胃癌的肿瘤微环境研究进展

肿瘤微环境是决定肿瘤细胞行为的主要影响因素,有别于正常细胞与其周围组织所形成的微环境,组织缺氧和酸中毒、间质高压形成、大量生长因子和蛋白水解酶的产生及免疫炎性反应等构成了肿瘤组织代谢环境的生物学特征,这种特性在肿瘤的发生、进展、转移中扮演重要的角色。胃癌早期症状不典型、转移迅速、死亡率高,是消化系统最常见的恶性肿瘤,目前,关于肿瘤微环境的研究尚处于起步阶段,对胃癌肿瘤微环境的研究有助于我们进一步认识胃癌发生发展的机制,并为临床诊断、治疗胃癌提供依据。因此,本文就近年来在胃癌肿瘤微环境方面的研究进展作一综述。     

Evaluation of Tempol Radioprotection in a Murine Tumor Model

Tempol, a stable nitroxide free radical compound, is an in vitro and in vivo radioprotector. Previous studies have shown that Tempol protects C3H mice against whole-body radiation-induced bone marrow failure. In this study, the radioprotection of tumor tissue was evaluated. RIF-1 tumor cells were implanted in female C3H mice 10 d prior to radiation. Groups of mice were injected intraperitoneally with Tempol (275 mg/kg) or PBS followed 10 min later by a single dose of radiation to the tumor bed. Tumor growth curves generated after 10 and 33.3 Gy doses of radiation showed no difference in growth between the Tempol- and PBS-treated animals. A full radiation dose-response experiment revealed a tumor control dose in 50% of the animals in 30 d (TCD_50/30) value of 36.7 Gy for Tempol-treated mice and 41.8 Gy for saline-treated mice suggesting no protection of the RIF-1 tumor by Tempol. Tumor pharmacokinetics were done to determine why Tempol differentially protected bone marrow and not tumor cells. Differential reduction of Tempol in the RIF-1 tumor and bone marrow was evaluated with EPR spectroscopy 10, 20, and 30 min after injection. Bioreduction of Tempol to its corresponding hydroxylamine (which is not a radioprotector) occurred to a greater extent in RIF-1 tumor cells compared to bone marrow. We conclude that the differences in radioprotection may result from enhanced intratumor bioreduction of Tempol to its nonradioprotective hydroxylamine analogue. The nitroxides as a class of compounds may provide a means to exploit the redox differences between normal tissues and tumors. © 1997 Elsevier Science Inc.     

Mitochondrial dysfunction and oxidative stress: cause and consequence of epileptic seizures

Mitochondrial dysfunction has been implicated as a contributing factor in diverse acute and chronic neurological disorders. However, its role in the epilepsies has only recently emerged. Animal studies show that epileptic seizures result in free radical production and oxidative damage to cellular proteins, lipids, and DNA. Mitochondria contribute to the majority of seizure-induced free radical production. Seizure-induced mitochondrial superoxide production, consequent inactivation of susceptible iron–sulfur enzymes, e.g., aconitase, and resultant iron-mediated toxicity may mediate seizure-induced neuronal death. Epileptic seizures are a common feature of mitochondrial dysfunction associated with mitochondrial encephalopathies. Recent work suggests that chronic mitochondrial oxidative stress and resultant dysfunction can render the brain more susceptible to epileptic seizures. This review focuses on the emerging role of oxidative stress and mitochondrial dysfunction both as a consequence and as a cause of epileptic seizures.     

