基于纳米递药系统的肿瘤微环境多靶点调控策略研究进展

肿瘤微环境(tumor microenvironment, TME)是由内皮细胞、周细胞、免疫细胞、肿瘤相关成纤维细胞(cancer-associated fibroblasts, CAFs)、肿瘤干细胞(cancer stem cells, CSCs)及细胞外基质(extracellular matrix, ECM)等成分组成的复杂生物环境。TME与肿瘤细胞间通过大量信号通路相互作用,参与肿瘤的发展、侵袭和转移进程。因此, TME成为了癌症治疗的潜在靶点,在肿瘤治疗领域展示出良好的治疗潜力和研究价值。目前,新型纳米技术被广泛应用于抗肿瘤治疗,纳米技术介导的药物递送系统正在被研究应用于TME调控从而抑制肿瘤生长。与传统治疗方式相比,纳米技术介导的药物递送具有许多优点,包括延长循环时间、提高生物利用度和降低毒性。本文综述了基于TME调控的靶向纳米递药系统研究现状,包括基于CSCs、CAFs、免疫细胞、ECM、肿瘤血管系统、外泌体、微生物群的调控策略。此外,本文总结了与传统治疗策略相比TME调控策略的优势及面临的机遇与挑战,为基于TME调控策略的纳米递药系统应用于肿瘤精准治疗提供了参考和借...     

肿瘤微环境的靶向和重塑策略

肿瘤微环境(tumor microenvironment, TME)由异常的肿瘤血管、细胞外基质组分、内皮细胞、周细胞、肿瘤相关成纤维细胞、平滑肌细胞和免疫细胞组成。TME在肿瘤的发生、生长和转移中起着至关重要的作用。TME中异常的肿瘤血管系统、细胞外基质组分及丰富的间质细胞等,影响了药物在肿瘤组织的分布和渗透,其免疫抑制状态也是导致包括免疫治疗在内的多种抗肿瘤失败的重要原因之一。近年来,许多研究致力于通过靶向和重塑TME以提高治疗效果。本文综述了基于乏氧状态、肿瘤血管系统、肿瘤相关成纤维细胞、细胞外基质组分、肿瘤相关巨噬细胞和树突细胞的靶向和重塑策略最新研究进展,并对其中存在的问题及未来的发展进行讨论。     

肿瘤微环境的免疫细胞、信号传导通路及相关治疗展望

肿瘤微环境（Tumor microenvironment,TME）是一个高度结构化的生态系统,包括多种免疫细胞、肿瘤相关的成纤维细胞（CAFs）、内皮细胞和细胞外基质（ECM）等。研究TME内部的免疫细胞及信号传导通路对于探索肿瘤治疗靶点、提高治疗效果具有重要意义。拟通过对TME中的免疫细胞及相关信号传导通路的研究进展综述,以期为肿瘤免疫、靶向治疗提供新的思路和方法。     

基于癌相关成纤维细胞的药物递释系统的研究进展

癌相关成纤维细胞(CAFs)是原发性肿瘤基质中最突出的细胞类型,是肿瘤微环境中的主要组成部分,对肿瘤的发生、发展及转移产生重要影响,具有促进肿瘤生长、侵袭和免疫抑制作用。通过抑制CAFs能够起到抗肿瘤的作用,构建基于靶向CAFs的药物递释系统已成为当今肿瘤治疗的重要策略。目前针对CAFs的治疗靶点主要有成纤维细胞生长因子受体、成纤维细胞活化蛋白和肌腱蛋白C等,药物递释系统主要包括以胶束、脂质体、纳米复合物以及无机纳米粒为载体的药物递释系统等。     

