结直肠癌微卫星不稳定（MSI）与其发病及预后的关系

抑癌基因及癌基因之间的相互作用是结直肠癌发病主要发病原因,近年研究发现微卫星不稳定成为结直肠癌发病另一重要机制,尤其是遗传性非息肉病性结直肠癌（hereditary non-polyposis colorectal cancer,HNPCC）及部分散发性结直肠癌发生的重要原因。微卫星不稳定的结直肠患者具有独特的临床病理特征,如低分化、黏液腺癌、多位于右半结肠、淋巴细胞浸润明显等。化疗是结直肠癌患者手术后重要治疗手段,氟尿嘧啶类药物为结直肠癌患者化疗的基本药物,因此结直肠癌患者对于氟尿嘧啶类药物敏感性成为患者能否从化疗中获益的重要因素,也成为各位学者的研究热点。近年来有学者提出微卫星不稳定及其他分子标记物可预测结直肠癌患者化疗敏感性,同时也可成为判断预后的指标。微卫星不稳定将来可成为结直肠癌患者的预后及化疗敏感性的判断因素,也可为个体化治疗提供理论依据,但目前尚需大样本的前瞻性临床试验进一步证实。结直肠癌目前在国内外发病率均逐渐升高,成为危害人类生命的重要疾病,且遗传倾向明显,是目前人类恶性肿瘤中遗传变化最明显的肿瘤。对于结直肠癌的发病研究表明,染色体不稳定（chromosome instability）为结直肠癌发病的主要原因,其机制仍未完全阐明。近年的研究发现微卫星不稳定（microsatelite instability）为结直肠癌发病的另一重要机制,是遗传性非息肉病性结直肠癌（heredi? tary non-polyposis colorectal cancer,HNPCC）及部分散发性结直肠癌发生的重要原因。目前关于微卫星不稳定的研究不仅于发病机制上,与结直肠癌预后的关系也成为目前研究的热点。      

结直肠癌差异表达及预后相关基因分析

目的:结直肠癌是发病率和病死率较高的消化系统恶性肿瘤,但结直肠癌发病的分子机制尚不明确.本研究基于生物信息学分析鉴定结直肠癌的关键基因、信号通路及预后相关基因,以更好地了解结直肠癌的分子机制,为结直肠癌的诊断、预后评估和治疗提供有价值的分子标志物.方法:从GEO数据库下载结直肠癌基因芯片数据集,分析筛选出差异表达基因(...     

结直肠癌分子分型临床研究进展

结直肠癌是生物学高度异质性的肿瘤,染色体不稳定性(chromosomal instahility,CIN)、微卫星不稳定(microsatel liteinstability,MSI)、通过CpG岛甲基化的表基因沉默(epigenetic sileneing through the CpG Island Methylator phenotype,CIMP)是目前临床预测、预后和指导治疗的重要分子机制。随着分子生物学技术的不断进步,可以根据CIN,MSI,CIMP在遗传学和表遗传学中的表达状态将CRC分6个亚群,即MSI-H,CIMP-H;MSI-H,CIMP-Low/0;MSI-L/MSS,CIMP-H;MSI-L,CIMP-Low;MSS,CIMP-Low;MSI-L/MSS,CIMP-0,它们在临床、病理、分子特征、治疗反应和生存期都有所不同。因此,对结直肠癌进行分子分型有利于判断患者的临床预后和指导临床治疗。文章就以上问题进行了综述。     

结直肠癌肝转移机制研究现状

结直肠癌肝转移是一个多步骤、多基因参与的复杂过程,其具体的细胞和分子机制仍不清楚。为此,本文总结近年来国内外相关文献,综述结直肠癌肝转移机制及其进展。     

MicroRNA-21在结直肠癌中的研究进展

结直肠癌是我国常见的消化系统恶性肿瘤之一。目前认为结直肠癌的形成是一个多因素、多步骤的过程,其具体的发病机制尚不清楚。microRNA（miRNA）是一类非编码的小分子RNA,能在转录后水平调控基因蛋白的表达,参与肿瘤细胞增殖、分化、侵袭和转移,对结直肠癌的发生和发展具有重要的作用。miRNA-21是当前研究miRNA在结直肠癌发病机制的热点之一,本文就miR-21在结直肠癌中的研究进展作一综述。      

