Relationship between intestinal microbiota and colorectal cancer

The human gastrointestinal tract hosts a complex and vast microbial community with up to 10¹¹-10¹² microorganisms colonizing the colon. The gut microbiota has a serious effect on homeostasis and pathogenesis through a number of mechanisms. In recent years, the relationship between the intestinal microbiota and sporadic colorectal cancer has attracted much scientific interest. Mechanisms underlying colonic carcinogenesis include the conversion of procarcinogenic diet-related factors to carcinogens and the stimulation of procarcinogenic signaling pathways in luminal epithelial cells. Understanding each of these mechanisms will facilitate future studies, leading to the development of novel strategies for the diagnosis, treatment, and prevention of colorectal cancer. In this review, we discuss the relationship between colorectal cancer and the intestinal microbiota.     

肠道微生物群衍生的代谢产物调控结直肠癌的新进展

肠道生态系统的改变会影响人类的健康,甚至引发结直肠癌。大量证据表明,在结直肠癌患者的肠道中普遍存在一种病理性微生物群失衡状态,失衡的微生物群衍生的代谢产物也会影响结直肠癌的发生发展。本文综述了由特定肠道微生物群代谢产物触发结直肠癌进程的方式,总结了肠道微生物群代谢产物对结直肠癌贡献的最新进展,并考虑代谢产物的积累效应以及多种代谢产物相结合的方式来预测和预防结直肠癌。     

肿瘤相关成纤维细胞在大肠癌发生发展中的研究进展

肿瘤相关成纤维细胞(Cancer-associated-fibroblasts,CAFs)是肿瘤外部微环境中最重要的细胞成分之一。CAFs可以与肿瘤细胞发生相互作用,分泌多种可溶性因子如生长因子、趋化因子等,并通过调控大肠癌进展过程中发挥关键作用的多条信号通路,参与大肠癌的增殖、侵袭、转移以及耐药等生物学过程。近年研究发现,CAFs相关标记物及基因可作为大肠癌患者预后判断的参考指标,因此,靶向CAFs有望成为大肠癌早期诊断、治疗以及预后判断的关键靶点。本文主要就CAFs的特征、募集与活化过程以及在大肠癌发生发展中的作用进行总结,以期为CAFs在大肠癌中作用机制研究及临床应用提供新的科研方向。     

人大肠癌癌旁不同部位组织生长活性与组织微环境相关细胞组分差异分析

背景与目的：肿瘤微环境已成为现今的肿瘤研究热点,而其对大肠癌启动也有重要意义。建立大肠癌癌旁组织体外培养实验体系,观察距大肠癌病灶不同距离肠上皮组织体外生长特性,并对这些不同部位肿瘤组织微环境中主要的细胞组分进行检测,研究不同部位组织体外生长特性与细胞组分间可能的相关性。方法：在距离大肠癌病灶近端手术切除取最远端(大于等于10 cm),癌旁(约2 cm)和二者中间位(约5 cm)分别取得组织样本,根据距病灶远近依次命名为1、2和3号位组织样本。通过重复贴壁法对组织块进行体外培养,观察组织的生长活性的差异。使用常规石蜡切片-HE染色方法和免疫组织化学检测3个部位中不同细胞组分标志物Cyclin D1(CD1)、CD133、细胞角蛋白(cytokeratin18,CK18)、波形蛋白(vimentin)和α平滑肌肌动蛋白(α-smooth muscle actin,α-SMA)的表达及分布情况。结果：在最靠近肿瘤病灶的3号位组织细胞生长活性最高,其爬出细胞量与速度均高于2号位和1号位,且3号位组织的生长活性与患者的肿瘤恶性分期相关。免疫组织化学检测结果表明,在1、2、3号位中,CD1、CD133、vimentin和α-SMA表达逐渐增高,而CK18表达逐渐降低。结论：在大肠癌变过程中,其组织结构和细胞组分发生了明显的变化,提示微环境的结构和成分改变可能促进肿瘤发生、发展。     