13C metabolic flux analysis clarifies distinct metabolic phenotypes of cancer cell spheroid mimicking tumor hypoxia

Cancer cells adapt their intracellular energy metabolism to the oxygen-deprived tumor microenvironment (TME) to ensure tumor progression. This adaptive mechanism has focused attention on the metabolic phenotypes of tumor cells under hypoxic TME for developing novel cancer therapies. Although widely used monolayer (2D) culture does not fully reflect in vivo hypoxic TME, spheroid (3D) culture can produce a milieu similar to the TME in vivo. However, how different metabolic phenotypes are expressed in 3D cultures mimicking tumor hypoxia compared with 2D cultures under hypoxia remains unclear. To address this issue, we investigated the metabolic phenotypes of 2D- and 3D-cultured cancer cells by ¹³C-metabolic flux analysis (¹³C-MFA). Principal component analysis of ¹³C mass isotopomer distributions clearly demonstrated distinct metabolic phenotypes of 3D-cultured cells. ¹³C-MFA clarified that 3D culture significantly upregulated pyruvate carboxylase flux in line with the pyruvate carboxylase protein expression level. On the other hand, 3D culture downregulated glutaminolytic flux. Consistent with our findings, 3D-cultured cells are more resistant to a glutaminase inhibitor than 2D-cultured cells. This study suggests the importance of considering the metabolic characteristics of the particular in vitro model used for research on cancer metabolism.     

Tumor bioenergetics: An emerging avenue for cancer metabolism targeted therapy

Cell proliferation is a delicately regulated process that couples growth signals and metabolic demands to produce daughter cells. Interestingly, the proliferation of tumor cells immensely depends on glycolysis, the Warburg effect, to ensure a sufficient amount of metabolic flux and bioenergetics for macromolecule synthesis and cell division. This unique metabolic derangement ould provide an opportunity for developing cancer therapeutic strategy, particularly when other diverse anti-cancer treatments have been proved ineffective in achieving durable response, largely due to the emergence of resistance. Recent advances in deeper understanding of cancer metabolism usher in new horizons of the next generation strategy for cancer therapy. Here, we discuss the focused review of cancer energy metabolism, and the therapeutic exploitation of glycolysis and OXPHOS as a novel anti-cancer strategy, with particular emphasis on the promise of this approach, among other cancer metabolism targeted therapies that reveal unexpected complexity and context-dependent metabolic adaptability, complicating the development of effective strategies. [BMB Reports 2014; 47(3): 158-166]     

靶向肿瘤微环境的CAR-T治疗研究*

癌症仍然是现阶段威胁人类健康的一大难题,随着医学的发展,癌症治疗方法除传统方法:手术、放疗、化疗,还可以采用免疫疗法。目前,癌症免疫疗法受到广泛关注,但在应用方面具有许多局限性,如 PD-1/PD-L1 抑制剂,在应用的过程中会出现获得性耐药现象,因此细胞免疫疗法(chimeric antigen receptor T cell, CAR-T) 应运而生,成为弥补免疫检查点抑制剂(immune checkpoint inhibitors, ICIs)和单克隆抗体药物缺陷的新兴治疗方式,简要介绍了 CAR-T 免疫疗法的产生、应用及对 TME 相关靶点的研究进展,为后续研究提供一定的思路。     

靶向肿瘤微环境的CAR-T治疗研究*

癌症仍然是现阶段威胁人类健康的一大难题,随着医学的发展,癌症治疗方法除传统方法:手术、放疗、化疗,还可以采用免疫疗法。目前,癌症免疫疗法受到广泛关注,但在应用方面具有许多局限性,如 PD-1/PD-L1 抑制剂,在应用的过程中会出现获得性耐药现象,因此细胞免疫疗法(chimeric antigen receptor T cell, CAR-T) 应运而生,成为弥补免疫检查点抑制剂(immune checkpoint inhibitors, ICIs)和单克隆抗体药物缺陷的新兴治疗方式,简要介绍了 CAR-T 免疫疗法的产生、应用及对 TME 相关靶点的研究进展,为后续研究提供一定的思路。     

