肿瘤干细胞niche与肿瘤

肿瘤干细胞(CSC)是肿瘤发生、发展、转移的根源,是未来肿瘤治疗的靶标.niche指一种微环境,是干细胞存在的基础.niche通过调控CSC的生长变化而参与肿瘤的发生发展,与肿瘤转移迁徙也密切相关,通过影响niche而根除CSC治愈肿瘤是一种新的治疗肿瘤的策略.     

肿瘤干细胞微环境与肿瘤转移

肿瘤干细胞(cancer stem cell,CSC)是肿瘤组织中一小部分具有自我更新、无限增殖能力和多向分化潜能的肿瘤细胞,是肿瘤发生、发展的根源,也可能是起始肿瘤转移发生的根本原因。由细胞外基质(extra cellular matrix,ECM)、血管微环境和骨髓微环境等组成了复杂的CSC微环境,为CSC的生长提供条件;同时,CSC还能招募、激活间充质干细胞等特殊类型的细胞形成适合CSC生长的微环境。并且,CSC微环境能分泌低氧诱导因子(hypoxia-inducible factor,HIF)、IL-1β等细胞因子,激活相关信号通路,通过诱导血管生成及抑制免疫等途径参与CSC的侵袭、转移等。近年来,靶向CSC微环境治疗肿瘤转移逐渐引起了研究人员的注意,尝试靶向一些分子和通路,如IL-6、IL-8及其受体、核因子-κB(nuclear factor-κB,NF-κB)和乙醛脱氢酶1(aldehyde dehydrogenase 1,ALDH1)等,借此抑制卵巢癌、乳腺癌中CSC的增殖,已经取得了一定成果。因此,针对CSC及其微环境的干扰的治疗将可能成为肿瘤治疗的新方向。     

以肿瘤干细胞为靶的免疫治疗

肿瘤干细胞(cancer stem cell,CSC)是肿瘤发生和转移的种子细胞,CSC具有自我更新、增殖和不完全分化的能力。CSC对化疗/放疗的抵抗以及免疫逃逸成为肿瘤复发的根源,要提高肿瘤治愈率必须彻底清除CSC。认识CSC的标记特征和"干性"调节关键分子才能有效和特异地攻击CSC。免疫治疗具有抗原识别的靶向性和时空效应性,是以CSC为靶的治疗的基础;以单克隆抗体和致敏的免疫细胞为主要治疗技术的免疫治疗清除CSC具有可实践性和挑战性。     

肿瘤干细胞niche与肿瘤

肿瘤干细胞(CSC)是肿瘤发生、发展、转移的根源,是未来肿瘤治疗的靶标.niche指一种微环境,是干细胞存在的基础.niche通过调控CSC的生长变化而参与肿瘤的发生发展,与肿瘤转移迁徙也密切相关,通过影响niche而根除CSC治愈肿瘤是一种新的治疗肿瘤的策略.

Abstract：

Cancer stem cell (CSC) is the source of tumor development and metastasis, and may become the target of cancer therapy in the future. Niche refers to a micro-environment that makes up the basis of stem cell existence. Niche is involved in tumor development by regulating the growth and changes of CSC. It is also closely related to tumor migration and metastasis. Eradicating CSC through modifying niche may be a new therapeutic strategy for curing cancer.     

靶向肿瘤干细胞的条件增殖腺病毒研究进展

肿瘤干细胞(CSC)具有自我更新及分化潜能,是肿瘤生长和转移的源泉,与化放疗抵抗密切相关,能否彻底根除CSC决定肿瘤治疗的成败.条件增殖腺病毒(CRAd)是一类仅在肿瘤细胞内特异增殖的新型病毒载体,可同时靶向肿瘤细胞和肿瘤干细胞,为彻底治愈肿瘤带来曙光.     