通过宏基因组学研究肠道微生物对结直肠癌患者影响的最新进展

人类肠道微生物已越来越受到医学界的广泛关注,人类肠道微生物不仅在人类健康方面,而且在人类疾病的发生和发展方面都有很大的作用。人们不断发现微生物与癌症之间的联系,特别是肠道微生物群和肠道肿瘤之间的联系。宏基因组学作为微生物研究的一种重要研究方法,在微生物与结直肠癌研究中发挥越来越重要的作用。近年来,通过宏基因组学研究肠道微生物菌群的变化为结直肠癌的发生和发展提供了新的见解,并且强调了癌症微生物群中宿主-微生物和微生物间相互作用的重要性。本综述回顾了通过宏基因组学研究肠道微生物与结直肠癌之间的关系,希望为癌症预防、诊断和治疗提供新的机会。     

Stratifying risk of recurrence in stage II colorectal cancer using deregulated stromal and epithelial microRNAs

MicroRNAs (miRNAs) enable colonic epithelial cells to acquire malignant characteristics and metastatic capabilities. Recently, cancer relevant miRNAs deregulated during disease progression have also been identified in tumor-associated stroma.By combining laser-microdissection (LMD) with high-throughput screening and high-sensitivity quantitation techniques, miRNA expression in colorectal cancer (CRC) specimens and paired normal colonic tissue was independently characterized in stromal and epithelial tissue compartments. Notably, deregulation of the key oncogene miR-21 was identified exclusively as a stromal phenomenon and miR-106a, an epithelial phenomenon in the malignant state.MiRNAs identified in this study successfully distinguished CRC from normal tissue and metastatic from non-metastatic tumor specimens. Furthermore, in a separate cohort of 50 consecutive patients with CRC, stromal miR-21 and miR-556 and epithelial miR-106a expression predicted short disease free survival (DFS) and overall survival (OS) in stage II disease: miR-21 (DFS: HR = 2.68, p = 0.015; OS: HR = 2.47, p = 0.029); miR-556 (DFS: HR = 2.60, p = 0.018); miR-106a (DFS: HR = 2.91, p = 0.008; OS: HR = 2.25, p = 0.049); combined (All High vs. All Low. DFS: HR = 5.83, p = 0.002; OS: HR = 4.13, p = 0.007).These data support the notion that stromal as well as epithelial miRNAs play important roles during disease progression, and that mapping patterns of deregulated gene expression to the appropriate tumor strata may be a valuable aid to therapeutic decision making in CRC.     

Association of Blastocystis hominis with colorectal cancer: A systematic review of in vitro and in vivo evidences

BACKGROUNDRecently, there have been several findings that showed intestinal colonisation of Blastocystis hominis (Blastocystis) as a risk factor to the worsening of colorectal cancer (CRC). However, studies have shown controversial results in the pathogenicity of Blastocystis.AIMTo review systematically the evidence available on the association between CRC and Blastocystis and the prevalence of Blastocystis in CRC patients and to investigate cytopathic and immunological effects of Blastocystis in in vitro and in vivo studies.METHODSPRISMA guidelines were utilised in conducting this systematic review. Original articles published before February 2, 2020 were included. PubMed, Science Direct, Scopus and Google scholar databases were searched. Manual searching was carried out to find articles missed during the online search.RESULTSOut of 12 studies selected for this systematic review, seven studies confirmed the prevalence of Blastocystis and found it to be between 2%-28% in CRC patients, whereby subtype 1 and subtype 3 were predominantly seen. A total of four studies employing in vitro human colorectal carcinoma cell line study models showed significant cytopathic and immunological effects of Blastocystis. In addition, one in vivo experimental animal model study showed that there was a significant effect of infection with Blastocystis on exacerbation of colorectal carcinogenesis.CONCLUSION Blastocystis is a commonly identified microorganism in CRC patients. These studies have provided supportive data that Blastocystis could exacerbate existing CRC via alteration in host immune response and increased oxidative damage. Future studies of CRC and Blastocystis should attempt to determine the various stages of CRC that are most likely to be associated with Blastocystis and its relationship with other intestinal bacteria.     