肿瘤相关成纤维细胞与肿瘤微环境

肿瘤的发展过程与肿瘤微环境密切相关,而肿瘤相关成纤维细胞（CAFs）是上述微环境中最主要的宿主细胞,CAFs是一类不同细胞源性的细胞群,可来源于多种细胞包括静止的成纤维细胞、上皮细胞、内皮细胞和间质干细胞的分化过程。体内和体外生物学实验均证实,成纤维细胞在肿瘤微环境中并不是被动的对肿瘤发展提供支持,而是发挥了至关重要的作用,所以靶向CAFs有望成为肿瘤治疗的新方向,对CAFs相关分子标记物和分子事件的进一步探索将为抗肿瘤的临床治疗提供新的思路。本文将对CAFs的来源以及CAFs对肿瘤发生发展、转移及VEGF耐受等方面的作用做一综述。     

成纤维细胞激活蛋白alpha与肿瘤免疫抑制的研究进展

成纤维细胞激活蛋白alpha（Fibroblast activation protein-alpha,FAP-alpha）是一种跨膜丝氨酸蛋白酶,高度表达在90 %的上皮性肿瘤的 间质--肿瘤相关成纤维细胞（Tumor association fibroblast,TAF）上。FAPalpha在促进上皮性肿瘤的恶性进展中起着十分重要的作用, 近年来研究发现,FAP琢在肿瘤微环境中发挥免疫抑制的作用。研究FAPalpha在肿瘤免疫抑制中的作用,已成为肿瘤研究的新的热 点。为基于以FAP-alpha为靶标的抗肿瘤免疫治疗提供参考,本文围绕引起肿瘤免疫抑制的因素、FAPalpha与肿瘤免疫抑制的研究进展 以及FAP-alpha在肿瘤的发展进程的作用作一综述。     

肿瘤相关成纤维细胞与肿瘤微环境

肿瘤的发展过程与肿瘤微环境密切相关,而肿瘤相关成纤维细胞(CAFs)是上述微环境中最主要的宿主细胞,CAFs是一类不同细胞源性的细胞群,可来源于多种细胞包括静止的成纤维细胞、上皮细胞、内皮细胞和间质干细胞的分化过程。体内和体外生物学实验均证实,成纤维细胞在肿瘤微环境中并不是被动的对肿瘤发展提供支持,而是发挥了至关重要的作用,所以靶向CAFs有望成为肿瘤治疗的新方向,对CAFs相关分子标记物和分子事件的进一步探索将为抗肿瘤的临床治疗提供新的思路。本文将对CAFs的来源以及CAFs对肿瘤发生发展、转移及VEGF耐受等方面的作用做一综述。     

Targeting amino acid metabolism in cancer growth and anti-tumor immune response

Recent advances in amino acid metabolism have revealed that targeting amino acid metabolic enzymes in cancer therapy is a promising strategy for the development of novel therapeutic agents. There are currently several drugs in clinical trials that specifically target amino acid metabolic pathways in tumor cells. In the context of the tumor microenvironment,however,tumor cells form metabolic relationships with immune cells,and they oftencompete for common nutrients. Many tumors evolved to escape immune surveillance by taking advantage of their metabolic flexibility and redirecting nutrients for their own advantage. This review outlines the most recent advances in targeting amino acid metabolic pathways in cancer therapy while giving consideration to the impact these pathways may have on the anti-tumor immune response.     

The architect who never sleeps: Tumor-induced plasticity

Tumor cell plasticity is an event that has been observed in several malignancies. In fact, most of the solid tumors are characterized by cellular heterogeneity and undergo constant changes as the tumor develops. The increased plasticity displayed by these cells allows them to acquire additional properties, enabling epithelial-mesenchymal transitions, dedifferentiation and the acquisition of stem cell-like properties. Here we discuss the particular importance of an inflammatory microenvironment for the bidirectional control of cellular plasticity and the potential for therapeutic intervention.     

Repetitive static muscle contractions in humans —a trigger of metabolic and oxidative stress?