钙-基因与结直肠腺瘤发病风险关联的研究进展

结直肠癌是胃肠道中常见的恶性肿瘤,近几年,结直肠癌的发病率和死亡率保持着上升趋势,居高不下。而结直肠腺瘤是结直肠癌最重要的癌前病变,其发病机制对于结直肠癌早期诊疗至关重要。结直肠腺瘤的发病机制较为复杂,一般涉及多个基因的相互作用和信号通路。且钙剂与结直肠腺瘤的关联研究在近年来也引起广泛关注。因此,本文对钙与基因的相互作用和结直肠腺瘤发病风险的关系进行综述,为结直肠癌的早期筛查、诊断和早期治疗提供参考。      

结直肠癌的微卫星不稳定与染色体不稳定

结直肠癌中存在微卫星不稳定（MSI）和染色体不稳定（CIN）。微卫星不稳定指微卫星序列中重复单位的获得或丢失，多由于DNA错配修复系统改变所致。染色体不稳定包括整条染色体的获得或缺失，染色体易位、重排等，结直肠癌中常见有1p和8p的删除、17p和18q的杂合性缺失以及20q的扩增。两种类型的结直肠癌具有不同的临床病理特征，在基因表达、疗效和预后等方面的差异性有待进一步研究。     

微卫星不稳定在结直肠癌预后及治疗指导中的研究进展

微卫星不稳定是基因组不稳定的表现之一,其在结直肠癌、乳癌、肺癌以及淋巴瘤等多种恶性肿瘤中均有存在,并且对肿瘤的发生、发展以及预后转归起到关键作用。近年来,国内外学者对微卫星不稳定的相关研究取得了显著成果,尤其在结直肠癌领域,其对结直肠癌免疫治疗和化学治疗的指导性意见已被纳入诊疗指南,并且成为该病治疗以及预后指导上的重要分子指标。本文就此总结国内外相关研究进展,以期为后续研究工作提供指导。     

早发性结直肠癌的研究进展

早发性结直肠癌(EO-CRC)近年来发病率持续上升,目前发病机制尚不清楚,其在流行病学、危险因素、临床特征等方面有别于结直肠癌,但治疗上往往采用结直肠癌的治法,临床缺少针对早发性结直肠癌的诊治方案。文章总结了早发性结直肠癌的流行病学特点、危险因素、临床特征、分子遗传学表征、治疗及预防策略,为临床早发性结直肠癌诊治提供理论依据。     

结直肠癌发生的基因机制研究进展

结直肠癌是常见的消化道恶性肿瘤,在我国发病呈上升趋势。近十余年,有很多关于结直肠癌相关基因和基因机制的研究报道。随着研究的进展和很多新的相关基因的出现,对结直肠癌的基因机制认识不断完善。本文对结直肠癌的分类、相关基因以及发病机制作简要综述。     

Molecular therapy of colorectal cancer: Progress and future directions

Colorectal cancer (CRC) remains one of the most common types of cancer and leading causes of cancer death worldwide. Although the introduction of cytotoxic drugs such as oxaliplatin, irinotecan and fluorouracil has improved the treatment of advanced CRC, the individual response to chemoradiotherapy varies tremendously from one patient to another. However, recent progress in CRC molecular therapies may provide new insight into the treatment of this disease. Currently, components of the EGFR, VEGF, Wnt and NF‐kB pathways are the most important targets for CRC therapy. This review chronicles the development of molecular CRC therapies over the past few decades. We also provide an update on the current progress of research concerning the molecular pathways leading to CRC and discuss the possible implications for CRC therapy.     

Multiple primary colorectal cancer: Individual or familial predisposition?

Colorectal carcinoma (CRC) is one of the most frequent cancers. Along the surface of the large bowel, several foci of CRC may appear simultaneously or over the time. The development of at least two different tumours has been defined as multiple primary CRC (MPCRC): When more than one tumour is diagnosed at the same time, it is known as synchronous CRC (SCRC), while when a second neoplasm is diagnosed some time after the resection and/or diagnosis of the first lesion, it is called metachronous CRC (MCRC). Multiple issues can promote the development of MPCRC, ranging from different personal factors, such as environmental exposure, to familial predisposition due to hereditary factors. However, most studies do not distinguish this dichotomy. High- and low-pentrance genetic variants are involved in MPCRC. An increased risk for MPCRC has been described in Lynch syndrome, familial adenomatous polyposis, and serrated polyposis. Non-syndromic familial CRCs should also be considered as risk factors for MPCRC. Environmental factors can promote damage to colon mucosae that enable the concurrence of MPCRC. Epigenetics are thought to play a major role in the carcinogenesis of sporadic MPCRC. The methylation state of the DNA depends on multiple environmental factors (e.g., smoking and eating foods cooked at high temperatures), and this can contribute to increasing the MPCRC rate. Certain clinical features may also suggest individual predisposition for MPCRC. Different etiopathogenic factors are suspected to be involved in SCRC and MCRC, and different familial vs individual factors may be implicated. MCRC seems to follow a familial pattern, whereas individual factors are more important in SCRC. Further studies must be carried out to know the molecular basis of risks for MPCRC in order to modify, if necessary, its clinical management, especially from a preventive point of view.     

