肿瘤微环境与肿瘤的靶向治疗

肿瘤微环境是肿瘤细胞赖以生存和发展的物质基础,肿瘤微环境和肿瘤细胞是一个相互依存、相互促进的整体。肿瘤微环境具有低氧、低pH、高间质液压的生理特性,其中存在着多种基质细胞、调控因子和蛋白酶等物质,为肿瘤的发生、发展、侵袭、转移、抵抗药物治疗和免疫反应等提供必要的物质基础。因此靶向肿瘤微环境的治疗策略成为治疗肿瘤的新思路,利用肿瘤微环境中的靶点和生理特性,靶向药物和靶向制剂能够更好地聚集在肿瘤部位,呈现出更好的治疗效果。     

肿瘤相关巨噬细胞在卵巢癌微环境中的作用及研究进展

卵巢癌在女性生殖系统肿瘤发病率中排名第三,但死亡率却位居第一,独特的肿瘤微环境(TME)促使其易于转移和复发。肿瘤相关巨噬细胞(TAM)作为肿瘤微环境中的重要角色分为M1和M2表型,通过分泌细胞因子参与调控肿瘤发展、耐药、预后、转移等过程。本文综述肿瘤相关巨噬细胞在卵巢癌微环境中的作用及研究进展,为以卵巢癌相关巨噬细胞分泌的细胞因子为靶标的靶向治疗提供依据,以期开辟卵巢癌靶向治疗新方式。     

肿瘤微环境在皮肤癌发生发展中的作用及相关治疗研究进展

目前,皮肤癌发病率高居不下且仍缺乏有效的治疗方案。肿瘤微环境是肿瘤发生发展的局部环境,由肿瘤相关成纤维细胞、肿瘤相关脂肪细胞、免疫细胞、内皮细胞和神经元等细胞成分及细胞外基质等非细胞成分组成,具有低氧、酸性和免疫抑制等特点,影响皮肤癌进展,并对维持皮肤癌异质性和耐药性起重要作用。靶向肿瘤微环境是对抗耐药性和降低皮肤癌死亡率的有效途径。本综述主要介绍肿瘤微环境中细胞外基质、相关基质细胞及低氧和酸性环境对皮肤癌进展的影响,讨论靶向肿瘤微环境的途径和方法,为皮肤癌治疗提供新思路。     

肿瘤血管生成机制及抗肿瘤血管新生的靶向药物研究进展

抗肿瘤血管新生治疗是以血管内皮细胞为靶点,通过降低血管活性因子的活性、抑制内皮细胞增殖和迁移、改变肿瘤生长微环境,从而抑制肿瘤生长过程中的血管新生,切断肿瘤的供养,最终达到遏制肿瘤生长和转移的目的,是一种全新的靶向肿瘤治疗方法.该方法具有高效特异性、不易产生耐药性、药物易于到达靶部位和毒副作用小等优点,可以有效地抑制肿瘤的转移和复发,现在已成为抗肿瘤血管生成药物研究的热点之一,该文综述了肿瘤血管生成的机制及抗血管新生治疗药物的最新研究进展.     

肿瘤微环境pH响应靶向载体设计研究进展

目的归纳和概括基于肿瘤微环境pH响应载体设计的方法与策略。方法以国内外具有代表性文献34篇为依据,对pH敏感靶向传递系统的设计原理方法进行分析、整理和归纳。结果 pH敏感靶向载体借助于其pH敏感基团对肿瘤微环境做出响应,可以实现药物的定向递送,杀死肿瘤细胞并降低药物对正常组织的毒副作用。结论构建pH敏感载体用作肿瘤的靶向治疗,具有重要的研究意义。     

肿瘤微环境响应性与调节性递药系统研究进展

肿瘤微环境的复杂性为肿瘤靶向递药带来挑战的同时也赋予其一定的机遇。一方面,通过利用肿瘤微环境的特征信号为刺激源,构建各种各样的响应性递药系统,可实现药物在肿瘤部位的靶向递送;另一方面,肿瘤部位异质的新生血管和异生的胶原等所引起的较高的固体瘤压力及肿瘤间质压等成为药物递送的巨大障碍,极大地降低了递药系统的递送效率。许多研究致力于通过调节肿瘤微环境,使其更利于药物在肿瘤部位的递送。本文综述了基于肿瘤微环境响应性纳米递药系统的设计及调节肿瘤微环境以提高肿瘤靶向递送效率的最新进展,并对其中存在的问题及未来的发展进行讨论。     