Repetitive static exercise (RSE) is a repetitive condition of partial ischaemia/reperfusion and may therefore be connected to the formation of oxygen-derived free radicals and tissue damage. Seven subjects performed two-legged intermittent knee extension exercise repeating at 10 s on and 10 s off at a target force corresponding to about 30% of the maximal voluntary contraction force. The RSE was continued for 80 min (n = 4) or to fatigue (n = 3). Four of the subjects also performed submaximal dynamic exercise (DE) at an intensity of about 60% maximal oxygen uptake (VO2max) for the same period. Whole body oxygen uptake (VO2) increased gradually with time during RSE (P less than 0.05), indicating a decreased mechanical efficiency. This was further supported by a slow increase in leg blood flow (P less than 0.05) and leg oxygen utilization (n.s.) during RSE. In contrast, prolonged RSE had no effect on VO2 during submaximal cycling. Maximal force (measured in six additional subjects) declined gradually during RSE and was not completely restored after 60 min of recovery. After 20 and 80 min (or at fatigue) RSE phosphocreatine (PC) dropped to 74% and 60% of the initial value, respectively. A similar decrease in PC occurred during DE. Muscle and arterial lactate concentrations remained low during both RSE and DE. The three subjects who were unable to continue RSE for 80 min showed no signs of a more severe energy imbalance than the other subjects. A continuous release of K+ occurred during both RSE and DE.(ABSTRACT TRUNCATED AT 250 WORDS)     

自噬与肿瘤关系的研究与进展

自噬是一个高度发达而且十分保守的生物学分解代谢过程。自噬与肿瘤的关系十分密切,在肿瘤发生发展的过程中,自噬活性的改变却是一把双刃剑。自噬,它既能够使肿瘤细胞耐受不同的应激条件而使其获得更好的生存,也可以通过各种信号途径减轻许多不良应激条件下的细胞损伤,如慢性炎症、慢性细胞死亡及基因组损伤等,从而而减少肿瘤的发生。再者,一方面,某些肿瘤的发生和发展过程中也同样依赖于自噬,并且肿瘤细胞可以利用自噬来对抗抗癌药物的一定的细胞毒性。而另一方面,有些癌症却需要利用自噬的作用来杀死肿瘤细胞。虽然自噬与肿瘤的关系是十分复杂的,也存在不少的分歧,但总的来说自噬在癌症中的作用是至关重要的。结合近年来国内外研究的发展,我们这篇综述重点讨论的是自噬在癌症中的作用,并且探讨其潜在的作用机制,以及目前自噬在癌症治疗中的应用。     

Expression of chemokine-like receptor 1 (CMKLR1) on J744A.1 macrophages co-cultured with fibroblast and/or tumor cells: modeling the influence of microenvironment

Maturation of macrophages is influenced by the composition of surrounding microenvironment. Expression of CMKLR1, the receptor for chemerin, is potentially associated with the differentiation status of macrophages. In this study, CMKLR1 was determined on peritoneal and tumor-infiltrating macrophages. CMKLR1 expression was found to be associated with the fibroblast-assisted maturation of J744A.1 monocyte/macrophage cells in the co-cultures established to model tumor microenvironment, whereas the presence of tumor cells was able to upregulate CMKLR1 expression independent of macrophage maturation. In addition, macrophages cultured with tumor cells or in tumor cell-conditioned media responded to recombinant chemerin(17-156) peptide and increased the expression of proinflammatory IL-1β, TNF-α and IL-12 p40 cytokines. The native form of chemerin (prochemerin) supplied by fibroblasts did not induce a functional response. These observations may indicate a potential role for chemerin and CMKLR1 in the regulation of inflammatory responses in the tumor microenvironment.     

Tumor suppressor microRNAs: A novel non-coding alliance against cancer

Tumor initiation and progression are the outcomes of a stepwise accumulation of genetic alterations. Among these, gene amplification and aberrant expression of oncogenic proteins, as well as deletion or inactivation of tumor suppressor genes, represent hallmark steps. Mounting evidence collected over the last few years has identified different populations of non-coding RNAs as major players in tumor suppression in almost all cancer types. Elucidating the diverse molecular mechanisms underlying the roles of non-coding RNAs in tumor progression might provide illuminating insights, potentially able to assist improved diagnosis, better staging and effective treatments of human cancers. Here we focus on several groups of tumor suppressor microRNAs, whose downregulation exerts a profound oncologic impact and might be harnessed for the benefit of cancer patients.     