Fibroblast Growth Factor Receptor-2 IIIc as a Novel Molecular Target in Colorectal Cancer

The prognosis of patients with colorectal carcinoma (CRC) is unfavorable once the disease has progressed to an unresectable stage. A high percentage of CRCs overexpress a number of growth factors and their receptors, including fibroblast growth factor receptor (FGFR). Expression of FGFR-2 IIIc, a splicing isoform of FGFR-2, correlated with distant metastasis and poor prognosis in CRC cases. FGFR-2 IIIc-transfected CRC cells showed increased cell growth, soft agar colony formation, migration, and invasion, as well as decreased adhesion to extracellular matrices. The administration of humanized anti-FGFR-2 IIIc monoclonal antibody inhibited CRC cell growth and migration. FGFR-2 IIIc might contribute to the aggressive growth of certain cancers, including CRC, and is a novel candidate for molecular targeted cancer therapies. In this article, we summarize the recent development of standardized treatments and molecular targeted therapies for CRC, with a focus on FGFR-2 IIIc.     

The Src Family of Protein Tyrosine Kinases: A New and Promising Target for Colorectal Cancer Therapy

Aberrant activation of the Src family of tyrosine kinases has been implicated in the development and progression of colorectal cancer (CRC). As a result, Src inhibitors are now being studied as possible therapeutic agents to treat metastatic disease. In this review, we discuss the effects of aberrant Src activation in CRC, Src as a target of single-agent drug therapy, and Src as a target of combination therapy with epidermal growth factor receptor inhibition and cytotoxic chemotherapy. The greatest potential for clinically relevant benefit most likely lies in combination regimens. Further evaluation with biomarkers will continue to define the molecular phenotype of patients with CRC who will benefit the most from Src-based therapy.     

The Role of the Insulin-like Growth Factor-1 Receptor (IGF-1R), Phosphatase and Tensin Homolog (PTEN), c-Met, and the PI3-Kinase Pathway in Colorectal Cancer

Colorectal cancer (CRC) is the second-leading cause of cancer deaths in the US and the third most common cancer malignancy annually. Overall prognosis of metastatic CRC is still poor, with five-year survival within 5?C8?%. Previous molecular studies of CRC established several key events in CRC disease progression, including APC inactivation, ??-catenin activation, and activating KRAS and BRAF mutations. More recent development of molecular therapeutics has led to the current use of anti-EGFR monoclonal antibody in targeted therapy of advanced CRC. Also, high-throughput cancer genome mutational analysis and newer second-generation cancer genome sequencing have, in recent years, resulted in a deeper understanding of the genome and of regulation of CRC. Most importantly, improved understanding of the involvement of many of the novel molecular targets in CRC tumorigenesis and tumor progression would engender the development of novel targeted therapeutics to treat the disease. Moreover, studies in molecular determinants of predictive and prognostic biomarkers of targeted therapy would further enable better strategies for the use of targeted therapeutics in preventing or overcoming treatment resistance. In this review, we focus on recent findings and their clinical relevance to actionable molecular targets??insulin-like growth factor-1 receptor (IGF-1R), phosphatase and tensin homolog (PTEN), c-Met and phosphatidylinositol 3-OH kinase (PI3-K)??in CRC personalized cancer therapeutics.     

