New insights into molecular pathways in colorectal cancer: Adiponectin,interleukin-6 and opioid signaling

Colorectal cancer (CRC) is one of the most common cause of death among neoplasms around the world. The environmental factors, like diet and obesity, are crucial in CRC pathogenesis by creating cancer-favorable microenvironment and hormonal changes. Adiponectin, the adipose tissue-specific hormone, is generally considered to negatively correlate with CRC development. The interleukin 6 (IL-6) is one of the most important pro-inflammatory cytokine connected with CRC, which is strongly inflammation-associated. The opioids are variable group substantially correlated with cancers - the endogenous opioids affect immune system and cell cycle including proliferation and cell death whereas exogenous opioids are leading clinically used analgesics in terminal cancer patients. In this review we discuss the involvement of adiponectin, IL-6 and opioids in CRC pathogenesis, their link with obesity, possible cross-talk and potential novel therapeutic approach in CRC treatment.     

Role of obesity-associated dysfunctional adipose tissue in cancer: a molecular nutrition approach

Obesity is a complex disease caused by the interaction of a myriad of genetic, dietary, lifestyle and environmental factors, which favors a chronic positive energy balance, leading to increased body fat mass. There is emerging evidence of a strong association between obesity and an increased risk of cancer. However, the mechanisms linking both diseases are not fully understood. Here, we analyze the current knowledge about the potential contribution that expanding adipose tissue in obesity could make to the development of cancer via dysregulated secretion of pro-inflammatory cytokines, chemokines and adipokines such as TNF-α, IL-6, leptin, adiponectin, visfatin and PAI-1. Dietary factors play an important role in the risk of suffering obesity and cancer. The identification of bioactive dietary factors or substances that affect some of the components of energy balance to prevent/reduce weight gain as well as cancer is a promising avenue of research. This article reviews the beneficial effects of some bioactive food molecules (n-3 PUFA, CLA, resveratrol and lipoic acid) in energy metabolism and cancer, focusing on the molecular mechanisms involved, which may provide new therapeutic targets in obesity and cancer.     

The intestinal microbiota, gastrointestinal environment and colorectal cancer: a putative role for probiotics in prevention of colorectal cancer?

Colorectal cancer (CRC) is the third most commonly diagnosed cancer in the United States, and, even though 5-15% of the total CRC cases can be attributed to individual genetic predisposition, environmental factors could be considered major factors in susceptibility to CRC. Lifestyle factors increasing the risks of CRC include elevated body mass index, obesity, and reduced physical activity. Additionally, a number of dietary elements have been associated with higher or lower incidence of CRC. In this context, it has been suggested that diets high in fruit and low in meat might have a protective effect, reducing the incidence of colorectal adenomas by modulating the composition of the normal nonpathogenic commensal microbiota. In addition, it has been demonstrated that changes in abundance of taxonomic groups have a profound impact on the gastrointestinal physiology, and an increasing number of studies are proposing that the microbiota mediates the generation of dietary factors triggering colon cancer. High-throughput sequencing and molecular taxonomic technologies are rapidly filling the knowledge gaps left by conventional microbiology techniques to obtain a comprehensive catalog of the human intestinal microbiota and their associated metabolic repertoire. The information provided by these studies will be essential to identify agents capable of modulating the massive amount of gut bacteria in safe noninvasive manners to prevent CRC. Probiotics, defined as "live microorganisms which, when administered in adequate amounts, confer a health benefit on the host" (219), are capable of transient modulation of the microbiota, and their beneficial effects include reinforcement of the natural defense mechanisms and protection against gastrointestinal disorders. Probiotics have been successfully used to manage infant diarrhea, food allergies, and inflammatory bowel disease; hence, the purpose of this review was to examine probiotic metabolic activities that may have an effect on the prevention of CRC by scavenging toxic compounds or preventing their generation in situ. Additionally, a brief consideration is given to safety evaluation and production methods in the context of probiotics efficacy.     

