肠道菌群稳态与结直肠癌研究进展

结直肠癌是一种涉及遗传、环境和生活方式等多风险因素的疾病。越来越多的研究表明肠道菌群在结直肠癌的发生发展中起重要作用,菌群与消化道之间的共生作用对维持肠道内环境的稳定也十分重要。菌群在炎症、药物代谢,甚至癌症的发展中扮演着许多角色,然而由感染、饮食或生活方式等变化引起的菌群组成的改变却可影响这种共生关系。同样,菌群组成的变化使部分菌种在肠内引发炎症反应甚至致癌,从而对结肠直肠癌的发生发展产生实质性的影响,综述将总结目前肠道菌群与结直肠癌之间潜在的联系,重点关注细菌在肠道中所参与的各种反应,从而为治疗结直肠癌提供更多的研究思路。     

Hippo-YAP信号通路在结直肠癌发生发展中的作用

结直肠癌是消化系统常见的恶性肿瘤,发生发展机制复杂。Hippo-YAP信号通路作为肿瘤抑制的一个重要信号通路,具有调节器官大小和维持细胞增殖与凋亡的动态平衡等功能。研究发现Hippo-YAP信号通路可以通过影响细胞的增殖、凋亡等从而参与结直肠癌的发生发展。本文就Hippo-YAP信号通路在结直肠癌中的作用及其机制进行综述。     

IGF-Ⅰ调节血脂异常在结直肠腺瘤发生和恶变中的作用

大量的研究表明脂类代谢异常与结直肠腺瘤的发生、复发及癌变有必然的联系,是结直肠腺瘤发生的独立风险因子.胰岛素样生长因子-Ⅰ(insulin-like growth factor-Ⅰ,IGF-Ⅰ)作为一种重要的循环内分泌多肽,参与了调节脂代谢、细胞的分化和成熟的过程,且已有众多研究证实IGF-Ⅰ在结直肠癌组织中高表达,在结直肠癌的发生及结直肠腺瘤向癌的发展过程中起重要作用.因此,本文将就IGF-Ⅰ调节血脂代谢在结直肠腺瘤发生和恶变中的作用作一综述.     

无菌鼠模型在结直肠癌研究中的应用

越来越多的证据表明,肠道微生物群的组成与结直肠癌的发生发展密切相关。无菌动物模型,尤其是无菌鼠模型简单、易获得,为研究微生物群、结直肠肿瘤及机体间的复杂关系提供了重要工具。无菌鼠模型的建立主要通过剖腹产及无菌隔离器饲养和繁育来实现。在此基础之上,可以根据特定的研究目的,建立转基因或药物诱导的特殊类型无菌鼠模型。目前,无菌鼠模型在结直肠癌研究中已经得到了广泛应用。基于无菌鼠模型的研究结果表明,微生物或微生物群可以激活免疫和诱发炎症,从而促进结直肠癌的发生发展;同时也证明,微生态失衡与结直肠癌的发生发展相辅相成、互为因果关系。由于无菌鼠模型是研究微生态失衡所致的结直肠癌及相关疾病研究重要且有效的研究载体,因此,值得进一步推广应用。     

结直肠癌中Hedgehog信号通路的研究进展

结直肠癌(colorectal cancer, CRC)是全球最常见的恶性肿瘤之一,其病因复杂且死亡率较高。结直肠癌的发展和转移涉及多个因素和机制。Hedgehog(Hh)信号在胚胎发生和体细胞发育中起重要作用。研究证明,Hh通路的异常激活与几种类型的人类肿瘤有关。然而,Hh信号传导在结直肠癌中的作用仍然是有争议的。在此综述中,我们将介绍近些年关于Hh信号及其在结直肠癌中的相关研究,讨论靶向Hh信号通路在治疗,预后和预防结直肠癌方面的潜力。     

Bcl—2家族与结直肠癌

bcl-2基因家族包括抑制细胞凋亡的基因和促进细胞凋亡的基因,其表达的蛋白在细胞凋亡：的调节中发挥重要作用。Bcl-2家族蛋白对肿瘤细胞凋亡的调节作用是当前肿瘤研究的热点之一。有关Bcl—2家族蛋白在结直肠癌方面的研究已不少。本文结合近年来国外的研究进展,对Bcl-2家族蛋白的主要结构、功能及其与结直肠癌的发生、发展、治疗、复发及预后的关系作一综述。     