肿瘤转移干细胞与抗转移策略

肿瘤干细胞（cancer stem cell,CSC）能自我更新,分化形成异质性的肿瘤子代细胞群,是肿瘤复发与转移的主要原因。肿瘤转移干细胞（metastatic cancer stem cell,MCSC）具有CSC特性,同时伴有转移能力。肿瘤转移既发生于肿瘤晚期,也发生于早期。MCSC在起源、上皮-间质转变（epithelial-mesenchymal transition,EMT）、间质-上皮转变（mesenchymal-epithelial transition,MET）和靶器官小生境（niche）等方面与CSC不同,因而MCSC是肿瘤转移的基础。杀灭CSC、阻断EMT和MET、抑制MCSC微血管黏附和阻断MCSC依赖的小生境可构建抗肿瘤转移的治疗策略。本文主要介绍MCSC的可能来源,MCSC的生物学特性,MCSC近期研究中可能取得的突破,以及针对MCSC的抗转移策略,为肿瘤转移机制研究和抗转移研究提供参考。     

肿瘤干细胞的靶向策略研究

当前针对恶性肿瘤的治疗策略具有一定的局限性,治疗无效的情况经常出现。多数恶性肿瘤治疗失败的原因是对化疗和放疗的抵抗以及肿瘤复发或转移。这些问题的出现与肿瘤干细胞（ cancer stem cell, CSC）密切相关,而很多治疗方法对大部分时间处于静止状态的CSC无效,并且也不是有选择性地针对肿瘤细胞,对健康组织也产生一定的伤害,故肿瘤患者通常会面临复发和转移的风险。因此,如何消除CSC成为治疗恶性肿瘤的关键。     

肿瘤干细胞的生物学特性与靶向治疗

 肿瘤干细胞（CSC）在肿瘤的发生、复发、转移和耐药中起着十分重要的作用。常规的化疗药物能杀死大部分恶性细胞，但对数量极少的CSC却作用甚微，残存的CSC足以使肿瘤复发和转移。采用针对CSC的靶向治疗，才有可能从根本上治愈肿瘤。深入了解CSC不同于肿瘤组织中其他细胞类型的生物学特性，有助于进一步研究和开展特异性针对CSC的靶向治疗。     

肿瘤干细胞免疫逃逸机制及相关免疫疗法的研究进展

肿瘤干细胞（cancer stem cell,CSC）与正常干细胞生物学特征相似,具有自我更新、无限增殖和抗化学毒物损伤的能力, 与肿瘤的发生、治疗、预后、复发和转移关系极为密切。在肿瘤发生初期,虽然机体的免疫监视系统可以有效地对肿瘤细胞进行识 别和清除,但CSC可通过下调抗原加工和提呈机制成分、分泌免疫抑制因子、高表达免疫检查点分子以及激活免疫耐受信号通路等 机制调控免疫细胞功能,或促进抑制性免疫微环境的建立以逃避免疫系统对其的清除,从而使肿瘤得以进展。目前,靶向CSC与免 疫系统相互作用的多种方法正在被积极研究中,一些靶向CSC的新型免疫疗法正处于临床研发阶段。本文综述了近年来CSC相关 免疫逃逸机制及针对免疫逃逸的可能有效的治疗手段（包括DC疫苗、CAR-T细胞、免疫检查点抑制剂等）的研究进展。     

肿瘤干细胞的临床意义

肿瘤干细胞(cancer stem cell, CSC)是近年来在许多肿瘤组织中发现的一类特殊干细胞。肿瘤干细胞具有自我更新和分化的能力,可以通过不断分化肿瘤细胞使新的肿瘤产生;肿瘤干细胞具有很强的耐药性和放射抗拒,这可以用来解释肿瘤的复发和转移。肿瘤干细胞可用于对肿瘤的诊断和治疗：通过对肿瘤干细胞标志物的鉴定可实现对一些肿瘤的早期诊断;一些新的治疗手段则通过作用于肿瘤干细胞的信号转导途径、表面标记和其生存的微环境,以及诱导其分化,从而达到靶向治疗肿瘤的目的。深入研究肿瘤干细胞的耐药性以及确定更多的肿瘤干细胞标志物,可为肿瘤治疗提供新途径。     