The remodeling roles of lipid metabolism in colorectal cancer cells and immune microenvironment

Lipid is a key component of plasma membrane, which plays an important role in the regulation of various cell biological behaviors, including cell proliferation, growth, differentiation and intracellular signal transduction. Studies have shown that abnormal lipid metabolism is involved in many malignant processes, including colorectal cancer (CRC). Lipid metabolism in CRC cells can be regulated not only by intracellular signals, but also by various components in the tumor microenvironment, including various cells, cytokines, DNA, RNA, and nutrients including lipids. In contrast, abnormal lipid metabolism provides energy and nutrition support for abnormal malignant growth and distal metastasis of CRC cells. In this review, we highlight the remodeling roles of lipid metabolism crosstalk between the CRC cells and the components of tumor microenvironment.     

后生元在结直肠癌防治中的应用潜能

后生元是指对宿主有益的无生命微生物及其组分的制剂,主要包括微生物本身的成分如细胞壁和胞壁肽,以及微生物代谢产生的产物。与之前的益生菌、益生元、合生元产品相比,后生元具有固定的化学结构、微生物已灭活而安全无毒的特性、更长的保质期等优点。近年来,结直肠癌的发病率增高呈现刻不容缓的态势,其与肠道微生物的关系也受到了人们的关注。在健康的肠道中,肠道微生物与宿主细胞相互作用,调节肠道的能量获取、代谢和免疫反应。当肠道微生物受到环境、病原微生物侵袭等多种因素影响时,会出现菌群失调,破坏肠道免疫,诱导结直肠癌的发生、发展。一些后生元如短链脂肪酸、胞外多糖、色氨酸代谢物等通过不同的机制展现抗癌活性,为结直肠癌的防治提供了新方向,但具体的临床可行性和治疗策略仍需进一步探究。本综述旨在通过介绍后生元的定义、分类、作用机制及其与结直肠癌的关系,结合国内外相关的最新研究进展,为后生元在结直肠癌防治中的应用提供理论依据。     

微生物群与胰腺癌

在高通量测序技术的推动下,近年来研究发现特定微生物群比例的变化与胰腺癌的发生发展有关,包括口腔中的微生物、胃肠道内菌群及胰腺内菌群等,其中口腔内牙龈卟啉单胞菌与胰腺癌风险呈正相关,这可能为胰腺癌的诊断提供新的生物学标志物。微生物群与胰腺癌的多种治疗方式密切相关,肠道菌群失调可影响化疗效果,胰腺癌内的细菌可诱导免疫耐受,合并细菌感染时可导致术后并发症发生率增多。     

Molecular insight of regorafenib treatment for colorectal cancer

Regorafenib is a multi-targeting kinase inhibitor approved for the treatment of metastatic colorectal cancer patients in refractory to standard chemotherapy. Similarly to sorafenib, this agent was originally developed as a RAF1 inhibitor. However, the kinase inhibitory profile is distinct from sorafenib. A broad-spectrum of kinase inhibition induces wide-range drug sensitivity, irrespective of mutation status of major oncogenes. This agent’s main therapeutic effects are anti-angiogenesis and the remodeling of tumor microenvironment through several mechanisms of action. The dual blockade of VEGF receptors and TIE2 can lead to both additive anti-angiogenesis effects and the suggestive unique regulation of vessel stability. Additionally, it inhibits molecular escape pathways to VEGF inhibition (e.g., FGF, PIGF, and PDGF signaling), enabling its continuous antiangiogenic effect even in tumors resistant to VEGF inhibitors. Furthermore, regorafenib has the important effect of enhancing anti-tumor immunity via macrophage modulation. Based on this concept, clinical trials have been recently launched for the development of a combination strategy with immune checkpoint inhibitors. Contrary to regorafenib induced clinical benefits and advances in the novel strategy, currently no predictive biomarkers have been identified. In the present review, we revisit and summarize regorafenib’s unique mechanisms of action. The review could highlight molecular insights and provide some perspective for the search of predictive biomarkers used in metastatic colorectal cancer patients treated with regorafenib.     