Focus on genetic and epigenetic events of colorectal cancer pathogenesis: implications for molecular diagnosis

Originally, colorectal cancer (CRC) tumorigenesis was understood as a multistep process that involved accumulation of tumor suppressor genes and oncogenes mutations, such as APC, TP53 and KRAS. However, this assumption proposed a relatively limited repertoire of genetic alterations. In the last decade, there have been major advances in knowledge of multiple molecular pathways involved in CRC pathogenesis, particularly regarding cytogenetic and epigenetic events. Microsatellite instability, chromosomal instability and CpG island methylator phenotype are the most analyzed cytogenetic changes, while DNA methylation, modifications in histone proteins and microRNAs (miRNAs) were analyzed in the field of epigenetic alterations. Therefore, CRC development results from interactions at many levels between genetic and epigenetic amendments. Furthermore, hereditary cancer syndrome and individual or environmental risk factors should not be ignored. The difficulties in this setting are addressed to understand the molecular basis of individual susceptibility to CRC and to determine the roles of genetic and epigenetic alterations, in order to yield more effective prevention strategies in CRC patients and directing their treatment. This review summarizes the most investigated biomolecular pathways involved in CRC pathogenesis, their role as biomarkers for early CRC diagnosis and their possible use to stratify susceptible patients into appropriate screening or surveillance programs.     

Exosomes in metastasis of colorectal cancers: Friends or foes?

Colorectal cancer (CRC), the third most common type of cancer worldwide, threaten human health and quality of life. With multidisciplinary, including surgery, chemotherapy and/or radiotherapy, patients with an early diagnosis of CRC can have a good prognosis. However, metastasis in CRC patients is the main risk factor causing cancer-related death. To elucidate the underlying molecular mechanisms of CRC metastasis is the difficult and research focus on the investigation of the CRC mechanism. On the other hand, the tumor microenvironment (TME) has been confirmed as having an essential role in the tumorigenesis and metastasis of malignancies, including CRCs. Among the different factors in the TME, exosomes as extracellular vesicles, function as bridges in the communication between cancer cells and different components of the TME to promote the progression and metastasis of CRC. MicroRNAs packaged in exosomes can be derived from different sources and transported into the TME to perform oncogenic or tumor-suppressor roles accordingly. This article focuses on CRC exosomes and illustrates their role in regulating the metastasis of CRC, especially through the packaging of miRNAs, to evoke exosomes as novel biomarkers for their impact on the metastasis of CRC progression.     

The implications of colorectal cancer molecular biology in clinical practice

Colorectal cancer (CRC) is the third most common malignancy in the United States. Advances in molecular biology have enhanced the understanding of colorectal carcinogenesis. Approximately 75% of CRCs are sporadic; the rest are hereditary or belong to a familial syndrome. Identification of familial forms of CRC have enabled the development of several models of carcinogenesis and made CRC a well-studied malignancy in terms of molecular pathogenesis. Pathways containing multiple mutations and genetic alterations that play a role in hereditary CRC pathogenesis have been elucidated. Many of the molecular changes seen in these pathways also are involved in the development of sporadic cancers.     

Promising targets and drugs in development for colorectal cancer

Colorectal cancer (CRC) is one of the most common cancers and causes of cancer death in the world despite incremental improvement in the treatment of this disease. Advancements in the molecular understanding of CRC have led to new areas of therapeutic research. In this endeavor, numerous compounds with specific molecular targets are being developed in preclinical and early clinical studies. Molecular pathways involved in CRC and potentially effective targeted agents in development will be reviewed.     

First-line use of anti-epidermal growth factor receptor monoclonal antibodies in metastatic colorectal cancer

Several molecular pathways have been shown to play key roles in the development and progression of colorectal cancer (CRC). This enhanced understanding of tumor biology has provided the rationale for the design and development of novel agents that are directed against important targets, including growth factors, receptors, and tumor-specific/tumor-selective antigens. The epidermal growth factor receptor (EGFR) signaling pathway has received much attention over the past 5-10 years because it is overexpressed in more than 85% of tumors from patients with metastatic CRC. Cetuximab and panitumumab are monoclonal antibodies presently approved for use by the FDA in the refractory disease setting, and they have provided significant advances in the treatment of advanced CRC. However, much focus has shifted toward using these biologic therapies in combination with cytotoxic chemotherapy in up-front settings, such as first-line therapy and in the neoadjuvant therapy of liver-limited disease. The clinical studies conducted to date suggest that cetuximab can be safely and effectively combined with oxaliplatin- and irinotecan-based chemotherapy in the first-line treatment of metastatic CRC. Moreover, the results of the CRYSTAL phase III study provide support for the use of the combination of FOLFIRI (5-fluorouracil/leucovorin/irinotecan) and cetuximab in the neoadjuvant setting and allow for R0 surgical resection with curative intent. Much work continues to investigate the critical molecular biomarkers that can be used to predict clinical response to chemotherapy and/or targeted therapies as well as to identify which patients might be at increased risk for developing drug-specific side effects.