丁酸与肿瘤

丁酸是食物纤维在肠道中生成的短链脂肪酸.实验表明,丁酸不仅能抑制肿瘤细胞增殖,还能诱导肿瘤细胞分化和凋亡.因其是人体正常代谢产物,不良反应少,在动物实验中亦未发现可知药物毒性,为肿瘤的药物治疗开辟了新的途径.     

丁酸与肿瘤

丁酸是食物纤维在肠道中生成的短链脂肪酸。实验表明。丁酸不仅能抑制肿瘤细胞增殖，还能诱导肿瘤细胞分化和凋亡。因其是人体正常代谢产物，不良反应少，在动物实验中亦未发现可知药物毒性，为肿瘤的药物治疗开辟了新的途径。     

脂肪酸代谢影响肿瘤免疫微环境与免疫治疗的研究进展

肿瘤免疫微环境是肿瘤细胞周围的微小结构,对肿瘤的发生、发展起着重要作用,也是多种免疫治疗靶向的核心区域, 其调控因素非常复杂。肿瘤免疫微环境中存在促进免疫耐受和肿瘤免疫逃逸的多种调控机制,除免疫检查点分子上调、抗原提 呈丢失等过程外,还包括免疫细胞的代谢重编程。免疫细胞的脂肪酸代谢是肿瘤免疫微环境的关键代谢过程,受肿瘤细胞的信 号调控和营养争夺影响可发生重编程,其在肿瘤免疫治疗中的调控规律是目前新兴的研究热点。本文集中回顾了脂肪酸代谢对 肿瘤免疫微环境中效应T细胞、记忆T细胞、调节性T细胞、肿瘤相关巨噬细胞等免疫细胞生存和功能的调节机制,讨论了近年来 免疫细胞脂肪酸代谢重编程影响免疫检查点阻断治疗、过继细胞治疗、肿瘤治疗性疫苗等免疫治疗效果的最新进展,总结了新近 出现的免疫相关的脂肪酸代谢调控靶点和相关药物,指出肿瘤相关免疫细胞脂肪酸代谢的独有特点和研究难点,为肿瘤免疫治 疗提供新的思路和见解。     

MAGE基因与恶性肿瘤

MAGE基因在许多恶性肿瘤细胞中表达,其产物是一种肿瘤排斥抗原,能诱导细胞毒性T淋巴细胞(CTL)特异性识别和杀伤肿瘤细胞,在肿瘤免疫治疗中具有重要意义。本文就MAGE基因与肿瘤的关系作一综述。     

三阴性乳腺癌肿瘤新抗原相关研究进展

三阴乳腺癌作为乳腺癌的一种独立临床病理类型,具有总生存期短、恶性程度高、侵袭能力强及早期复发率高等特点,目前治疗仍以化疗为主。新抗原是由体细胞DNA突变产生的肿瘤特异性抗原,在免疫治疗中与疗效和预后具有一定的相关性,肿瘤新抗原的研究有望进一步揭示免疫治疗的机制,近年来已经成为肿瘤领域研究热点。本文综述了肿瘤新抗原的鉴定识别、新抗原与免疫治疗的关系、新抗原疫苗及在三阴性乳腺癌中的相关进展。     

短链脂肪酸抗癌机制研究进展

肠道微生物及其代谢产物与机体的相互作用在癌症的发生发展中发挥了重要的作用。短链脂肪酸（short-chain fatty acid,SCFA）是肠道微生物酵解膳食纤维所得到的重要代谢产物,包括醋酸盐、丙酸盐和丁酸盐等,研究表明其具有明显的抗癌效应。SCFA通过作用于G蛋白偶联受体（G protein-coupled receptor,GPCR）、上调组蛋白乙酰化及巴豆酰化,促进癌细胞凋亡、周期阻滞,减弱癌细胞的转移和侵袭能力。此外,本文总结了SCFA通过增强免疫细胞功能发挥抗癌作用的机制。      