成纤维细胞激活蛋白α与肿瘤微环境的免疫抑制

成纤维细胞激活蛋白α(FAPα)是肿瘤微环境中特异性表达于肿瘤相关成纤维细胞(TAF)表面的抗原分子,属丝氨酸蛋白酶家族Ⅱ型膜整合糖蛋白,具有二肽酶和胶原酶活性,对肿瘤微环境的免疫抑制和肿瘤浸润转移有重要作用.因此,FAPα已被视为理想的肿瘤治疗靶标.本文综述了FAPα阳性细胞对肿瘤微环境免疫抑制状态的形成及靶向FAPα治疗的研究.     

肿瘤微环境调节型细胞器靶向递药系统的研究进展

近年来,利用机体免疫系统进行抗肿瘤的免疫疗法受到了广泛关注。然而抑制性肿瘤微环境限制了免疫治疗的效果,因此克服肿瘤微环境及其中的免疫抑制性细胞的作用成为肿瘤免疫疗法的一大热点。纳米制剂具有重新编程免疫抑制性微环境的巨大潜力,为免疫治疗提供了有效策略。随着主动靶向性纳米载体技术的不断发展和对药物作用位点研究的不断深入,具有更精准主动靶向功能的亚细胞器靶向性纳米载体材料也受到越来越多的关注。本文简要介绍了各亚细胞器与肿瘤的关系,概述了基于酸碱性调节、活性氧含量、免疫原性及免疫抑制细胞的肿瘤微环境特点的纳米药物靶向递送系统的设计策略与研究进展,为亚细胞器途径靶向递药系统的构建及其在肿瘤免疫治疗方面的应用提供借鉴和参考。     

基于肿瘤微环境的纳米靶向载体研究进展

目的:为纳米靶向载体研制提供参考。方法:以"肿瘤微环境""纳米靶向载体""靶向治疗""pH sensitive""Enzyme responsive""Redox responsive"等为关键词,组合查询2005-2016年在Pub Med、Elsevier、Springer Link、中国知网、万方、维普等数据库中的相关文献,对肿瘤组织微环境的特点和肿瘤微环境响应性纳米载药系统研究进行综述。结果与结论:共检索到相关文献235篇,其中有效文献39篇。肿瘤组织微环境主要特点包括微酸性、酶代谢异常、细胞内外存在还原性差异、存在影响肿瘤血管生成的因子和信号通路等。基于上述特点,分别研究出基于肿瘤滞留效应设计的纳米载体、pH响应型纳米载体、还原响应型纳米载体、酶响应型纳米载体、温度响应型纳米载体。与这些单响应载体比较,肿瘤微环境多重刺激响应型纳米载体更能充分发挥不同肿瘤微环境响应性物质之间的特点,对实现药物的特异性递送更有意义,这也将是今后的主要研究热点。     

肿瘤微环境MMP酶响应性纳米给药系统研究进展

肿瘤靶向纳米制剂的研究是近些年医药领域内的研究热点之一。其中,肿瘤微环境在肿瘤增殖、侵袭和转移中发挥关键性作用,肿瘤微环境响应性纳米制剂的研究日益受到关注。研究发现,以基质金属蛋白酶(matrix metalloproteinase, MMP)为代表的酶类在多种肿瘤微环境中高度表达,其底物可被设计应用于药物传递及成像系统,并显示出了对肿瘤微环境内MMP的高度响应。本文将对肿瘤微环境内以MMP为代表的高表达酶为靶点的纳米给药系统的研究进展做一概述。     

Impact of immune infiltration on tumor development and progression

Recently, immune infiltration has a crucial role in modulating tumor progression and response to therapy which comprised cells from the innate and adaptive immune response. Infiltrating immune cells can be detected in biopsy specimens and exploited to promote cancer metastasis, angiogenesis and growth. Mounting evidence demonstrates that many cancer-associated cell types within the tumor stromal support tumor growth and development, greatly modifying cancer cell behavior,facilitating invasion and metastasis and controlling sensitivity to drug therapy. Furthermore,immune infiltration of the tumor microenvironment has been associated with improved survival for some patients with solid tumors which have prognostic value. Infiltrating immune cells are both prognostic and predictive of response to cancer therapies. Understanding the interactions between tumor and immune infiltration is critical to find prognostic biomarkers,reduce drug resistance, and developnew therapies.Therefore, cancer immunotherapy based on tumor-infiltrating cell populations has become arguably the most promising advancement in cancer research and therapy in recent years. In this review, we provide an updated overview of key components of the immune infiltrating cells in the tumor microenvironment and the impact of immune infiltration on tumor development and progression. Moreover, we discuss the intricacy of the reciprocal interactions between cancer-associated immune cell types and signal transduction pathways, which appear to be crucially linked to cancer progression in response to the tumor microenvironment. Finally, we focus on the current immunotherapeutic strategies and emerging results from ongoing clinical trials are presented.     