The clinical and therapeutic implications of cancer stem cell biology

Cancer stem cells (CSCs) have provided new insights into the tumorigenesis and metastatic potential of cancer. The discovery of CSCs has provided many new insights into the complexities of cancer therapy: tumor initiation, treatment resistance, metastasis, recurrence, assessment of prognosis and prediction of clinical course. Recent rapid advances in molecular analysis have contributed to the better understanding of the molecular attributes and pathways that give CSCs their unique attributes. Use of these molecular techniques has facilitated elucidation of specific surface markers and pathways that favor propagation of CSCs - allowing for targeted therapy. Furthermore, it has been discovered that a specific microenvironment, or niche, is essential for the genesis of tumors from CSCs. Therapeutic strategies that alter these microenvironments compromise CSC proliferation and constitute another method of targeted cancer therapy. We review the clinical and therapeutic implications of CSCs, with a focus on treatment resistance and metastasis, and the emerging approaches to target CSCs and their microenvironments in order to attain improved outcomes in cancer. It is noteworthy that CSCs are the only cells capable of sustaining tumorigenesis; however, the cell of origin of cancer, in which tumorigenesis is initiated, may be distinct from CSCs that propagate the tumor.     

The clinical and therapeutic implications of cancer stem cell biology

Cancer stem cells (CSCs) have provided new insights into the tumorigenesis and metastatic potential of cancer. The discovery of CSCs has provided many new insights into the complexities of cancer therapy: tumor initiation, treatment resistance, metastasis, recurrence, assessment of prognosis and prediction of clinical course. Recent rapid advances in molecular analysis have contributed to the better understanding of the molecular attributes and pathways that give CSCs their unique attributes. Use of these molecular techniques has facilitated elucidation of specific surface markers and pathways that favor propagation of CSCs – allowing for targeted therapy. Furthermore, it has been discovered that a specific microenvironment, or niche, is essential for the genesis of tumors from CSCs. Therapeutic strategies that alter these microenvironments compromise CSC proliferation and constitute another method of targeted cancer therapy. We review the clinical and therapeutic implications of CSCs, with a focus on treatment resistance and metastasis, and the emerging approaches to target CSCs and their microenvironments in order to attain improved outcomes in cancer. It is noteworthy that CSCs are the only cells capable of sustaining tumorigenesis; however, the cell of origin of cancer, in which tumorigenesis is initiated, may be distinct from CSCs that propagate the tumor.     

Targeting cancer stem cell-specific markers and/or associated signaling pathways for overcoming cancer drug resistance

Cancer stem cells (CSCs) are a small subpopulation of tumor cells with capabilities of self-renewal, dedifferentiation, tumorigenicity, and inherent chemo-and-radio therapy resistance. Tumor resistance is believed to be caused by CSCs that are intrinsically challenging to common treatments. A number of CSC markers including CD44, CD133, receptor tyrosine kinase, aldehyde dehydrogenases, epithelial cell adhesion molecule/epithelial specific antigen, and ATP-binding cassette subfamily G member 2 have been proved as the useful targets for defining CSC population in solid tumors. Furthermore, targeting CSC markers through new therapeutic strategies will ultimately improve treatments and overcome cancer drug resistance. Therefore, the identification of novel strategies to increase sensitivity of CSC markers has major clinical implications. This review will focus on the innovative treatment methods such as nano-, immuno-, gene-, and chemotherapy approaches for targeting CSC-specific markers and/or their associated signaling pathways.     

Targeting cancer stem‐like cells in glioblastoma and colorectal cancer through metabolic pathways

Cancer stem‐like cells (CSCs) are thought to be the main cause of tumor occurrence, progression and therapeutic resistance. Strong research efforts in the last decade have led to the development of several tailored approaches to target CSCs with some very promising clinical trials underway; however, until now no anti‐CSC therapy has been approved for clinical use. Given the recent improvement in our understanding of how onco‐proteins can manipulate cellular metabolic networks to promote tumorigenesis, cancer metabolism research may well lead to innovative strategies to identify novel regulators and downstream mediators of CSC maintenance. Interfering with distinct stages of CSC‐associated metabolics may elucidate novel, more efficient strategies to target this highly malignant cell population. Here recent discoveries regarding the metabolic properties attributed to CSCs in glioblastoma (GBM) and malignant colorectal cancer (CRC) were summarized. The association between stem cell markers, the response to hypoxia and other environmental stresses including therapeutic insults as well as developmentally conserved signaling pathways with alterations in cellular bioenergetic networks were also discussed. The recent developments in metabolic imaging to identify CSCs were also summarized. This summary should comprehensively update basic and clinical scientists on the metabolic traits of CSCs in GBM and malignant CRC.     

