consideration of growth factors, cytokines, proteinases, and angiotropic factors that might influence SPARC activity and tumor progression.     

Regulation of invadopodia by the tumor microenvironment

The tumor microenvironment consists of stromal cells, extracellular matrix (ECM), and signaling molecules that communicate with cancer cells. As tumors grow and develop, the tumor microenvironment changes. In addition, the tumor microenvironment is not only influenced by signals from tumor cells, but also stromal components contribute to tumor progression and metastasis by affecting cancer cell function. One of the mechanisms that cancer cells use to invade and metastasize is mediated by actin-rich, proteolytic structures called invadopodia. Here, we discuss how signals from the tumor environment, including growth factors, hypoxia, pH, metabolism, and stromal cell interactions, affect the formation and function of invadopodia to regulate cancer cell invasion and metastasis. Understanding how the tumor microenvironment affects invadopodia biology could aid in the development of effective therapeutics to target cancer cell invasion and metastasis.     

肿瘤酸性微环境的研究进展

研究表明,肿瘤转移是恶性肿瘤的临床治疗失败的根本原因。肿瘤转移不仅取决于肿瘤细胞自身的特性,还涉及其与肿瘤酸性微环境之间的相互作用。肿瘤微环境构成非常复杂,可促进肿瘤的增生、转移、侵袭,以及逃避宿主免疫监视和治疗耐药性。肿瘤细胞的生存依赖于在酸性微环境条件下的适应,肿瘤细胞可以通过一些离子交换体维持酸性微环境,缺氧的肿瘤组织酸化可以释放蛋白酶如纤维蛋白酶及MMPs降解细胞外基质、上调VEGF基因表达促进肿瘤新生血管生成等促进肿瘤侵袭转移。近年来,影响肿瘤微环境的因素已经成为癌症研究领域中的新兴话题。     

Targeting multiple tyrosine kinase receptors with Dovitinib blocks invasion and the interaction between tumor cells and cancer-associated fibroblasts in breast cancer

A constitutive and dynamic interaction between tumor cells and their surrounding stroma is a prerequisite for tumor invasion and metastasis. Fibroblasts and myofibroblasts (collectively called cancer associated fibroblasts, CAFs) often represent the major cellular components of tumor stroma. Tumor cells secret different growth factors which induce CAFs proliferation and differentiation, and, consequently, CAFs secrete different chemokines, cytokines or growth factors which induce tumor cell invasion and metastasis. In this study we showed here that CAFs from breast cancer surgical specimens significantly induced the invasion of breast cancer cells in vitro. Most interestingly, the novel multiple tyrosine kinase inhibitor Dovitinib significantly blocked the CAFs-induced invasion of breast cancer cells by, at least in part, inhibition of the expression and secretion of CCL2, CCL5 and VEGF in CAFs. Inhibition of PI3K/Akt/mTOR signaling could be responsible for the effects of Dovitinib, since Dovitinib antagonized the promoted phosphorylated Akt after treatment with PDGF, FGF or breast cancer cell-conditioned media. Treatment with Dovitinib in combination with PI3K/Akt/mTOR signaling inhibitors Ly294002 or RAD001 resulted in additive inhibition of cell invasion. This is the first in vitro study to show that the multiple tyrosine kinase inhibitor has therapeutic activities against breast cancer metastasis by targeting both tumor cells and CAFs.     

Enhanced expression of Hab18g/CD147 and activation of integrin pathway in HCC cells under 3-D co-culture conditions

CD147 is reported to be correlated with the malignancy of some cancers, and its overexpression affects the progression of tumor. In the present study, we investigated the function of HAb18G/CD147, a member of CD147 family, on hepatocellular carcinoma (HCC) adhesion, invasion and metastasis in 3-dimensional (3-D) cell co-culture model. The results showed that the extracellular microenvironment could determine the cellular phenotypes and then affected the cellular functions. The expressions of HAb18G/CD147 in HCC cells and fibroblasts were both obviously elevated in 3-D co-culture model. The overexpression of HAb18G/CD147 increased MMPs' (MMP-2 and MMP-9) production (P < 0.01), and was obviously accompanied with enhanced expressions of paxillin, FAK and p-FAK in 3-D cell co-culture model. All the results suggest that HAb18G/CD147 plays an important role in HCC adhesion, invasion and metastasis mainly via modulating synthesis of MMPs and activating integrin signal pathways in fibroblasts and tumor cells themselves under the 3-D co-culture conditions.     

The role of HMGB1-RAGE axis in migration and invasion of hepatocellular carcinoma cell lines

High mobility group protein box1 (HMGB1) and its receptor—receptor for advanced glycation end products (RAGE) are pivotal factors in the development and progression of many types of tumor, but the role of HMGB1-RAGE axis in hepatocellular carcinoma (HCC) especially its effects on metastasis and recurrence remains obscure. Here, we report the role of HMGB1-RAGE axis in the biological behaviors of HCC cell lines and the underlying molecular mechanism. We show that the expressions of HMGB1, RAGE, and extracellular HMGB1 increase consistently according to cell metastasis potentials, while the concentration of soluble form of RAGE (sRAGE) is inversely related to metastasis potential of HCC cells. Furthermore, our data show that rhHMGB1 promotes cellular proliferation, migration, and invasion, and increases the level of nuclear factor kappa B (NF-κB), while administrations of HMGB1-siRNA, RAGE-siRNA, anti-HMGB1 neutralizing antibody, anti-RAGE neutralizing antibody, and sRAGE inhibit cellular proliferation, migration, and invasion. Moreover, we also demonstrate that the expression of NF-кB is inhibited by knockdown of HMGB1 or RAGE. Collectively, these data demonstrate that HMGB1 activates RAGE signaling pathways and induces NF-кB activation to promote cellular proliferation, invasion, and metastasis, in HCC cell lines. Taken together, HMGB1-RAGE axis may become a potential target in HCC therapy.     