Nanomedicine-based drug delivery towards tumor biological and immunological microenvironment

The complex tumor microenvironment is a most important factor in cancer development. The biological microenvironment is composed of a variety of barriers including the extracellular matrix and associated cells such as endothelia cells, pericytes, and cancer-associated fibroblasts. Different strategies can be utilized to enhance nanoparticle-based drug delivery and distribution into tumor tissues addressing the extracellular matrix or cellular components. In addition to the biological microenvironment, the immunological conditions around the tumor tissue can be very complicated and cancer cells have various ways of evading immune surveillance. Nanoparticle drug delivery systems can enhance cancer immunotherapy by tuning the immunological response and memory of various immune cells such as T cells, B cells, macrophages, and dendritic cells. In this review, the main components in the tumor biological and immunological environment are discussed. The focus is on recent advances in nanoparticle-based drug delivery systems towards targets within the tumor microenvironment to improve cancer chemotherapy and immunotherapy.     

Tumor immune escape mechanisms that operate during metastasis

Immune cells actively influence, among other factors, each step of tumor development determining the chance of a cancer cell to survive in a threaten microenvironment. Antitumor immune-mediated mechanisms are activated as soon as the first cancer cell is detected and operate both during primary tumor formation and during metastasis. However, when both innate and adaptive immunity becomes impaired, tumor development occurs. In this sense, compelling evidences indicate that tumor cells employ mechanisms that circumvent or thwart the immune response to enhance their own growth. These mechanisms include the secretion of immunosuppressive factors and the induction of distinct regulatory lymphoid or myeloid cells and, as occur with the immune response, they operate both during primary tumor formation and metastasis. Interestingly, cellular and molecular mechanisms of the immune response are important components of the tumor microenvironment and have the ability to promote or suppress tumor progression depending of the context of each cell interaction. In that sense, researchers are focusing their attention in the study of the influence of the tumor microenvironment in tumor growth and metastasis to better understand cancer biology and to formulate novel therapeutic approach. This review will focus on the present knowledge about interaction between immune cells and tumors in the context of metastasis, discussing the participation of different components of innate and adaptive immune response in the process of metastasis formation and dissemination.     

Inflammatory fibroblasts in cancer

The association between inflammation and cancer has been studied widely. Indeed, the tumor microenvironment is influenced by inflammatory cells and affects tumor progression, tumor growth, and the survival of cancer cells. Also, the tumor microenvironment is essential to invasion and metastasis of cancer. Fibroblasts, immune cells, the extracellular matrix and other various components all constitute the tumor stroma, ordinarily referred to as the ‘reactive stroma’. Cancer-associated fibroblasts (CAFs), which are activated fibroblasts and one of the components of the tumor microenvironment, are associated with cancer progression, invasiveness and metastasis, and their functional contributions to these processes are beginning to emerge. CAFs mediate tumor-promoting inflammation through various signaling pathways. Epithelial–mesenchymal transition is a process for producing mesenchymal cells during invasion and metastasis of cancer cells. Fibroblasts have been identified as a key player in this mechanism. In the present review, we summarize the relationships between fibroblasts, inflammatory response, the tumor microenvironment and cancer progression. This review provides useful information for the development of cancer prevention and treatment therapies through controlling the inflammatory responses.     