Targeting Glioblastoma with the Use of Phytocompounds and Nanoparticles

Glioblastoma multiforme (GBM) are extremely lethal and still poorly treated primary brain tumors, characterized by the presence of highly tumorigenic cancer stem cell (CSC) subpopulations, considered responsible for tumor relapse. In order to successfully eradicate GBM growth and recurrence, new anti-cancer strategies selectively targeting CSCs should be designed. CSCs might be eradicated by targeting some of their cell surface markers and transporters, inducing their differentiation, impacting their hyper-glycolytic metabolism, inhibiting CSC-related signaling pathways and/or by targeting their microenvironmental niche. In this regard, phytocompounds such as curcumin, isothiocyanates, resveratrol and epigallocatechin-3-gallate have been shown to prevent or reverse cancer-related epigenetic dysfunctions, reducing tumorigenesis, preventing metastasis and/or increasing chemotherapy and radiotherapy efficacy. However, the actual bioavailability and metabolic processing of phytocompounds is generally unknown, and the presence of the blood brain barrier often represents a limitation to glioma treatments. Nowadays, nanoparticles (NPs) can be loaded with therapeutic compounds such as phytochemicals, improving their bioavailability and their targeted delivery within the GBM tumor bulk. Moreover, NPs can be designed to increase their tropism and specificity toward CSCs by conjugating their surface with antibodies specific for CSC antigens, with ligands or with glucose analogues. Here we discuss the use of phytochemicals as anti-glioma agents and the applicability of phytochemical-loaded NPs as drug delivery systems to target GBM. Additionally, we provide some examples on how NPs can be specifically formulated to improve CSC targeting. Open image in new window     

Targeting breast cancer stem cells: fishing season open!

Studies describing the tumor as a hierarchically organized cell population have changed the classical oncogenesis view and propose new therapeutic strategies. Cancer stem cells (CSCs) are thought to sustain tumor initiation/maintenance, therapy resistance, and systemic metastases. Targeting this tumor cell population is crucial to achieve a true cancer cure. A large research effort is now aiming to develop drugs targeting CSCs, based either on a priori understanding of key pathways regulating CSC biology or on high-throughput screening to identify novel targets and compounds.     

Stem cell-like cancer cells in cancer cell lines

Both stem cells and cancer cells are thought to be capable of unlimited proliferation. Moreover, a small number of cancer cells express stem cell markers, including CD133 and ATP-binding cassette transporters, by which the cells can pump out specific fluorescence dyes, such as Hoechst33342, as well as anti-cancer drugs, suggesting that either cancer cells resemble stem cells or cancers contain stem cell-like cancer cells, called "cancer stem cells (CSCs)". Using the common characteristics of tissue-specific stem cells, it was demonstrated that many types of tumors and cancer cell lines contain CSCs, which self-renew, express stem cell markers, and are tumorigenic. It was also shown that CSCs are resistant to anti-cancer drugs and irradiation. Thus CSCs might be a crucial target for the therapy. Because tumors contain CSCs and recruited normal stem cells, both of which contribute to tumorigenesis, it is difficult to separate CSCs from tumors. By contrast, cancer cell lines do not have any contaminating normal stem cells that quickly loose mulitpotentiality and differentiate in normal culture condition, suggesting that cancer cell lines could be an attractive alternative source of cells for CSC research. In this review I summarize the recent progress in CSC research using cancer cell lines.     

小细胞肺癌干细胞信号通路的研究进展

小细胞肺癌是具有高度侵袭性的肺肿瘤,其主要临床特征是化疗有效率高但易在短时间内复发转移,这一特点可能与肿瘤干细胞的存在有关。肿瘤干细胞被认为是恶性肿瘤发生发展、耐药、复发及转移的根源。目前多认为肿瘤干细胞与正常干细胞有着相同的信号通路,如Hedgehog、Notch、Wnt等通路。本文就这几条信号通路在小细胞肺癌干细胞中所起的作用以及针对这几条信号通路治疗药物的研究进展和可能的信号通路交互作用等方面进行综述。