Role of cancer-associated fibroblasts in breast cancer development and prognosis

Since Paget's "Seed and Soil" hypothesis in 1889 on cancer growth and metastasis, several studies on various solid tumors have confirmed the active role of the tumor milieu on the onset, growth and spread of neoplastic cells. Fibroblasts constitute the major components of the tumor microenvironment (stroma), and are therefore the most studied cell type. Therefore, a large amount of data has emerged showing the cancer-promoting function of these cells through paracrine effects that escort tumor cells through all the carcinogenesis steps. This involves many signaling proteins that transmit the message in both directions, allowing cooperative crosstalk between cancer cells and their stroma. This prompted several researchers to investigate the potential use of the molecular and cellular features of active stromal fibroblasts to generate specific tools for prevention, prognosis and treatment of cancer. Herein, I review the cellular and molecular features of active cancer-associated fibroblasts and their origin. Additionally, I summarize our current understanding of the procarcinogenic actions of these cells and their potential prognostic value for breast cancer patients.     

Systems Analysis of a Mouse Xenograft Model Reveals Annexin A1 as a Regulator of Gene Expression in Tumor Stroma

Annexin A1 is a multi functional molecule which is involved in inflammation, innate and adaptive immune systems, tumor progression and metastasis. We have previously showed the impaired tumor growth, metastasis, angiogenesis and wound healing in annexin A1 knockout mice. While tumor is a piece of heterogeneous mass including not only malignant tumor cells but also the stroma, the importance of the tumor stroma for tumor progression and metastasis is becoming increasingly clear. The tumor stroma is comprised by various components including extracellular matrix and non-malignant cells in the tumor, such as endothelial cells, fibroblasts, immune cells, inflammatory cells. Based on our previous finding of pro-angiogenic functions for annexin A1 in vascular endothelial cell sprouting, wound healing, tumor growth and metastasis, and the previously known properties for annexin A1 in immune cells and inflammation, this study hypothesized that annexin A1 is a key functional player in tumor development, linking the various components in tumor stroma by its actions in endothelial cells and immune cells. Using systems analysis programs commercially available, this paper further compared the gene expression between tumors from annexin A1 wild type mice and annexin A1 knockout mice and found a list of genes that significantly changed in the tumor stroma that lacked annexin A1. This revealed annexin A1 to be an effective regulator in tumor stroma and suggested a mechanism that annexin A1 affects tumor development and metastasis through interaction with the various components in the microenvironment surrounding the tumor cells.     

血小板反应蛋白4通过诱导肿瘤相关巨噬细胞M2型极化促进肝癌细胞转移

血小板反应蛋白4 (thrombospondin 4, THBS4) 属于THBS家族成员,是细胞外基质分泌的蛋白质,参与调控细胞增殖、黏附及血管生成等多种生理过程。近来研究表明,机体在炎症刺激下加速产生THBS4并诱导巨噬细胞粘附与积累。我们的前期研究证实,THBS4在肝癌(hepatocellular carcinoma,HCC)中发挥促癌作用,但THBS4对肝癌免疫微环境的影响尚不明确。本文旨在分析THBS4通过诱导肿瘤相关巨噬细胞M2型极化,促进肝癌细胞转移的作用。通过肝癌条件培养基(HCC conditioned medium,HCM)模拟肿瘤微环境,发现在HCM作用下巨噬细胞中THBS4表达呈时间依赖性升高(P＜0.05);下调THBS4促使M1型巨噬细胞标志物IL-1β、CD86的表达升高(P＜0.01),而M2型标志物 IL-10和CD206表达降低(P＜0.01)。进一步通过Transwell共培养实验检测THBS4诱导的M2型巨噬细胞对肝癌转移的影响。将下调THBS4的M2型巨噬细胞(M2-TAMs)与HepG2肝癌细胞进行共培养。结果显示,下调THBS4的M2-TAMs明显抑制了HepG2细胞的侵袭和迁移能力(P均＜0.01)。综上所述,肿瘤微环境促进巨噬细胞中THBS4表达,THBS4可能通过诱导巨噬细胞M2型极化促进肝癌细胞侵袭转移。本文为探究THBS4诱导肝癌免疫微环境的建立提供了一些新的实验依据。     

Prostate tumor-stroma interaction: molecular mechanisms and opportunities for therapeutic targeting

Maintenance of cell and tissue homeostasis is dependent upon the dynamic balance of cell proliferation, differentiation, and apoptosis through interactions between cells and their microenvironment. The unique prostatic cellular phenotypes are induced and maintained by interaction between epithelium and adjacent stroma through intimate intercellular signaling pathways. In this article, we summarize current advances in the tumor-stroma interaction and its biologic and therapeutic implications. We specifically emphasize current studies of the possible factors driving the "vicious cycle" between stroma and emerging prostate tumor epithelial cells that may be responsible for carcinogenesis and metastasis to bone. Stroma responds both genotypically and phenotypically to tumor epithelium upon co-culture under 3-D conditions. Likewise, the emerging carcinoma responds to stromal signals that drive progression to malignancy. A vicious cycle mediated by soluble and insoluble molecules secreted by tumor cells and stroma appear be the critical factors supporting and sustaining tumor colonization in bone. Co-targeting tumor and stroma with therapeutic agents has yielded promising results both in pre-clinical models of prostate cancer and bony metastasis and in clinical trials of patients treated with a dual tumor and stroma targeting strategies. In conclusion, understanding and targeting the interaction of the tumor and its stromal microenvironmant may improve the prognosis, reduce the suffering and increase the survival of patients with advanced cancer metastasis.