Diet and cancer prevention: Dietary compounds,dietary MicroRNAs,and dietary exosomes

Cancer is one of main health public problems worldwide. Several factors are involved in beginning and development of cancer. Genetic and internal/external environmental factors can be as important agents that effect on emerging and development of several cancers. Diet and nutrition may be as one of important factors in prevention or treatment of various cancers. A large number studies indicated that suitable dietary patterns may help to cancer prevention or could inhibit development of tumor in cancer patients. Moreover, a large numbers studies indicated that a variety of dietary compounds such as curcumin, green tea, folat, selenium, and soy isoflavones show a wide range anti‐cancer properties. It has been showed that these compounds via targeting a sequence of cellular and molecular pathways could be used as suitable options for cancer chemoprevention and cancer therapy. Recently, dietary microRNAs and exosomes have been emerged as attractive players in cancer prevention and cancer therapy. These molecules could change behavior of cancer cells via targeting various cellular and molecular pathways involved in cancer pathogenesis. Hence, the utilization of dietary compounds which are associated with powerful molecules such as microRNAs and exosomes and put them in dietary patterns could contribute to prevention or treatment of various cancers. Here, we summarized various studies that assessed effect of dietary patterns on cancer prevention shortly. Moreover, we highlighted the utilization of dietary compounds, dietary microRNAs, and dietary exosomes and their cellular and molecular pathways in cancer chemoprevention.     

The role of exosomes in colorectal cancer disease progression and response to therapy

Colorectal cancer (CRC) is the second leading cause of cancer mortality in both men and women worldwide. Survival of patients is significantly associated with disease stage at diagnosis. Recent studies highlighted a role of exosomes in CRC development and progression, thus raising the interest on these nanosized vesicular structures as possible biomarkers. Exosomes contain a large variety of molecules, including proteins, lipids and nucleic acids, that are exchanged between cells either within tumor microenvironment or at distant sites from the primary tumor, where they prepare a suitable soil for tumor metastases. The present review summarizes the principal effects of exosomes on CRC development, progression, and provides an update of the most recent findings on the use of exosomal molecules as diagnostic, prognostic and predictive biomarkers in CRC.     

A genome-wide association study on copy-number variation identifies a 11q11 loss as a candidate susceptibility variant for colorectal cancer

Colorectal cancer (CRC) is a complex disease, and therefore its development is determined by the combination of both environmental factors and genetic variants. Although genome-wide association studies (GWAS) of SNP variation have conveniently identified 20 genetic variants so far, a significant proportion of the observed heritability is yet to be explained. Common copy-number variants (CNVs) are one of the most important genomic sources of variability, and hence a potential source to explain part of this missing genetic fraction. Therefore, we have performed a GWAS on CNVs to explore the relationship between common structural variation and CRC development. Phase 1 of the GWAS consisted of 881 cases and 667 controls from a Spanish cohort. Copy-number status was validated by quantitative PCR for each of those common CNVs potentially associated with CRC in phase I. Subsequently, SNPs were chosen as proxies for the validated CNVs for phase II replication (1,342 Spanish cases and 1,874 Spanish controls). Four common CNVs were found to be associated with CRC and were further replicated in Phase II. Finally, we found that SNP rs1944682, tagging a 11q11 CNV, was nominally associated with CRC susceptibility (p value = 0.039; OR = 1.122). This locus has been previously related to extreme obesity phenotypes, which could suggest a relationship between body weight and CRC susceptibility.     

New frontiers in the treatment of colorectal cancer: Autophagy and the unfolded protein response as promising targets

Colorectal cancer (CRC), despite numerous therapeutic and screening attempts, still remains a major life-threatening malignancy. CRC etiology entails both genetic and environmental factors. Macroautophagy/autophagy and the unfolded protein response (UPR) are fundamental mechanisms involved in the regulation of cellular responses to environmental and genetic stresses. Both pathways are interconnected and regulate cellular responses to apoptotic stimuli. In this review, we address the epidemiology and risk factors of CRC, including genetic mutations leading to the occurrence of the disease. Next, we discuss mutations of genes related to autophagy and the UPR in CRC. Then, we discuss how autophagy and the UPR are involved in the regulation of CRC and how they associate with obesity and inflammatory responses in CRC. Finally, we provide perspectives for the modulation of autophagy and the UPR as new therapeutic options for CRC treatment.     

Gut bacteria in health and disease: a survey on the interface between intestinal microbiology and colorectal cancer

A healthy human body contains at least tenfold more bacterial cells than human cells and the most abundant and diverse microbial community resides in the intestinal tract. Intestinal health is not only maintained by the human intestine itself and by dietary factors, but is also largely supported by this resident microbial community. Conversely, however, a large body of evidence supports a relationship between bacteria, bacterial activities and human colorectal cancer. Symbiosis in this multifaceted organ is thus crucial to maintain a healthy balance within the host-diet-microbiota triangle and accordingly, changes in any of these three factors may drive a healthy situation into a state of disease. In this review, the factors that sustain health or drive this complex intestinal system into dysbiosis are discussed. Emphasis is on the role of the intestinal microbiota and related mechanisms that can drive the initiation and progression of sporadic colorectal cancer (CRC). These mechanisms comprise the induction of pro-inflammatory and pro-carcinogenic pathways in epithelial cells as well as the production of (geno)toxins and the conversion of pro-carcinogenic dietary factors into carcinogens. A thorough understanding of these processes will provide leads for future research and may ultimately aid in development of new strategies for CRC diagnosis and prevention.     