长链酰基辅酶A合成酶家族的功能及在肿瘤中的研究进展

脂肪酸是维持人体正常生理功能的必需营养物质,在体内需被相关酶激活后才可以进入正常代谢途径,脂肪酸代谢失调与肿瘤发生密切相关。长链酰基辅酶A合成酶(ACSLs)负责激活长链脂肪酸, ACSLs家族包括5个成员,分别为ACSL1、ACSL3、ACSL4、ACSL5、ACSL6,不同亚型具有不同细胞定位及功能,可以催化不同脂类并影响其代谢去路。ACSLs通过调节脂肪酸代谢,广泛参与内质网应激、铁死亡、耐药和肿瘤炎症微环境,ACSLs在肿瘤中经常去调控,可以影响脂肪酸代谢,而脂肪酸可以通过激活多种转录因子与基因反应原件结合激活不同的ACSLs,肿瘤细胞和蛋白泛素化可以调节ACSLs基因的表达,从而导致肿瘤发生代谢紊乱和其他代谢性疾病的发生。Triacsin C是一种ACSLs抑制剂,对开发抗肿瘤药物有巨大潜力。本文就ACSLs在细胞中的表达与定位、生理作用、在肿瘤中的功能、分子机制进行综述,结果表明,ACSLs与肿瘤中的炎症反应、脂质代谢紊乱、肿瘤侵袭与转移相关,对肿瘤发生、发展具有重要意义,可能成为肿瘤治疗有价值的生物标志物和治疗靶点。     

乳酸脱氢酶与肿瘤免疫代谢研究进展

不同免疫细胞亚群的代谢特征有所不同,抗肿瘤免疫细胞主要以有氧酵解和谷氨酰胺分解代谢提供代谢的物质与能量,而促进肿瘤发生和进展的抑制性免疫细胞亚群可利用肿瘤细胞代谢产物通过脂肪酸代谢等途径获取能量及中间产物。乳酸作为糖酵解途径的重要产物,直接或间接地影响肿瘤生物学行为,参与肿瘤免疫微环境调控。乳酸代谢的关键酶乳酸脱氢酶（LDH）常在肿瘤组织中高表达,是肿瘤微环境中连接各种免疫细胞代谢的关键酶之一,可激活某些信号传导途径和调控免疫应答参与肿瘤发生、发展。LDH水平升高主要由于肿瘤糖酵解活性增加和肿瘤缺氧坏死引起,其为免疫抑制性微环境的重要驱动者,LDH水平在一定程度上反映并可用于肿瘤糖酵解活性和免疫代谢状态的评估。本文对LDH与T淋巴细胞、巨噬细胞、树突状细胞等免疫细胞的代谢相关研究进行综述,旨在探究其在恶性肿瘤预后评估、抗肿瘤治疗尤其是免疫治疗疗效预测及监测中的可能应用。     

腺瘤性息肉和结肠癌患者食物纤维在结肠内酵解为短链脂肪酸

流行病学研究表明,环境因素影响结直肠癌的发病率,其中食物是最重要的因素。食物纤维在结肠内由细菌酵解后产生醋酸盐、丙酸盐、丁酸盐等短链脂肪酸(SCFAs),其中丁酸盐具有促进正常结肠粘膜增殖,但有抑制肿瘤细胞的作用。故食物纤维对结肠新生物的作用可能与结肠产生的短链脂肪酸(特别是丁酸     

肠道菌群与肿瘤免疫治疗

免疫治疗在难治性肿瘤的临床实践中取得重大突破, 但在临床应用中依然存在治疗结果的个体差异性和耐药性问题。肠道菌群是近年来逐渐受到重视的免疫调节因素, 越来越多的研究关注到其对肿瘤免疫治疗效果的影响。以肠道菌群为靶点, 提高肿瘤患者对免疫治疗的应答效果, 具有潜在的临床应用价值。     

Reversible proliferation arrest of rat 3y1 fibroblasts and selective killing of simian-virus transformed derivation of 3y1 by short-chain Fatty-acids

