肺癌引起的恶性胸腔积液的研究和治疗进展

肺癌引起的恶性胸腔积液(malignant pleural effusion,MPE)发病率高且临床治疗效果不佳.出现MPE的肺癌患者生活质量明显下降,病死率明显增高.近期科学研究对MPE的病理生理过程进行了更多的阐述——宿主胸膜受肿瘤侵犯后分泌大量血管活性物质,促成了适合肿瘤生长的微环境和MPE的形成,同时肿瘤细胞通过激活某些信号通路、分泌重要的炎症介质来募集宿主细胞.同样地,宿主细胞也可激活细胞内信号通路、分泌炎症介质影响肿瘤细胞的功能.两者共同影响肿瘤的生长和MPE的产生.一些生物实验为MPE的形成提供了新的靶向治疗的方法,并且其得到的阳性结果为后续MPE的治疗提供了新的思路.     

质子泵抑制剂提高肿瘤化学治疗敏感性的研究进展

恶性肿瘤对化学治疗药物产生耐药是肿瘤患者化学治疗失败的主要原因.肿瘤细胞外微环境高度酸化是肿瘤细胞对化学治疗药物产生耐药的机制之一.改变肿瘤细胞内外pH梯度是逆转耐药的一种有效方法.用于治疗酸相关疾病的质子泵抑制剂能通过抑制质子泵功能,改变胞内外pH 梯度而阻断肿瘤微环境酸化,达到提高肿瘤对化学治疗药物敏感性的目的.此文就其在化学治疗增敏方面的研究进展作一综述.     

多发性骨髓瘤的靶位治疗

多发性骨髓瘤(MM)的靶位治疗是针对骨髓微环境中MM细胞生长和生存的治疗方法。在治疗过程中既要针对MM细胞(杀伤肿瘤细胞,抑制其生长,诱导其凋亡),又要充分考虑到肿瘤细胞生长生存的骨髓微环境,这些微环境是MM细胞赖以生存的必要条件。通过药物治疗,改变微环境,改变     

肿瘤微环境在胰腺癌研究中的进展

肿瘤微环境是决定肿瘤细胞行为的主要影响因素.胰腺癌肿瘤微环境能促进肿瘤生长、侵袭,保护其免受免疫系统的攻击.此文主要介绍了胰腺癌肿瘤微环境的主要组成部分及其各组成部分之间的相互作用,并阐述微环境中一些重要的蛋白酶、生长因子的作用.     

消化系统肿瘤源性外泌体在肿瘤微环境中对免疫细胞作用的研究进展

消化系统肿瘤是中国常见的恶性肿瘤,由于目前治疗方法存在局限性,研究方向从单纯研究肿瘤细胞内部机制延伸至研究肿瘤微环境中的外泌体与免疫细胞之间的作用和关系.消化系统肿瘤微环境中的外泌体可以通过传递信号抑制免疫细胞的杀伤能力,促进肿瘤的发生、发展.肿瘤细胞通过释放外泌体传递信息,诱导巨噬细胞极化,抑制免疫细胞活性,促进肿瘤...     

低氧微环境与胃癌

低氧是恶性肿瘤微环境的特征之一,胃癌低氧状态能促进肿瘤血管生成、抑制肿瘤细胞凋亡、影响细胞周期和增殖、增加放化疗及手术的抵抗性,使肿瘤对放化疗的疗效明显下降,并且促进肿瘤的侵袭和远处转移.通过体内氧电极测定、放射自显影、核磁影像技术等方法能够检测胃癌肿瘤的低氧微环境.采用吸入高压氧、Carbogen或ARCON气体、给予缺氧细胞放射增敏剂等方法能提高肿瘤的放疗疗效.虽然胃癌肿瘤的低氧微环境对其治疗产生了一定影响,但其低氧微环境也为临床治疗提供了新的治疗方法,使胃癌低氧靶向治疗成为可能.因此,针对肿瘤低氧的低氧标记药物、HIF-1抑制剂、HIF-1基因治疗等将成为今后的研究热点.     