肠道微生物与结直肠癌

结直肠癌(colorectal cancer, CRC)是最常见的恶性肿瘤之一,严重威胁着人类健康。肠道微生态作为人体内最复杂、最庞大的微生态系统,与CRC密切相关。CRC患者的肠道微生物群落多样性构成能调节CRC疾病的发生与发展。本综述旨在讨论CRC肠道微生物群的构成、微生物群相关致癌机制、微生物群作为CRC生物标志物的潜力,为临床应用肠道菌群治疗CRC提供新策略与新思路。     

Urolithin A induces cell cycle arrest and apoptosis by inhibiting Bcl-2, increasing p53-p21 proteins and reactive oxygen species production in colorectal cancer cells

Colorectal cancer (CRC) is the second most common gastrointestinal cancer globally. Prevention of tumor cell proliferation and metastasis is vital for prolonging patient survival. Polyphenols provide a wide range of health benefits and prevention from cancer. In the gut, urolithins are the major metabolites of polyphenols. The objective of our study was to elucidate the molecular mechanism of the anticancer effect of urolithin A (UA) on colorectal cancer cells. UA was found to inhibit the cell proliferation of CRC cell lines in a dose-dependent and time-dependent manner in HT29, SW480, and SW620 cells. Exposure to UA resulted in cell cycle arrest in a dose-dependent manner along with alteration in the expression of cell cycle–related protein. Treatment of CRC cell lines with UA resulted in the induction of apoptosis. Treatment of HT29, SW480, and SW620 with UA resulted in increased expression of the pro-apoptotic proteins, p53 and p21. Similarly, UA treatment inhibited the anti-apoptotic protein expression of Bcl-2. Moreover, exposure of UA induced cytochrome c release and caspase activation. Furthermore, UA was found to generate reactive oxygen species (ROS) production in CRC cells. These findings indicate that UA possesses anticancer potential and may be used therapeutically for the treatment of CRC.Supplementary InformationThe online version contains supplementary material available at 10.1007/s12192-020-01189-8.     

Colorectal cancer: Metabolic interactions reshape the tumor microenvironment

Colorectal cancer (CRC) is one of the most common cancers worldwide, which ranks third in terms of incidence and the second leading cause of cancer-related mortality. Metabolic reprogramming within the tumor microenvironment (TME) has been proved intimately involved in the initiation and malignant progression of CRC. Signal messengers, including cytokines, metabolites, and exosomes among others, derived from cancer cells can be utilized by the surrounding cells within the TME to induce metabolic alteration and cancer-associated transformation. In turn, the cargos secreted from cancer-associate cells further provide the nutrition and energy supply for cancer cells, supporting their metabolic reprogramming to promote proliferation, migration, metastasis, and radiochemoresistance.In this review, we focus on the main cellular components in the TME: CAFs, TAMs, lymphocytes and neutrophils, and enumerate and integrate how the metabolic interactions between these components and cancer cells reshape TME to foster CRC malignancy.     

Nanoencapsulation of polyphenols for protective effect against colon–rectal cancer

The human population at large is exposed to many critical factors (e.g. bad food habits, chemical substances, and stress) leading to the development of serious diseases. Colon or colorectal cancer is one of the most prevalent types of cancer in many countries. Despite being a multi-factorial chronic disease, resulting from the interaction of multiple genetic and environmental factors, the critical factor is mostly a poor diet regimen. Therefore, an accumulation of constant mutations leads to a complex arrangement of events during tumor initiation, development and propagation. It is well known that many plants are rich in polyphenols with anti-oxidant, anti-atherogenic, anti-diabetic, anti-cancer, anti-viral, and anti-inflammatory properties. These compounds are secondary metabolites with the ability to donate electrons to free radicals through different mechanisms. In recent years, a large number of studies have attributed a protective effect to polyphenols and foods containing these compounds (e.g. plants, vegetables, cereals, tea, coffee or chocolate). Polyphenolic compounds have been described to inhibit cancer development and propagation, being used as chemopreventive agents. Some polyphenols reported a preventive action against colon cancer, e.g. curcumin, gallic acid, ellagic acid, and epigallocatechin-3-gallate. The present article focuses on the properties of these molecules as chemopreventive agents and the recent advances on their formulation in nanoparticulate systems for targeted therapy and increased bioavailability.     