结直肠癌患者中IGF2 LOI以及表达的研究

目的:结直肠癌(CRC)在全球范围内位居恶性肿瘤的第3位,是我国最为高发的恶性肿瘤之一.作为表观调控的一种,基因组印记丢失(LOI)被证明在结直肠癌的发生发展中具有重要的作用.本次研究通过检测结直肠癌患者中胰岛样生长因子2(IGF2)基因组印迹丢失,探讨其在结直肠癌发生及其发展的病理过程中的作用.方法:采用聚合酶链式反应—限制性酶切片段多态性(PCR-RFLP)法筛选出47名结直肠癌患者的杂合子携带者,采用RT-PCR及PCR-RFLP法检测杂合子患者中IGF2 LOI.采用荧光定量PCR检测肿瘤患者体内肿瘤组织中IGF2的表达情况.结果:在31例的杂合子中,发现有11例肿瘤组织发生LOI.对患者的年龄、性别、吸烟史、肿瘤等级以及病理分期的比较结果显示,IGF2 LOI的患者与IGF2基因印记正常的患者中未发现存在显著差异无统计学意义(P＞0.05).IGF2 LOI的患者相比较,IGF2印记正常的患者更易出现肿瘤的转移(P＜0.05).IGF2 LOI患者的IGF2表达量明显高于IGF2印记正常的患者(P＜0.05).结论:本次实验表明IGF2 LOI在结直肠癌发生发展中具有重要作用,特别是结直肠癌伴转移的患者常常表现出IGF2 LOI这一现象.IGF2 LOI可以作为一个新的表现遗传学标志,用于临床结直肠癌的早期诊断,以及肿瘤转移的评估和预防.     

产白介素-17T细胞在肺部细菌感染中的研究进展

目前产白介素-17(IL-17)T细胞主要包括了产IL-17 CD4+T细胞即Th17细胞、产IL-17γδT细胞和产IL-17 CD8+T细胞等。随着对Th17这一系细胞功能研究的不断深入,发现它们能通过产生IL-17和IL-22等细胞因子参与炎症反应。该文将对产IL-17 T细胞在肺部细菌感染中所起作用的最近研究进展进行综述。     

神经导向因子在肿瘤中的作用及其机制

神经导向因子Netrins作为分泌蛋白与膜结合蛋白,在神经细胞迁移、分化及凋亡等生物学过程中发挥重要的作用。自发现以来,Netrins被认为负责指导中枢神经系统组织形态的发育,随后发现它也广泛参与一些非神经组织的黏附、迁移和分化等生理过程,如血管生成、淋巴管形成和炎症等。最近的研究表明,Netrins也参与调控肿瘤的发生与发展,在结直肠癌、胰腺导管腺癌等多种肿瘤组织中发挥重要的调控作用。由于Netrins的功能多样性且通过结合不同受体在肿瘤组织中发挥不同的生物学效应,其在肿瘤中的具体作用机制尚不清楚。文中结合课题组目前的实验研究进展,阐述了近年来关于Netrins的研究,特别是在肿瘤领域取得的最新研究结果,总结了其作用机制,并对其研究及应用前景进行了展望。     

Targeting interleukin-17 enhances tumor response to immune checkpoint inhibitors in colorectal cancer

Although immune checkpoint inhibitors (ICIs) have gained much attention in managing cancer, only a minority of patients, especially those with tumors that have been classified as immunologically “cold” such as microsatellite stable (MSS) colorectal cancers (CRC), experience clinical benefit from ICIs. Surprisingly, interleukin-17 (IL-17) and its primary source Th17 are enriched in CRC and inversely associated with patient outcome. Our previous study revealed that IL-17A could upregulate programmed death-ligand 1 (PD-L1) expression and impede the efficacy of immunotherapy. IL-17, therefore, can be a possible target to sensitize tumor cells to ICIs. The detailed clinical results from our trial, which is the first to show the benefits of the combination of anti-PD-1 with anti-IL-17 therapy for MSS CRC, have also been presented. In this review, we highlight the role of IL-17 in ICIs resistance and summarize the current clinical evidence for the use of combination therapy. Directions for future strategies to warm up immunologically “cold” MSS CRCs have also been proposed.     