肿瘤微环境对乳腺癌发生发展的影响

摘要： 肿瘤微环境 （TME） 在局部耐药性、 免疫逃脱和远端转移等多个肿瘤发生、 发展的步骤中起关键作用。依据 不同个体的 TME, 准确评估和选择临床用药, 可有效控制原位癌和转移癌的恶性转化。目前, 治疗癌症的主要方法 是化疗, 由于 TME 中良性细胞可调节癌细胞对标准化疗和靶向药物治疗的反应, 因此, 结合靶向 TME 治疗会取得更 理想的临床疗效。本文就乳腺癌 TME 中细胞外基质 （ECM）、 肿瘤相关成纤维细胞、 肿瘤相关巨噬细胞、 调节性 T 细 胞和骨髓间质干细胞对肿瘤发生、 发展的作用机制进行综述。     

肿瘤相关成纤维细胞及其标记物的研究现状

肿瘤相关成纤维细胞(CAFs)是肿瘤基质中最丰富的和关键的成分之一,具有多种肿瘤抑制/促进作用,并且在耐药性等领域起着关键作用。α-SMA、FAP、S100A4、PDGFRα/β和PDPN等可作为CAF的标记物。然而,各种常用的成纤维细胞标记物的表达是非常不同的,并且在不同的CAF亚群之间有很大的差异。最近基于特定细胞表面标记的CAF的表征不仅加深了我们对其表型异质性和功能多样性的认识,而且将CAF靶向治疗肿瘤提上了议事日程。本文综述了目前对CAFs的致瘤意义、起源和异质性的理解,以及不同的CAFs标记物在肿瘤发生、发展中的作用,为靶向CAFs的抗肿瘤临床治疗提供提供理论依据。     

肿瘤相关成纤维细胞治疗策略及其递送系统研究进展

肿瘤组织中大量的肿瘤相关成纤维细胞(cancer-associated fibroblasts, CAFs)为肿瘤的发展构建了良好的环境。CAFs不仅可以抑制免疫细胞的活化和功能,还能阻止药物与免疫细胞向肿瘤组织的深层渗透,从而降低肿瘤治疗效果。通过调控CAFs或克服其屏障作用抑制肿瘤是肿瘤治疗的新手段。设计纳米载体靶向调控CAFs以抑制肿瘤进展,促进药物穿过CAFs屏障以提高肿瘤部位的药物蓄积是目前肿瘤治疗研究的热点。基于此,本文对纳米载体用于以CAFs为靶点的肿瘤治疗研究进展进行综述,以期为肿瘤临床治疗提供参考。     

肿瘤微环境调节型纳米材料的研究进展

肿瘤微环境(tumor microenvironment,TME)是由免疫细胞、炎症细胞、肿瘤相关成纤维细胞、微血管,以及各种细胞因子和趋化因子所构成的一个复杂的综合系统,作为肿瘤细胞的生存环境,它与肿瘤的发生、转移及复发密切相关.肿瘤微环境的特点包括:弱酸性环境、低氧、活性氧(reactive oxygen spec...     

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。     

唾液酸结合受体——令人瞩目的肿瘤治疗靶标

在肿瘤发展的各个阶段普遍存在着糖基化异常,其中唾液酸(sialic acid, SA)修饰聚糖在不同类型的肿瘤细胞表面显著高表达,这些高度唾液酸化的肿瘤细胞通过与外周免疫细胞或内皮细胞上的SA结合受体唾液酸结合性免疫球蛋白样凝集素(sialic acid binding immunoglobulin-like lectins, Siglecs)或选择素(selectins)相互作用,促进肿瘤免疫抑制环境的形成并帮助肿瘤细胞获得转移潜能。因此,针对Siglecs或selectins与其配体间相互作用的肿瘤治疗策略正受到研究者们的广泛关注,这些治疗策略主要包括靶向SA结合受体的特异性抗体吉妥珠单抗(Mylotarg)或聚糖类物质、SA及其衍生物修饰的纳米药物递送系统等。本文综述了Siglecs或selectins参与的促进肿瘤发展和转移过程的具体机制,以及靶向SA结合受体的肿瘤治疗策略,并对这些治疗策略进行了理性评价与反思。     

Synergistic tumor microenvironment targeting and blood–brain barrier penetration via a pH-responsive dual-ligand strategy for enhanced breast cancer and brain metastasis therapy