肿瘤病毒的发现历程及在肿瘤发生机制中的研究意义

1911年Peyton Rous发现禽肉瘤病毒,从而建立了肿瘤病毒学这一学科领域。20世纪30年代,Richard发现哺乳动物肿瘤病毒,60年代发现第一个人类肿瘤病毒--EB病毒,随后相继鉴定出乙型肝炎病毒(HBV)和乳头状瘤病毒(HPV)。肿瘤病毒的深入研究带动了癌基因概念的确立和抑癌基因功能的发现,促进癌症疫苗的研究,后者可以抑制病毒的传染性并降低肿瘤的发病率。20世纪80-90年代发现了人T细胞白血病Ⅰ型病毒(HTLV-1),丙型肝炎病毒(HVC)及卡波西肉瘤病毒(KSHV)。目前已知6种病毒(EBV、HBV、HPV、HTLV-1、HCV、KSHV)引起世界范围10%-15%的癌症,因此,病毒不仅是许多人类癌症的病原体,还可以作为揭示人类恶性肿瘤发病机制的研究工具。     

Tumor interstitial fluid — A treasure trove of cancer biomarkers

Tumor interstitial fluid (TIF) is a proximal fluid that, in addition to the set of blood soluble phase-borne proteins, holds a subset of aberrantly externalized components, mainly proteins, released by tumor cells and tumor microenvironment through various mechanisms, which include classical secretion, non-classical secretion, secretion via exosomes and membrane protein shedding. Consequently, the interstitial aqueous phase of solid tumors is a highly promising resource for the discovery of molecules associated with pathological changes in tissues. Firstly, it allows one to delve deeper into the regulatory mechanisms and functions of secretion-related processes in tumor development. Secondly, the anomalous secretion of molecules that is innate to tumors and the tumor microenvironment, being associated with cancer progression, offers a valuable source for biomarker discovery and possible targets for therapeutic intervention. Here we provide an overview of the features of tumor-associated interstitial fluids, based on recent and updated information obtained mainly from our studies of breast cancer. Data from the study of interstitial fluids recovered from several other types of cancer are also discussed. This article is a part of a Special Issue entitled: The Updated Secretome.     

Pan-cancer analysis of the metabolic reaction network

Metabolic reprogramming is considered a hallmark of malignant transformation. However, it is not clear whether the network of metabolic reactions expressed by cancers of different origin differ from each other or from normal human tissues. In this study, we reconstructed functional and connected genome-scale metabolic models for 917 primary tumor samples across 13 types based on the probability of expression for 3765 reference metabolic genes in the sample. This network-centric approach revealed that tumor metabolic networks are largely similar in terms of accounted reactions, despite diversity in the expression of the associated genes. On average, each network contained 4721 reactions, of which 74% were core reactions (present in >95% of all models). Whilst 99.3% of the core reactions were classified as housekeeping also in normal tissues, we identified reactions catalyzed by ARG2, RHAG, SLC6 and SLC16 family gene members, and PTGS1 and PTGS2 as core exclusively in cancer. These findings were subsequently replicated in an independent validation set of 3388 genome-scale metabolic models. The remaining 26% of the reactions were contextual reactions. Their inclusion was dependent in one case (GLS2) on the absence of TP53 mutations and in 94.6% of cases on differences in cancer types. This dependency largely resembled differences in expression patterns in the corresponding normal tissues, with some exceptions like the presence of the NANP-encoded reaction in tumors not from the female reproductive system or of the SLC5A9-encoded reaction in kidney-pancreatic-colorectal tumors. In conclusion, tumors expressed a metabolic network virtually overlapping the matched normal tissues, raising the possibility that metabolic reprogramming simply reflects cancer cell plasticity to adapt to varying conditions thanks to redundancy and complexity of the underlying metabolic networks. At the same time, the here uncovered exceptions represent a resource to identify selective liabilities of tumor metabolism.