研究发现酸性微环境与肿瘤细胞生存率相关

正来自莫菲特癌症中心的研究人员与来自南佛罗里达州立大学以及韦恩州立大学的研究人员发现,肿瘤细胞的生存依赖于肿瘤酸性微环境。癌症的发展是一个多阶段的过程,其发生发展过程受到某些物理性质如肿瘤微环境的影响。肿瘤细胞通过自噬适应这些微环境存活、增殖,并最终发生转移。据研究人员说,到目前为止没有多少人了解细胞在酸性条件下的存活机制,但研究已经证实,酸度可以改变基因的表达,     

胃肠胰神经内分泌肿瘤的肿瘤微环境

肿瘤微环境为肿瘤提供了特有的营养代谢环境,使得肿瘤细胞生物学行为受到自身遗传学及其周边微环境的双重调控.胃肠胰神经内分泌肿瘤(gastroenteropancreatic neuroendocrine neoplasms,GEP-NENs)是起源于消化系统神经内分泌细胞的异质性肿瘤,它以分泌生物活性物质为特点.GEP-NENs早期症状不典型,确诊时常已发生转移,对其肿瘤微环境的研究有助于我们进一步认识GEP-NENs的发生发展机制,并能为临床诊断、治疗GEP-NENs提供新的依据.本篇文章综述了肿瘤微环境中不同细胞成分、细胞外基质重塑蛋白、可溶性生长因子以及嗜铬粒蛋白在GEP-NENs进展中的作用.     

粘附分子和表皮生长因子受体表达与胃癌浸润转移

肿瘤浸润转移是肿瘤细胞与宿主间复杂、多步骤相互作用的结果,也是胃癌治疗失败和死亡的主要原因.     

针对肿瘤缺氧微环境探寻新的治疗方法

肿瘤缺氧微环境与肿瘤的发展、转移和患者预后,以及治疗的效果密切相关,已经成为癌症研究的热点.本文介绍了针对肿瘤缺氧微环境所进行的新治疗方法的探索,包括阻断肿瘤缺氧诱导通路、利用缺氧微环境将无活性的药物前体转化为细胞毒性药物、改变缺氧诱导因子上下游基因的表达等.最后介绍了作者和研究小组针对肿瘤缺氧微环境的系列研究进展,包括阻断缺氧诱导因子-1α表达或过表达vonHippel-Lindau蛋白提高免疫治疗、抗新生血管生成治疗、化疗和肝动脉插管治疗恶性肿瘤疗效的研究.     

Host epithelial geometry regulates breast cancer cell invasiveness

Breast tumor development is regulated in part by cues from the local microenvironment, including interactions with neighboring nontumor cells as well as the ECM. Studies using homogeneous populations of breast cancer cell lines cultured in 3D ECM have shown that increased ECM stiffness stimulates tumor cell invasion. However, at early stages of breast cancer development, malignant cells are surrounded by normal epithelial cells, which have been shown to exert a tumor-suppressive effect on cocultured cancer cells. Here we explored how the biophysical characteristics of the host microenvironment affect the proliferative and invasive tumor phenotype of the earliest stages of tumor development, by using a 3D microfabrication-based approach to engineer ducts composed of normal mammary epithelial cells that contained a single tumor cell. We found that the phenotype of the tumor cell was dictated by its position in the duct: proliferation and invasion were enhanced at the ends and blocked when the tumor cell was located elsewhere within the tissue. Regions of invasion correlated with high endogenous mechanical stress, as shown by finite element modeling and bead displacement experiments, and modulating the contractility of the host epithelium controlled the subsequent invasion of tumor cells. Combining microcomputed tomographic analysis with finite element modeling suggested that predicted regions of high mechanical stress correspond to regions of tumor formation in vivo. This work suggests that the mechanical tone of nontumorigenic host epithelium directs the phenotype of tumor cells and provides additional insight into the instructive role of the mechanical tumor microenvironment.     