Anti-tumor immune response varies among individuals: A gene expression profiling of mouse melanoma

Melanoma is amongst the most aggressive malignant tumors. The purpose of this study is to detect the tumor microenvironment systematically using multi-omics analyses and to propose strategies for precision medicine. Multiple factors of tumor microenvironment contribute to the drug resistance and immune surveillance failure. Here we analyzed genome mutations and characterized the immune state of tumor microenvironments in mouse melanoma by whole exome sequencing (WES) and RNA sequencing (RNA-Seq) approaches. Somatic mutation analysis revealed 35.1% novel mutations in mouse tumors when compared with B16F10 cell line, provided a basis for multi-site sequencing for accurate neoantigen selection. Mutation cluster, gene expression comparison, and gene ontology (GO) analyses by R packages proved DNA repair damage, inflammation, slower cell division, and metabolic change in tumor microenvironment. Further analyses of T-cell receptor (TCR) sequences, immune signaling pathway activation, tumor infiltrated immune cells and chemokine expression revealed extensive difference of antitumor immune response among individuals. Our study revealed the characteristics of tumor microenvironment with mouse melanoma model, suggested the need of comprehensive genome mutations and personal immune state analyses for cancer precision medicine.     

溶瘤病毒联合其他药物用于肿瘤治疗的研究进展

溶瘤病毒作为一种抗肿瘤生物制剂,在肿瘤治疗中选择性地感染裂解肿瘤细胞,增加肿瘤抗原暴露,重塑肿瘤微环境,增加肿瘤微环境中免疫细胞浸润,激活免疫系统,发挥抗肿瘤作用.由于溶瘤病毒单药治疗效果不佳,而溶瘤病毒与其他抗癌药物联用的多个临床研究均表现出良好的抗肿瘤效果,联合用药有望释放溶瘤病毒疗法抗肿瘤方面的巨大潜能.本文从溶...     

The interaction of NK cells and dendritic cells in the tumor environment: how to enforce NK cell & DC action under immunosuppressive conditions?

The crosstalk of natural killer (NK) and dendritic cells (DCs) plays an important role in the induction of the tumor-specific immune response against cancer. During the last decade, our advanced understanding of the immune system led to the development of new therapeutic strategies in the field of immunotherapy and cellular immunology. However, these immunotherapeutic concepts have not been as successful as initially expected because of their inability to counteract cancer-induced immunosuppressive pathways. Some of the major difficulties of effective cellular immunotherapy are the highly immunosuppressive factors induced by tumor cells themselves or by their microenvironment. Therefore, one major challenge in immunotherapy is the question: "How to enforce NK cell & DC action under immunosuppressive conditions?" This review focuses on the current knowledge on the tumor microenvironment, the crosstalk of NK cells and DCs, as well as their deregulation in the complex interplay with the immunosuppressive tumor microenvironment. We further discuss possible strategies to minimize the negative impact of the tumor microenvironment on the immune system.     

Tumor associated macrophages in the molecular pathogenesis of ovarian cancer

The tumor microenvironment is a critical factor that enhances cancer progression, drug resistance, and failure of therapeutic approaches. Several cellular and non-cellular factors are involved in cancer promotion. Among the several cell populations in the tumor microenvironment, macrophages, as one of the most abundant innate immune cells within the tumor milieu, have attracted extensive attention among several researchers because of their critical role in innate pathophysiology of multiple disorders, as well as ovarian cancer. High plasticity and consequent high ability to adapt to environmental alternations by adjusting their cellular metabolism and immunological phenotype is the notable characteristic of macrophages. Therefore, the critical function of tumor-associated macrophages in ovarian cancer is highlighted in the growing body of recent studies. In this article, we will comprehensively focus on significant impacts of the macrophages on ovarian cancer progression, by discussing the role of macrophages as one of the fundamental immune cells present in tumor milieu, in metabolic reprogramming of transformed cells, and involvement of these cells in the ovarian cancer initiation, progression, invasion, and angiogenesis. Moreover, we will summarise recent studies evaluating the effects of targeting macrophages in ovarian cancer.     

Targeting the cancer-stroma interaction: a potential approach for pancreatic cancer treatment

Recent studies have demonstrated that the interaction between the cancer and the stroma, play a key role in the development of pancreatic cancer. The desmoplasia, which consists of fibroblasts, pancreatic stellate cells, lymphatic and vascular endothelial cells, immune cells, pathologic increased nerves, and the extracellular matrix (ECM), creates a complex tumor microenvironment that promotes pancreatic cancer development, invasion, metastasis, and resistance to chemotherapy. Thus, the potential approach for targeting the components of this desmoplastic reaction or the pancreatic tumor microenvironment might represent a novel therapeutic approach to advanced pancreatic carcinoma. Novel therapies that target on the pancreatic tumor microenvironment should become one of the more effective treatments for pancreatic cancer.