We examined the effect of saturated fatty acids with carbon number from 2 to 10 on proliferation and survival of rat untransformed fibroblast 3Y1 cells and its transformed derivation induced by Simian virus 40 (SV-3Y1). Acetic acid (C2) had no effect on proliferation of these cells. Among medium-chain fatty acids (C6-C10), caproic acid (C6) showed the lowest proliferation inhibitory effect. Caprylic (C8), pelargonic (C9), and capric acid (C10) exerted killing activity to both 3Y1 cells and SV-3Y1 cells, and the toxicity increased with the elongation of their alkyl chains. The toxicity was a little greater to 3Y1 cells than to SV-3Y1 cells. In contrast, short-chain fatty acids caused reversible proliferation arrest in 3Y1 cells at 25 mM in propionic (C3), 5 mM in butyric (C4) and 10 mM in valeric (C5) acids. These short-chain fatty acids arrested 3Y1 cells not only in the GI phase but also in the G2 phase of the cell cycle. To SV-3Y1 cells, however, these short-chain fatty acids were cytotoxic. The cytotoxicity to SV-3Y1 cells was the greatest in butyric acid among short-chain fatty acid tested. These results suggest that short-chain fatty acids exert ploliferation-arresting activity against normal cells while exerting killing activity to the transformed cells.     

Control of growth, morphology, and alkaline phosphatase activity by butyrate and related short-chain fatty acids in the retinoid-responsive 9-1C rat prostatic adenocarcinoma cell

The actions of butyrate and related short-chain fatty acids were analyzed on the 9-1C retinoid-responsive rat prostatic adenocarcinoma cell. The 9-1C cells, which are inducible for alkaline phosphatase (AP) by retinoic acid, were also inducible for the enzyme by three- to six-carbon fatty acids. The most effective inducer was the four-carbon acid, butyrate, which caused an essentially linear increase in AP activity in the concentration range of 2 to 10 mM. A comparison of AP induction by butyrate and retinoic acid showed the retinoid to be a more potent inducer of the enzyme by several orders of magnitude. Butyrate and related short-chain fatty acids also suppressed 9-1C cell growth, an effect which is not mediated by retinoic acid in these cells. Total growth suppression was achieved at butyrate concentrations of 5 mM and above; 1.5 mM caused 50% inhibition. As in the case of AP induction, all three- to six-carbon fatty acids suppressed growth to some extent, although butyrate was the most effective. The order of carbon chain length effectiveness for both AP induction and growth suppression by the fatty acids was 4 greater than 5 greater than 3 greater than 6. Butyrate appeared to be unique among the various fatty acids in causing an increase in cell protein. The protein content of 9-1C cells cultured in the presence of 4 mM butyrate for 72 h was more than 4-fold greater than that of control cells. This observation paralleled observations on cell volumes analyzed by forward-angle light-scatter flow cytometry, which showed a concentration-related increase in the cross-sectional areas of 9-1C cells following butyrate treatment. This effect has also been shown, in a recent study, to be mediated by retinoids. One of the most striking effects of butyrate treatment was on cellular morphology. The fatty acid caused 9-1C cells, which normally grow in a disorganized array with no apparent affinity for each other, to spread out and become organized into parallel tracts through the monolayer.     

肠道菌群紊乱与肝癌的研究进展

肝细胞肝癌（HCC）是常见的消化系统恶性肿瘤,HCC的发生涉及多种因素,如环境、代谢与基因等。近期研究发现,肠道菌群失调与HCC的发生发展有着密切联系,其可能的机制包括菌群移位与内毒素血症引起肝细胞的慢性炎性反应以及肠道菌群代谢产物如短链脂肪酸、胆汁酸等对HCC的诱导等。目前多种改善肠道菌群紊乱的方法在HCC的治疗中显示出较为光明的前景。本文将对肠道菌群引起HCC的多种机制以及针对肠道菌群失调的HCC预防与治疗措施进行综述。     

Effect of short-chain fatty acids on Epstein-Barr virus early and viral capsid antigen induction in P3HR-1 cells

The effects of short-chain fatty acids were assayed for their capacity to induce Epstein-Barr virus (EBV) from the EBV genome-carrying human lymphoblastoid P3HR-1 cells. Not only the n-butyric acid, the activity of which is now well established, but also the n-valeric acid was found to induce EBV-associated early antigen (EA) and viral capsid antigen (VCA) at an appreciable level. Similarly, i-valeric acid showed a considerably lower, but significant, level of this activity, while the i-butyric acid was inactive. All other fatty acids with either a chain shorter than butyric or longer than valeric showed only a marginal effect or none at all. Thus, the decisive factor for EBV-inducing capacity of the fatty acids concerns adequate length and configuration of the basic structure of the molecules.     