Identification of alterations in DNA copy number in host stromal cells during tumor progression

The interactions between cancer cells and the surrounding host stromal tissue play a critical role in tumor progression and metastasis, but the molecular nature of this relationship remains largely uncharacterized. Furthermore, although genetic changes of neoplastic cells in tumors contribute significantly to tumor progression, it is not known whether similar changes occur in the adjacent host stromal microenvironment and whether they contribute to or inhibit tumorigenesis. To address this question in an unbiased and genome-wide manner, we applied high-resolution DNA copy number analysis to murine stromal DNA isolated from human xenograft tumors that were formed in immunodeficient mice. We show that numerous amplifications and deletions are found within the host stromal microenvironment, suggesting that alterations in host DNA copy number can occur and may play a significant role in modifying tumor-stromal interactions.     

Immune microenvironmental shift along human colorectal adenoma-carcinoma sequence: is it relevant to tumor development, biomarkers and biotherapeutic targets?

Human colorectal carcinoma (CRC) is one of the leading cancers. Every year, the WHO estimates a total of 945,000 new CRC cases, with 492,000 deaths worldwide. Most CRCs arise from the main premalignant lesion, colorectal adenomas, and the progression of colorectal adenoma to CRCs may take a long-term time course. The development of human CRCs is not only determined by the adenomatous cells, but also by the interaction between adenomatous cells and host immune environment. In response to tumor initiation or invasion, many inflammatory cells and components will be inevitably activated and form an inflammatory microenvironment surrounding the CRC tumors. Accumulative evidence has revealed that inflammatory response plays a key role in the development of human CRCs by implicating in many aspects including in determining the microenvironmental immune function shift from immunosurveillance to immunosuppression and significantly influences the progression of precancerous lesions to cancers. In this review, the functional changes of immune microenvironment from precancerous stage (adenoma) to cancer stage are summarized, and their potential as predictive biomarkers and biotherapeutic significance in preventing the development of CRCs are discussed.     

肝星状细胞在肝细胞癌形成和发展中的作用

肿瘤的发生、侵袭及转移是长久以来备受关注的问题,肿瘤细胞与其周围基质物质的关系作为其中的关键因素愈加收到重视,肝星状细胞(HSC)作为肝癌微环境中的重要组成部分,在"炎症-肝纤维化/肝硬化-肿瘤"这一发生发展过程中充当了重要的介质。介绍了HSC的来源及其活化过程,并进一步阐述HSC自身与其分泌的多种细胞因子在肝细胞癌增殖、迁移、侵袭过程中对机体免疫反应发挥的作用。认为HSC不仅是肿瘤生长的"温床",也为肿瘤抵御了免疫系统的追踪和清除。因此在单一抗肿瘤治疗无法取得明显效果时,对于肝癌微环境的多方位治疗成为值得探讨的方案。     

人胃癌裸鼠原位移植模型的生物学行为研究

目的建立人胃癌裸鼠胃壁原位移植瘤模型，并与相应的皮下移植瘤作比较，以探讨宿主器官微环境对胃癌细胞浸润及转移等生物学行为的影响．方法将人胃癌细胞系ＭＧｃ８０３及其克隆株Ｃ１１癌细胞分别接种于裸鼠胃壁及背部皮下，比较原位和皮下移植瘤的成瘤率、生长率、生长方式及浸润、转移等生物学行为，以及体外回复培养后瘤细胞的增殖能力．结果胃壁原位及皮下移植瘤体内成瘤率、生长率及形态学上均无明显不同；其体外增殖能力也无显著性差异．但皮下移植瘤多呈局限性生长，无肝、脾、肾转移，其转移仅限于肺及个别局部淋巴结．胃壁原位移植瘤则浸润破坏胃壁各层组织结构，并直接蔓延到邻近各器官组织．其转移既有经血道至肝、肺、脾、肾等部位，也有经淋巴道至多数局部及远处淋巴结，其淋巴结的转移率较皮下移植瘤有显著增高（Ｐ＜００５）；且多伴有腹、盆腔内广泛种植性转移．结论裸鼠胃壁微环境较皮下组织更适合于人胃癌ＭＧｃ８０３及Ｃ１１移植瘤的浸润及转移的表达，该原位移植瘤模型的恶性生物学行为更接近临床胃癌患者的体内侵袭及转移的实际．     