Familial adenomatous polyposis and changes in the gut microbiota: New insights into colorectal cancer carcinogenesis

Patients with familial adenomatous polyposis (FAP), an autosomal dominant hereditary colorectal cancer syndrome, have a lifetime risk of developing cancer of nearly 100%. Recent studies have pointed out that the gut microbiota could play a crucial role in the development of colorectal adenomas and the consequent progression to colorectal cancer. Some gut bacteria, such as Fusobacterium nucleatum, Escherichia coli, Clostridium difficile, Peptostreptococcus, and enterotoxigenic Bacteroides fragilis, could be implicated in colorectal carcinogenesis through different mechanisms, including the maintenance of a chronic inflammatory state, production of bioactive tumorigenic metabolites, and DNA damage. Studies using the adenomatous polyposis coli^Min/+ mouse model, which resembles FAP in most respects, have shown that specific changes in the intestinal microbial community could influence a multistep progression, the intestinal “adenoma-carcinoma sequence”, which involves mucosal barrier injury, low-grade inflammation, activation of the Wnt pathway. Therefore, modulation of gut microbiota might represent a novel therapeutic target for patients with FAP. Administration of probiotics, prebiotics, antibiotics, and nonsteroidal anti-inflammatory drugs could potentially prevent the progression of the adenoma-carcinoma sequence in FAP. The aim of this review was to summarize the best available knowledge on the role of gut microbiota in colorectal carcinogenesis in patients with FAP.     

结直肠肿瘤中长链非编码RNA的研究进展

近年来许多长链非编码RNA(lncRNA)被发现,lncRNA表达量的异常与肿瘤的发生、发展密切相关,根据其作用可以分为促进肿瘤作用lncRNA和抑制肿瘤作用lncRNA,lncRNA普遍高表达于实体肿瘤内部,是参与肿瘤侵袭、增殖和转移的重要因素,且与肿瘤预后有关。本文介绍了目前lncRNA的研究现状,着重讲述了当前研究较为透彻的几个lncRNA(如:HOTAIR、H19、MALAT-1、LincRNA-p21、GAS5等)的功能及其在结直肠肿瘤组织中的表达情况,提示调控lncRNA表达量可能为结直肠肿瘤的诊断和治疗提供新的依据。     

结直肠癌中LC3与不同表型肿瘤相关巨噬细胞的相关性及其临床意义

背景与目的：肿瘤免疫逃逸成为免疫治疗的难点,而结直肠癌中过度自噬可引起肿瘤微环境内抗原物质的增加,进而诱导抗肿瘤免疫。通过检测自噬相关因子LC3、不同表型肿瘤相关巨噬细胞（tumor-associated macrophage,TAM）及其分泌产物在结直肠癌中的表达,探讨其相关性及临床意义。方法：采用免疫组织化学EnVision法检测滨州医学院附属医院病理科及滨州市第二人民医院病理科2013年1月—2014年12月存档的结直肠癌样本中LC3、CD16、CD163、IL-1、IL-10、TNF-α、TGF-β的表达,计数CD4 ⁺ 、CD8 ⁺ 、CD20 ⁺ 淋巴细胞及CD68 ⁺ 、CD16 ⁺ 、CD163 ⁺ 巨噬细胞,并分析其与临床病理学特征及预后的相关性。结果：自噬相关因子LC3、CD16、CD163在结直肠癌组织中的表达均高于癌旁正常黏膜组织（P<0.05）。LC3与M1型TAM及其在巨噬细胞中的占比均呈正相关,而与M2型TAM及其在巨噬细胞中的占比均呈负相关（P<0.05）。LC3、M1型TAM与IL-1、TNF-α的表达及CD4 ⁺ 、CD8 ⁺ 、CD20 ⁺ 淋巴细胞的浸润量呈正相关;而M2型TAM与IL-10、TGF-β的表达呈正相关,而与CD4 ⁺ 、CD8 ⁺ 、CD20 ⁺ 淋巴细胞的浸润量呈负相关（P<0.05）。LC3、CD16、CD163与肿瘤直径、浸润深度及淋巴结转移密切相关（P<0.05）。Kaplan-Meier及COX回归模型分析显示,LC3、CD16、CD163及淋巴结转移与结直肠癌患者预后密切相关,是结直肠癌预后的独立危险因素。结论：结直肠癌中LC3的表达增加与M1型TAM极化、肿瘤进展密切相关,提示患者预后不良。结直肠癌中自噬水平的增高可诱导巨噬细胞募集并向M1型TAM极化,进而诱导免疫细胞聚集,因此调控自噬可成为诱导结直肠癌中TAM极化、增强抗肿瘤免疫的新思路。     