Genetics of colorectal cancer

Colorectal cancer (CRC) is the second leading cause of cancer-related mortality in the United States. As such, it assumes a significant role in both health policy decision-making and scientific research. CRC has been a model for investigating the molecular genetics of cancer development and progression; this is in part due to the easily detectable, sequential transition of cells from normal colonic epithelium to adenoma and then to adenocarcinoma. In addition, familial syndromes that predispose to CRC, such as familial adenomatous polyposis (FAP) and hereditary nonpolyposis colorectal cancer (HNPCC), have significantly contributed to our understanding of the genetic mechanisms underlying CRC formation. It is now well recognized that hereditary CRC syndromes are due to germline mutations of genes that function as tumor suppressors or, less frequently, oncogenes. Accumulation of subsequent mutations in other genes with related functions results in the stepwise progression to carcinoma. It is important to note that somatic changes in similar genes are involved in the formation of sporadic CRC. The identification of these important CRC-related genes may help facilitate the early diagnosis, prevention, and treatment of CRC. This article reviews the various familial CRC syndromes along with their genetic etiology, as well as discusses the principle of genetic testing for these conditions.     

Serum cytokine profile as a potential prognostic tool in colorectal cancer patients – one center study

AimComparison of 14 cytokines levels between a control group and prospectively enrolled CRC patients to confirm their significance in CRC development. We tested if a model based on 14 cytokines levels could predict prognosis in Caucasian CRC patients treated with 5-FU based chemotherapy.BackgroundNovel prognostic tools in colorectal cancer (CRC) are necessary to optimize treatment, reduce toxicity and chemotherapy (CHT) costs.Materials and MethodsWe assessed prognostic significance of 14 cytokines: IL-1 beta, IL-1RA, IL-2, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL-10, IL12p70, IL-13, IL-17A in 75 prospectively enrolled CRC patients before initiation of palliative or adjuvant CHT and in 22 control subjects. Readings were taken using the Bio-Plex 200 System. Response to treatment was assessed after 6 months from initiation of CHT. The treated group was divided depending on the response into a progressors (death, progression of disease) and non-progressors group (stable disease, partial response, complete response).ResultsWe found that increased concentration of IL-8 was a negative prognostic factor in the whole group and palliative subgroup, whereas increased level of IL-10, IL-7, and IL-12p70 was a negative predictor in the adjuvant group CHT.ConclusionsWe proposed a statistical model based on circulating cytokine levels, showing a good prognostic value in prediction of the response to CHT (AUC = 0.956). The model, including combined IL-2, IL-8, IL-10 and IL-13 levels, established in the whole treated group, should be validated in larger trials.     

Human Papillomavirus Infection Correlates with Inflammatory Stat3 Signaling Activity and IL-17 Level in Patients with Colorectal Cancer

BackgroundColorectal cancer (CRC) is a major burden of public health and healthcare worldwide. Microbiota has been suggested in promoting chronic inflammation in the intestine which, in turn, promotes tumor development. This study focuses on possible correlations of human papillomavirus (HPV) infection with proinflammatory Stat3 signaling activities and the resulting levels of its downstream proinflammatory cytokine IL-17 in CRC patients.MethodsHPV was examined using HPV Genotyping Chip technology and constitutively active Stat3 (p-Stat3) and IL-17 levels were tested using immunohistochemistry (IHC) in paraffin-embedded cancerous and adjacent normal tissues (ANT) from a cohort of 95 CRC patients. Correlation analyses were performed between HPV infection and clinicopathological characteristics, Stat3 activities and IL-17 levels among these CRC patients.ResultsThree major findings were observed: (1) HPV infection existed in a high rate of CRC cases (48.4%, 46/95), of which 45 cases (45/46, 97.8%) were high-risk HPV16-positive and only one case was HPV53-positive. (2) HPV infection correlated with poorer clinical stages (III+IV) of CRC. (3) HPV infection strongly correlated with both constitutively higher Stat3 activities (P<0.01) and higher IL-17 levels (P<0.01) only in CRC tissues but not in ANT tissues.ConclusionsHPV infection is common in CRC patients suggesting potentially preventive effectiveness of HPV vaccination among high-risk young individuals. We have for the first time revealed a tri-lateral relationship among HPV infection, constitutive Stat3 activity and IL-17 level, whose collaborative act may orchestrate a proinflammatory microenvironment in the colorectum that, in turn, may promote carcinogenesis and possibly facilitate progression of CRC.     