Cancer associated fibroblasts (CAFs) which shape the tumor microenvironment (TME) and the presence of blood brain barrier (BBB) remain great challenges in targeting breast cancer and its brain metastasis. Herein, we reported a strategy using PTX-loaded liposome co-modified with acid-cleavable folic acid (FA) and BBB transmigrating cell penetrating peptide dNP2 peptide (cFd-Lip/PTX) for enhanced delivery to orthotopic breast cancer and its brain metastasis. Compared with single ligand or non-cleavable Fd modified liposomes, cFd-Lip exhibited synergistic TME targeting and BBB transmigration. Moreover, upon arrival at the TME, the acid-cleavable cFd-Lip/PTX showed sensitive cleavage of FA, which reduced the hindrance effect and maximized the function of both FA and dNP2 peptide. Consequently, efficient targeting of folate receptor (FR)-positive tumor cells and FR-negative CAFs was achieved, leading to enhanced anti-tumor activity. This strategy provides a feasible approach to the cascade targeting of TME and BBB transmigration in orthotopic and metastatic cancer treatment.     

Targeted nanomedicines remodeling immunosuppressive tumor microenvironment for enhanced cancer immunotherapy

Cancer immunotherapy has significantly flourished and revolutionized the limited conventional tumor therapies, on account of its good safety and long-term memory ability. Discouragingly, low patient response rates and potential immune-related side effects make it rather challenging to literally bring immunotherapy from bench to bedside. However, it has become evident that, although the immunosuppressive tumor microenvironment (TME) plays a pivotal role in facilitating tumor progression and metastasis, it also provides various potential targets for remodeling the immunosuppressive TME, which can consequently bolster the effectiveness of antitumor response and tumor suppression. Additionally, the particular characteristics of TME, in turn, can be exploited as avenues for designing diverse precise targeting nanomedicines. In general, it is of urgent necessity to deliver nanomedicines for remodeling the immunosuppressive TME, thus improving the therapeutic outcomes and clinical translation prospects of immunotherapy. Herein, we will illustrate several formation mechanisms of immunosuppressive TME. More importantly, a variety of strategies concerning remodeling immunosuppressive TME and strengthening patients' immune systems, will be reviewed. Ultimately, we will discuss the existing obstacles and future perspectives in the development of antitumor immunotherapy. Hopefully, the thriving bloom of immunotherapy will bring vibrancy to further exploration of comprehensive cancer treatment.     

Tumor-stromal interactions in lung cancer: novel candidate targets for therapeutic intervention

INTRODUCTION: Lung cancer is the leading cause of cancer deaths worldwide. Although standard treatment regimens have produced promising results with neoadjuvant and adjuvant strategies, outcomes for patients with lung cancer are still considered disappointing. Recent data provide evidence that the tumor-stromal environment is a leading player in carcinogenesis, not just a supporting tumor compartment. AREAS COVERED: This article reviews the current understanding of the lung cancer microenvironment and the complex bidirectional interplay between the tumor and lung microenvironment in non-small cell lung cancer (NSCLC). In particular, this review emphasizes the role of fibroblasts, mesenchymal stem cells and myeloid cells as well as mediators and molecular pathways regulated by these cells within the tumor microenvironment (TME) that contribute to lung tumor initiation, progression and metastasis. In addition, this review also summarizes the therapeutic strategies currently being applied in preclinical and clinical trials. EXPERT OPINION: Considering the recent advances in understanding lung tumor stroma, lung cancer progression could be effectively hampered by combining cytotoxic strategies with therapies that target the TME. However, more preclinical and clinical research is needed to prove the efficacy of this strategy for treating NSCLC.     