代谢综合征与结直肠癌的相关性研究

代谢综合征（ MS）是以胰岛素抵抗（ IR）为病理生理基础,表现为多种代谢性疾病并发的一组临床症候群,主要包括肥胖、高血糖、高血压、血脂异常、非酒精性脂肪肝等几大组分。近年多项研究表明结直肠癌（ CRC）的发生发展与MS各组分关系密切。本文就MS主要组分与CRC发病关系的研究进展做一综述。     

Telomere function in colorectal cancer

Colorectal cancer is the third most common form of cancer and the second leading cause of cancer-related death in the western world. Tumour cells acquire the hallmarks of cancer during the carcinogenic selection process. Cell immortality is one of the principal features acquired during this process which involves the stabilization of telomere length. It is achieved mainly, by telomerase activation. Thus, the discovery of telomeres and telomerase allowed an understanding of the mechanisms by which cells can become immortalized. Different studies have shown that tumour cells have shorter telomeres than nontumour cells and have detected telomerase activity in the majority of tumours. Survival studies have determined that telomere maintenance and telomerase activity are associated with poor prognosis. Taking into account all the results achieved by different groups, quantification and evaluation of telomerase activity and measurement of telomere length may be useful methods for additional biologic and prognostic staging of colorectal carcinoma.     

Screening for colorectal cancer

This review will comprise a general overview of colorectal cancer (CRC) screening. We will cover the impact of CRC, CRC risk factors, screening modalities, and guideline recommendations for screening in average-risk and high-risk individuals. Based on this data, we will summarize our approach to CRC screening.     

Synaptophysin-like 2 expression correlates with lymph node metastasis and poor prognosis in colorectal cancer patients

BACKGROUNDColorectal cancer (CRC) is one of the most common and fatal cancers worldwide. Synaptophysin-like 2 (SYPL2) is a neuroendocrine-related protein highly expressed in skeletal muscle and the tongue. The involvement of SYPL2 in CRC, including its level of expression and function, has not been evaluated.AIMTo evaluate the correlations of SYPL2 expression with lymph node metastasis (LNM) and prognosis in patients with CRC.METHODSThe levels of expression of SYPL2 in CRC and normal colorectal tissues were analyzed in multiple public and online databases. The associations between clinical variables and SYPL2 expression were evaluated statistically, and the associations between SYPL2 expression and prognosis in patients with CRC were analyzed using the Kaplan-Meier method and univariate/multivariate Cox regression analyses. SYPL2 expression was assessed in 20 paired CRC tissue and adjacent normal colorectal tissue samples obtained from Fuyang People’s Hospital, and the associations between SYPL2 expression and the clinical characteristics of these patients were investigated. Correlations between the levels of expression of SYPL2 and key targeted genes were determined by Pearson’s correlation analysis. The distribution of immune cells in these samples was calculated using the CIBERSORT algorithm. Gene set enrichment analysis (GSEA) was performed to evaluate the biofunction and pathways of SYPL2 in CRC.RESULTSSYPL2 expression was significantly lower in CRC tissue samples than in normal colorectal tissue samples (P < 0.05). High SYPL2 levels in CRC tissues correlated significantly with LNM (P < 0.05) and a poorer patient prognosis, including significantly shorter overall survival (OS) [hazard ratio (HR) = 1.9, P < 0.05] and disease-free survival (HR = 1.6, P < 0.05). High SYPL2 expression was an independent risk factor for OS in both univariate (HR = 2.078, P = 0.014) and multivariate (HR = 1.754, P = 0.018) Cox regression analyses. In addition, SYPL2 expression correlated significantly with the expression of KDR (P < 0.0001, r = 0.47) and the BRAF^V600E mutation (P < 0.05). Higher SYPL2 expression was associated with the enrichment of CD8 T-cells and M0 macrophages in the tumor microenvironment. GSEA revealed that SYPL2 was associated with the regulation of epithelial cell migration, vasculature development, pathways in cancer, and several vital tumor-related pathways.CONCLUSIONSYPL2 expression was lower in CRC tissue than in normal colorectal tissue. Higher SYPL2 expression in CRC was significantly associated with LNM and poorer survival.