肿瘤相关成纤维细胞在肝细胞癌生长和转移中的作用

肿瘤的发生发展过程与肿瘤微环境密切相关,肿瘤相关成纤维细胞(CAF)是肿瘤微环境中重要组成成分之一,在肿瘤的发生、血管生成、侵袭和转移过程中扮演着十分重要的角色。从CAF的募集、活化、促血管生成及调节肿瘤免疫等方面对CAF在肝细胞癌(HCC)的发生及发展过程中的作用进行综述,为HCC的治疗提供新的思路。     

Cooperative effects of aminopeptidase N (CD13) expressed by nonmalignant and cancer cells within the tumor microenvironment

Processes that promote cancer progression such as angiogenesis require a functional interplay between malignant and nonmalignant cells in the tumor microenvironment. The metalloprotease aminopeptidase N (APN; CD13) is often overexpressed in tumor cells and has been implicated in angiogenesis and cancer progression. Our previous studies of APN-null mice revealed impaired neoangiogenesis in model systems without cancer cells and suggested the hypothesis that APN expressed by nonmalignant cells might promote tumor growth. We tested this hypothesis by comparing the effects of APN deficiency in allografted malignant (tumor) and nonmalignant (host) cells on tumor growth and metastasis in APN-null mice. In two independent tumor graft models, APN activity in both the tumors and the host cells cooperate to promote tumor vascularization and growth. Loss of APN expression by the host and/or the malignant cells also impaired lung metastasis in experimental mouse models. Thus, cooperation in APN expression by both cancer cells and nonmalignant stromal cells within the tumor microenvironment promotes angiogenesis, tumor growth, and metastasis.     

Prognostic value of innate and adaptive immunity in colorectal cancer

Colorectal cancer(CRC) remains one of the major public health problems throughout the world.Originally depicted as a multi-step dynamical disease,CRC develops slowly over several years and progresses through cytologically distinct benign and malignant states,from single crypt lesions through adenoma,to malignant carcinoma with the potential for invasion and metastasis.Moving from histological observations since a long time,it has been recognized that inflammation and immunity actively participate in the pathogenesis,surveillance and progression of CRC.The advent of immunohistochemical techniques and of animal models has improved our understanding of the immune dynamical system in CRC.It is well known that immune cells have variable behavior controlled by complex interactions in the tumor microenvironment.Advances in immunology and molecular biology have shown that CRC is immunogenic and that host immune responses influence survival.Several lines of evidence support the concept that tumor stromal cells,are not merely a scaffold,but rather they influence growth,survival,and invasiveness of cancer cells,dynamically contributing to the tumor microenvironment,together with immune cells.Different types of immune cells infiltrate CRC,comprising cells of both the innate and adaptive immune system.A relevant issue is to unravel the discrepancy between the inhibitory effects on cancer growth exerted by the local immune response and the promoting effects on cancer proliferation,invasion,and dissemination induced by some types of inflammatory cells.Here,we sought to discuss the role played by innate and adaptive immune system in the local progression and metastasis of CRC,and the prognostic information that we can currently understand and exploit.     

Zebrafish model: worth considering in defining tumor angiogenesis

The process of angiogenesis is essential for tumor progression and metastasis; however, antiangiogenesis therapy-induced hypoxia and inflammation are perhaps the driving force for tumor escape and metastasis formation, thereby compromising its efficacy. This warrants the complete understanding of the molecular and cellular basis of antiangiogenesis therapy and necessitates the identification of potential signaling events in the host microenvironment, which are involved in tumor angiogenesis and metastasis, to improve the treatment of cancer. In this context, the zebrafish/tumor xenograft model represents an emerging vertebrate system to study the correlation between tumor angiogenesis, inflammation, and metastasis and to better understand the modification of tumor microenvironment by antiangiogenesis therapy. This review article describes the necessity to study the microenvironment of host-tumor interface by introducing basic concepts of angiogenesis, emerging paradigms, and challenges of antiangiogenesis therapy and provides an update on the importance of the zebrafish/tumor xenograft model to address these issues.