Identification of transforming activity of free fatty acid receptor 2 by retroviral expression screening

Gallbladder cancer (GBC) is a highly fatal malignancy in humans. Genetic alterations in KRAS or TP53 as well as overexpression of ERBB2 have been shown to contribute to the development of certain types of GBC. However, many cases of GBC do not harbor such genetic changes, with other transforming events awaiting discovery. We here tried to identify novel cancer-promoting genes in GBC, with the use of a retroviral cDNA expression library. A retroviral cDNA expression library was constructed from a surgically resected clinical specimen of GBC, and was used to infect 3T3 fibroblasts in a focus formation assay. cDNA incorporated into the transformed foci was rescued by PCR. One such cDNA was found to encode free fatty acid receptor 2 (FFAR2), a G protein-coupled receptor for short-chain fatty acids. The oncogenic potential of FFAR2 was confirmed both in vitro with the focus formation assay and by evaluation of cell growth in soft agar as well as in vivo with a tumorigenicity assay in nude mice. The isolated FFAR2 cDNA had no sequence alterations, suggesting that upregulation of FFAR2 expression may contribute to malignant transformation. Indeed, all of quantitative RT-PCR, in situ hybridization, and immunohistochemical analyses showed that the amount of FFAR2 mRNA and its protein product was increased in digestive tract cancer specimens. Furthermore, short-chain fatty acids potentiated the mitogenic action of FFAR2 in 3T3 cells. Our data thus, for the first time, implicate FFAR2 in carcinogenesis of the digestive tract. ( Cancer Sci 2009)     

Specific fatty acids and human colorectal cancer: an overview

BACKGROUND: Evidence suggests that dietary fats are associated with risk of colorectal cancer. The effect of fats depends not only on the quantity, but also on their composition in specific fatty acids. Moreover, fats are peroxidizable, and peroxidation products as well as antioxidants play a role in the pathogenic process of colorectal cancer. METHODS: The published literature was reviewed for the relationship between dietary intake or concentration of specific fatty acids in adipose tissue, erythrocytes, plasma or feces in relation to colorectal cancer. RESULTS: Increased concentrations of short-chain fatty acids (SCFAs) and eicosanopentaenoic acid (EPA) seem to protect against colorectal cancer. Increased concentrations of medium-chain fatty acids (MCFAs) and arachidonic acid (AA) might be associated with increased risk. Long-chain saturated fatty acids (LCSFAs) seem unrelated to colorectal cancer, while the associations between monounsaturated fatty acids (MUFAs), trans fatty acids, polyunsaturated fatty acids (PUFAs) such as linoleic acid (LA), alpha-linolenic acid (ALA), docosahexaenoic acid (DHA), omega-3/omega-6 ratio and colorectal cancer are unconvincing. CONCLUSIONS: It is suggested that the substitution of food with high MCFAs and AA content by a SCFAs- and EPA-rich diet may contribute to reduced risk of colorectal cancer.     

Essential fatty acid consumption and risk of breast cancer

Summary Animal and ecological studies of essential fatty acids suggest that omega-3 fatty acids found in fish oils and omega-6 fatty acids found in vegetable oils may be playing a role in the etiology of breast cancer. Essential fatty acids may modulate breast cancer risk by interacting with prostaglandins, which have immunosuppressive and platelet aggregative capabilities. The fatty acid composition of adipose tissue reflects the dietary consumption of essential fatty acids over a period of years. Biochemical techniques have been used in epidemiological studies to accurately estimate fatty acid consumption. However, analytical epidemiology studies that have used biochemical measurements of adipose tissue fatty acid composition, have not supported a relationship between consumption of these essential fatty acids and breast cancer risk.     