Comprehensive analysis of lncRNA-associated ceRNA network in colorectal cancer

Colorectal cancer (CRC) is one of the most common malignancies and morbidity and mortality are increasing rapidly. Increasing evidence showed the close correlation between aberrant expression of certain RNAs and the occurrence and development of CRC. However, comprehensive analyses of differentially expressed profiles of linRNA in CRC based on large sample size have been lacking. In the present study, based on RNA-seq data obtained from the TCGA (The Cancer Genome Atlas) database, we identified 1176 lncRNAs, 245 miRNAs and 2083 mRNAs whichaberrantly expressed in the colorectal cancer tissues compared with the adjacent non-tumorous tissues. A Kaplan-Meier curve analysis was used to study the overall survival rate of the three RNA-related CRC patients. After constructing the ceRNA network, we performed the KEGG enrichment pathway analysis on ceRNA-related differentially expressed mRNAs and found that these mRNAs were remarkably enriched in the pathways associated with CRC. Combining the differentially expressed lncRNAs with clinical pathological variables of CRC patients, we also found that LINC00400 and LINC00355 not only contribute to the regulation of ceRNA network, but also show significantchanges in its expression in multiple CRC pathological stages, indicating that LINC00400 and LINC00355 can be considered as promising therapeutic targets for CRC.     

The NOTCH4-GATA4-IRG1 axis as a novel target in early-onset colorectal cancer

The early onset of colorectal cancer (CRC) in individuals younger than 50 years is an emerging phenomenon, and obesity is a strong risk factor. Inflammatory mechanisms are mediated by immune cells, with macrophages and their phenotypical changes playing a significant role in CRC. Obesity-related hormones, such as leptin and adiponectin, affect macrophage polarization and cytokine expression. Macrophage metabolism, and therefore polarization, directly affects tumor progression and survival in patients with CRC. Altered obesity-related hormone levels induce phosphoinositide kinase-3 (PI3K)/serine-threonine-protein kinase (AKT) activation in colon cancer, causing increased cell survival, hyperplasia, and proliferation. Investigating the effects of obesity-related mechanisms on PI3K/Akt signaling can provide new insights for targeting mechanisms in CRC and obesity among the young. Central molecules for the control of cell proliferation, differentiation, and tumorigenesis within the gastrointestinal tract include downstream targets of the PI3K/AKT pathway, such as Neurogenic locus notch homolog 4 (Notch4) and GATA binding proteins (GATA). Leptin and adiponectin both alter gene expression within this pathway, thereby affecting TAM-mediated CRC progression. Our goal is to introduce the NOTCH4-GATA4-IRG1 axis as a link between inflammation and sporadic CRC and to discuss this pathway as a new potential immunotherapeutic target in individuals affected with obesity and early-onset CRC.     

Therapeutic potential of melatonin in colorectal cancer: Focus on lipid metabolism and gut microbiota

Colorectal cancer (CRC) is one of the most common gastrointestinal malignancies. The occurrence and development of CRC are complicated processes. Obesity and dysbacteriosis have been increasingly regarded as the main risk factors for CRC. Understanding the etiology of CRC from multiple perspectives is conducive to screening for some potential drugs or new treatment strategies to limit the serious side effects of conventional treatment and prolong the survival of CRC patients. Melatonin, a natural indoleamine, is mainly produced by the pineal gland, but it is also abundant in other tissues, including the gastrointestinal tract, retina, testes, lymphocytes, and Harder's glands. Melatonin could participate in lipid metabolism by regulating adipogenesis and lipolysis. Additionally, many studies have focused on the potential beneficial effects of melatonin in CRC, such as promotion of apoptosis; inhibition of cell proliferation, migration, and invasion; antioxidant activity; and immune regulation. Meaningfully, gut microbiota is the main determinant of all aspects of health and disease (including obesity and tumorigenesis). The gut microbiota is of great significance for understanding the relationship between obesity and increased risk of CRC. Although the current understanding of how the melatonin-mediated gut microbiota coordinates a variety of physiological and pathological activities is fairly comprehensive, there are still many unknown topics to be explored in the face of a complex nutritional status and a changeable microbiota. This review summarizes the potential links among melatonin, lipid metabolism, gut microbiota, and CRC to promote the development of melatonin as a preventive and therapeutic agent for CRC.     