MicroRNA: A new player in response to therapy for colorectal cancer

Colorectal cancer (CRC) is one of the important malignancies that result in cancer-related deaths worldwide. Multiple lines of evidence have indicated that different responses to therapy in CRC cells led to the failure of the current therapies. Hence, identification of the underlying cellular and molecular pathways involved in the emergence of different responses from CRC cells could contribute to finding and designing new therapeutic platforms to overcome the present limitations. Among the various targets involved in CRC pathogenesis, microRNAs (miRNAs) have key roles in many signaling pathways that are associated with the initiation and progression of CRC. Increasing evidence has confirmed that miRNAs as epigenetic regulators could play critical roles in the response (resistance or sensitivity) to therapy. Cancer stem cells are well-known players in resistance to therapy in CRC. They have been shown to play significant roles via inhibition and activation of many miRNA networks. Hence, miRNAs could be involved in the resistance and sensitivity of therapy in CRC cells via affecting different mechanisms, such as activation of cancer stem cells. Here, we summarized the role of various miRNAs in response to therapy of CRC cells. Moreover, we highlighted the roles of these molecules in the function of cancer stem cells, which are known as important players in the resistance to therapy in CRC.     

The role of focal adhesion kinase in tumor initiation and progression

Focal adhesion kinase (FAK) is a nonreceptor tyrosine kinase that acts as a primary regulator of focal adhesion signaling to regulate cell proliferation, survival, and migration. While FAK is known to directly influence many fundamental adhesion and growth factor signaling pathways important in cancer, and FAK is overexpressed in multiple human cancers, studies addressing a causal role for FAK in tumor initiation and progression using transgenic models of human cancer had not been performed. Recently, using tissue-specific FAK-knockout in mouse models of human cancer, the consequences of FAK ablation in carcinoma were demonstrated by multiple independent research groups. Strong consensus evidence indicates that epithelial cells are able to transform in the absence of FAK, but do not undergo a malignant conversion to invasive carcinoma, and as such, metastasis is impaired. This is likely the consequence of decreased Src and p130Cas activation in concert with misregulated actin cytoskeleton dynamics and Rho GTPase signaling. Hence, FAK, as well as the FAK-regulating/regulated signaling network, are viable candidates for cancer metastasis therapies.     

ERp29 forms a feedback regulation loop with microRNA-135a-5p and promotes progression of colorectal cancer

Expression of endoplasmic reticulum (ER) stress-associated genes is often dysregulated in cancer progression. ER protein 29 (ERp29) is abnormally expressed in many neoplasms and plays an important role in tumorigenesis. Here, we showed ERp29 is a novel target for microRNA-135a-5p (miR-135a-5p) to inhibit the progression of colorectal cancer (CRC); correspondingly, ERp29 acts as an oncoprotein in CRC by promoting proliferation and metastasis of CRC cells, and suppressing apoptosis of the cells. More importantly, we found that miR-135a-5p expression is reversely upregulated by ERp29 through suppressing IL-1β-elicited methylation of miR-135a-5p promoter region, a process for enterocyte to maintain a balance between miR-135a-5p and ERp29 but dysregulated in CRC. Our study reveals a novel feedback regulation loop between miR-135a-5p and ERp29 that is critical for maintaining appropriate level of each of them, but partially imbalanced in CRC, resulting in abnormal expression of miR-135a-5p and ERp29, which further accelerates CRC progression. We provide supporting evidence for ERp29 and miR-135a-5p as potential biomarkers for diagnosis and treatment of CRC.Subject terms: Cell death, Oncogenes     

Immune cells: plastic players along colorectal cancer progression

Inflammatory cells are involved in tumour initiation and progression. In parallel, the adaptive immune response plays a key role in fighting tumour growth and dissemination. The double‐edged role of the immune system in solid tumours is well represented in colorectal cancer (CRC). The development and progression of CRC are affected by the interactions between the tumour and the host's response, occurring in a milieu named tumour microenvironment. The role of immune cells in human CRC is being unravelled and there is a strong interest in understanding their dynamics as to tumour promotion, immunosurveillance and immunoevasion. A better definition of immune infiltration would be important not only with respect to the ‘natural history’ of CRC, but in a clinically relevant perspective in the 21st century, with respect to its post‐surgical management, including chemotherapy responsiveness. While it is becoming established that the amount of tumour‐infiltrating lymphocytes influences the post‐surgical progression of early‐stage CRC, the relevance of this immune parameter as to chemotherapy responsiveness remains to be clarified. Despite recent experimental work supporting the notion that infiltrating immune cells may influence chemotherapy‐mediated tumour cell death, tumour‐infiltrating cells are not employed to identify patients who are more likely to benefit from adjuvant treatment. This review focuses on studies addressing the role of innate and adaptive immune cells along the occurrence and the progression of potentially curable CRC.