Cytotoxic drugs efficacy correlates with adipose tissue docosahexaenoic acid level in locally advanced breast carcinoma

Experimental studies indicated that long-chain polyunsaturated fatty acids may increase sensitivity of mammary tumours to several cytotoxic drugs. To evaluate this hypothesis in breast cancer, we have prospectively studied the association between levels of fatty acids stored in breast adipose tissue and the response of the tumour to chemotherapy in 56 patients with an initially localized breast carcinoma. Adipose breast tissue was obtained at the time of biopsy, and individual fatty acids were measured as a percentage of total fatty acids using capillary gas chromatography. Patients then received primary chemotherapy, combining mitoxantrone, vindesine, cyclophosphamide and 5-fluorouracil every 4 weeks. Tumour size was reassessed after three cycles of chemotherapy. Tumour response was evaluated according to World Health Organization criteria. Complete or partial response to chemotherapy was achieved in 26 patients (47%). Level of n-3 polyunsaturated fatty acids in adipose tissue was higher in the group of patients with complete or partial response to chemotherapy than in patients with no response or with tumour progression (P < 0.004). Among n-3 polyunsaturated, only docosahexaenoic acid (22:6n-3) was significantly associated with tumour response (P < 0.005). In a logistic regression analysis taking into account age, body mass index and tumour size, 22:6 n-3 level proved to be an independent predictor for chemosensitivity (P = 0.03). These results suggest that, in breast cancer, 22:6 n-3 may increase the response of the tumour to the cytotoxic agents used.     

Extracellular lipid-mediated signaling in tumor-cell activation and pseudopod protrusion

We have pioneered an in vitro pseudopod-generation model wherein suspended tumor cells are stimulated to form pseudopods into glass micropipettes in response to soluble collagen type IV (CIV). Pertussis toxin and removing intracellular calcium were found previously to be inhibitory to that process. We now extend those observations to dissect the roles of transmembrane calcium influx and circulating fatty acids on pseudopod extension. Removal of fatty acids from BSA in basal media resulted in abrogation of pseudopod formation, while reconstitution of free fatty acids restored cell pseudopod protrusion. We thus hypothesized that fatty acids may provide necessary pseudopod stimulatory signals. Addition of lysophosphatidic acid (LPA) to the fatty acid-free CIV solution or in an opposite pipette without CIV permitted approximately 50% pseudopod recovery in all pipette directions in a dose-dependent fashion. Thapsigargin (TG), an agent that releases internal calcium stores and causes opening of store-operated calcium channels, restored pseudopod protrusion up to 80% in CIV with fatty acid-free albumin. [Ca(2+)](i) release was non-additive when cells were stimulated by TG and LPA, suggesting overlapping [Ca(2+)](i) stores. The combination of TG and LPA in fatty acid-free albumin fully restored the pseudopod response to CIV. Addition of EGTA to chelate stimulatory media calcium blocked the pseudopod response to CIV in the presence of fatty acids. This indicates that pseudopod protrusion requires transmembrane calcium entry. Thus, extracellular lipids and calcium mobilization are required to complement CIV in pseudopod protrusion from suspended cells.     

Action of long-chain fatty acids on protein kinase C activity: comparison of omega-6 and omega-3 fatty acids.

The results presented in this paper indicate that long chain free fatty acids have a dual modulatory effect on Protein Kinase C (PKC) activity purified from rat colon. Saturated (stearic) and monounsaturated (oleic) fatty acids are weak activators of PKC in the absence of phosphatidyl serine (PS) and diolein (DO), but have no significant effect on the PS/DO stimulated activity. Increasing the degree of unsaturation of the fatty acid, such as linolenic, arachidonic and eicosapentaenoic acids, also increases their stimulatory action toward unstimulated PKC, as well as their inhibition of PS/DO stimulated enzyme activity. Within this group of fatty acids there is no significant difference in the response of PKC toward omega-6 versus omega-3 type fatty acids. However, docosahexaenoic acid, a 22 carbon omega-3 polyunsaturated fatty acid found primarily in fish oil affected PKC differently from all other fatty acids studied. This compound was unable to stimulate dormant PKC activity, but was a highly potent inhibitor of PS/DO stimulated PKC. It is hypothesized that the inhibitory action of this omega-3 fatty acid may contribute to the protective role of fish oil consumption on colon tumorigenesis.