Identification of metastasis-associated exoDEPs in colorectal cancer using label-free proteomics

Exosomes are secreted nanovesicles consisting of biochemical molecules, including proteins, RNAs, lipids, and metabolites that play a prominent role in tumor progression. In this study, we performed a label-free proteomic analysis of exosomes from a pair of homologous human colorectal cancer cell line with different metastatic abilities. A total of 115 exoDEPs were identified, with 31 proteins upregulated and 84 proteins downregulated in SW620 exosome. We also detected 30 proteins expressed only in SW620 exosomes and 60 proteins expressed only in SW480 exosomes. Bioinformatics analysis enriched the components and pathways associated with the extracellular matrix, cytoskeleton-related pathways, and immune system changes of colorectal cancer (CRC). Cellular function experiments confirmed the role of SW620 exosomes in promoting the proliferation, migration, and invasion of SW480 cells. Further verifications were performed on six upregulated exoDEPs (FGFBP1, SIPA1, THBS1, TGFBI, COL6A1, and RPL10), three downregulated exoDEPs (SLC2A3, MYO1D, and RBP1), and three exoDEPs (SMOC2, GLG1, and CEMIP) expressed only in SW620 by WB and IHC. This study provides a complete and novel basis for exploring new drug targets to inhibit the invasion and metastasis of CRC.     

后GWAS时代结直肠癌致病SNP功能机制的研究进展

结直肠癌(colorectal cancer, CRC)是受遗传与环境因素共同影响的复杂疾病,其中遗传因素发挥重要作用。至今,全基因组关联研究(genome-wide association studies, GWAS)已经发现了大量与结直肠癌风险相关的遗传变异。随之而来的后GWAS时代,越来越多的研究侧重于利用多组学数据和功能实验对潜在的致病位点进行解析。分析表明绝大多数风险单核苷酸多态性(single nucleotide polymorphism,SNP)位于非编码区,可能通过影响转录因子结合、表观遗传修饰、染色质可及性、基因组高级结构等,调控靶基因表达。本文对后GWAS时代结直肠癌致病位点的机制研究进行综述,阐述了后GWAS对于理解结直肠癌分子机制的重要意义,并探讨了结直肠癌GWAS的应用和前景,为实现GWAS成果转化提供参考。     

Mouse models for unraveling the importance of diet in colon cancer prevention

Diet and genetics are both considered important risk determinants for colorectal cancer, a leading cause of death worldwide. Several genetically engineered mouse models have been created, including the Apc^Min mouse, to aid in the identification of key cancer related processes and to assist with the characterization of environmental factors, including the diet, which influence risk. Current research using these models provides evidence that several bioactive food components can inhibit genetically predisposed colorectal cancer, while others increase risk. Specifically, calorie restriction or increased exposure to n-3 fatty acids, sulforaphane, chafuroside, curcumin and dibenzoylmethane were reported protective. Total fat, calories and all-trans retinoic acid are associated with an increased risk. Unraveling the importance of specific dietary components in these models is complicated by the basal diet used, the quantity of test components provided and interactions among food components. Newer models are increasingly available to evaluate fundamental cellular processes, including DNA mismatch repair, immune function and inflammation as markers for colon cancer risk. Unfortunately, these models have been used infrequently to examine the influence of specific dietary components. The enhanced use of these models can shed mechanistic insights about the involvement of specific bioactive food and components and energy as determinants of colon cancer risk. However, the use of available mouse models to exactly represent processes important to human gastrointestinal cancers will remain a continued scientific challenge.     

A new method for post Genome-Wide Association Study (GWAS) analysis of colorectal cancer in Taiwan

Recently, single nucleotide polymorphisms (SNPs) located in specific loci or genes have been identified associated with susceptibility to colorectal cancer (CRC) in Genome-Wide Association Studies (GWAS). However, in different ethnicities and regions, the genetic variations and the environmental factors can widely vary. Therefore, here we propose a post-GWAS analysis method to investigate the CRC susceptibility SNPs in Taiwan by conducting a replication analysis and bioinformatics analysis. One hundred and forty-four significant SNPs from published GWAS results were collected by a literature survey, and two hundred and eighteen CRC samples and 385 normal samples were collected for post-GWAS analysis. Finally, twenty-six significant SNPs were identified and reported as associated with susceptibility to colorectal cancer, other cancers, obesity, and celiac disease in a previous GWAS study. Functional analysis results of 26 SNPs indicate that most biological processes identified are involved in regulating immune responses and apoptosis. In addition, an efficient prediction model was constructed by applying Jackknife feature selection and ANOVA testing. As compared to another risk prediction model of CRC for European Caucasians population, which performs 0.616 of AUC by using 54 SNPs, the proposed model shows good performance in predicting CRC risk within the Taiwanese population, i.e., 0.724 AUC by using 16 SNPs. We believe that the proposed risk prediction model is highly promising for predicting CRC risk within the Taiwanese population. In addition, the functional analysis results could be helpful to explore the potential associated regulatory mechanisms that may be involved in CRC development.