The road to integrative cancer therapies: emergence of a tumor-associated fibroblast protease as a potential therapeutic target in cancer

Great inroads have been made in defining the oncogenic pathways intrinsic to neoplastic cells and the mechanisms by which they are activated in tumors. Knowledge of these pathways provides numerous opportunities that are actively being pursued to develop targeted therapies for cancer. Complementary studies, focused on the non-transformed components of the tumor microenvironment (TME), have revealed that the extrinsic cues provided by the TME are also essential for tumor cells to manifest a fully transformed phenotype, angiogenesis and metastasis. Delineation of these cues and their underlying cellular and molecular pathways will thus lead to a new era of integrative cancer therapy based on combinatorial drug regiments that act synergistically to destroy the neoplastic cells by targeting both the intrinsic and extrinsic pro-oncogenic pathways. Tumor-associated fibroblasts (TAFs) and proteases are two of the key regulators of epithelial-derived tumors that represent potential targets of such integrative therapies. Herein, we consider the potential therapeutic benefit of inhibiting the function of fibroblast activation protein (FAP), a cell surface serine protease with dipeptidyl peptidase and endopeptidase activity that is expressed on TAFs and pericytes, in an integrative approach to treating cancer.     

Hedgehog signaling in gastrointestinal carcinogenesis and the gastrointestinal tumor microenvironment

The Hedgehog (HH) signaling pathway plays important roles in gastrointestinal carcinogenesis and the gastrointestinal tumor microenvironment (TME). Aberrant HH signaling activation may accelerate the growth of gastrointestinal tumors and lead to tumor immune tolerance and drug resistance. The interaction between HH signaling and the TME is intimately involved in these processes, for example, tumor growth, tumor immune tolerance, inflammation, and drug resistance. Evidence indicates that inflammatory factors in the TME, such as interleukin 6 (IL-6) and interferon-γ (IFN-γ), macrophages, and T cell-dependent immune responses, play a vital role in tumor growth by affecting the HH signaling pathway. Moreover, inhibition of proliferating cancer-associated fibroblasts (CAFs) and inflammatory factors can normalize the TME by suppressing HH signaling. Furthermore, aberrant HH signaling activation is favorable to both the proliferation of cancer stem cells (CSCs) and the drug resistance of gastrointestinal tumors. This review discusses the current understanding of the role and mechanism of aberrant HH signaling activation in gastrointestinal carcinogenesis, the gastrointestinal TME, tumor immune tolerance and drug resistance and highlights the underlying therapeutic opportunities.Key words: Hedgehog, Carcinogenesis, Tumor microenvironment, Gastrointestinal cancer, Cancer stem cells, Drug resistance     

Crosstalk between cancer cells and endothelial cells: implications for tumor progression and intervention

Communication between tumor cells and stromal cells is crucial to tumor development and progression. Fibroblasts and macrophages are the most common stromal cells in the tumor microenvironment. Endothelial cells are another type of stromal cell in the tumor microenvironment required for angiogenesis via interaction with tumor cells. Tumor angiogenesis provides not only oxygen and nutrients for tumor cells but also the necessary anchorage to facilitate tumor metastasis. The present review summarizes studies on the crosstalk between cancer cells and endothelial cells with a focus on implications for tumor progression. The following four categories are discussed in this review: (1) cell–cell communication in tumor microenvironment; (2) induction of metastasis by interaction between cancer cells and endothelial cells; (3) angiogenesis induced by tumor cells; (4) therapeutic strategies targeting adhesion and signaling molecules as well as chemokines. This review provides useful information highlighting the process of cancer aggressiveness affected by the crosstalk between cancer cells and endothelial cells, and suggests therapeutic strategies against tumor progression.     

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.     

靶向血小板与肿瘤细胞相互作用药物的现状和未来

血小板与肿瘤细胞的相互作用不仅可以促进恶性肿瘤的转移还可以影响恶性肿瘤相关性血栓的形成.当肿瘤细胞进入血液后,会立即激活血小板,使其黏附于肿瘤细胞表面,保护肿瘤细胞免受血流剪切力和机体免疫系统的攻击,从而促进肿瘤转移;同时,血小板的大量黏附也有可能导致血栓的形成.本文运用生物反应信号网络分析(ingenuity pat...