Exploring mechanisms of diet-colon cancer associations through candidate molecular interaction networks

Background

Epidemiological studies in the recent years have investigated the relationship between dietary habits and disease risk demonstrating that diet has a direct effect on public health. Especially plant-based diets -fruits, vegetables and herbs- are known as a source of molecules with pharmacological properties for treatment of several malignancies. Unquestionably, for developing specific intervention strategies to reduce cancer risk there is a need for a more extensive and holistic examination of the dietary components for exploring the mechanisms of action and understanding the nutrient-nutrient interactions. Here, we used colon cancer as a proof-of-concept for understanding key regulatory sites of diet on the disease pathway.

Results

We started from a unique vantage point by having a database of 158 plants positively associated to colon cancer reduction and their molecular composition (~3,500 unique compounds). We generated a comprehensive picture of the interaction profile of these edible and non-edible plants with a predefined candidate colon cancer target space consisting of ~1,900 proteins. This knowledge allowed us to study systematically the key components in colon cancer that are targeted synergistically by phytochemicals and identify statistically significant and highly correlated protein networks that could be perturbed by dietary habits.

Conclusion

We propose here a framework for interrogating the critical targets in colon cancer processes and identifying plant-based dietary interventions as important modifiers using a systems chemical biology approach. Our methodology for better delineating prevention of colon cancer by nutritional interventions relies heavily on the availability of information about the small molecule constituents of our diet and it can be expanded to any other disease class that previous evidence has linked to lifestyle.     

Metformin Treatment Does Not Inhibit Growth of Pancreatic Cancer Patient-Derived Xenografts

There is currently tremendous interest in developing anti-cancer therapeutics targeting cell signaling pathways important for both cancer cell metabolism and growth. Several epidemiological studies have shown that diabetic patients taking metformin have a decreased incidence of pancreatic cancer. This has prompted efforts to evaluate metformin, a drug with negligible toxicity, as a therapeutic modality in pancreatic cancer. Preclinical studies in cell line xenografts and one study in patient-derived xenograft (PDX) models were promising, while recently published clinical trials showed no benefit to adding metformin to combination therapy regimens for locally advanced and metastatic pancreatic cancer. PDX models in which patient tumors are directly engrafted into immunocompromised mice have been shown to be excellent preclinical models for biomarker discovery and therapeutic development. We evaluated the response of four PDX tumor lines to metformin treatment and found that all four of our PDX lines were resistant to metformin. We found that the mechanisms of resistance may occur through lack of sustained activation of adenosine monophosphate-activated protein kinase (AMPK) or downstream reactivation of the mammalian target of rapamycin (mTOR). Moreover, combined treatment with metformin and mTOR inhibitors failed to improve responses in cell lines, which further indicates that metformin alone or in combination with mTOR inhibitors will be ineffective in patients, and that resistance to metformin may occur through multiple pathways. Further studies are required to better understand these mechanisms of resistance and inform potential combination therapies with metformin and existing or novel therapeutics.     

Therapeutic targets and new directions for antibodies developed for ovarian cancer

Antibody therapeutics against different target antigens are widely used in the treatment of different malignancies including ovarian carcinomas, but this disease still requires more effective agents. Improved understanding of the biological features, signaling pathways, and immunological escape mechanisms involved in ovarian cancer has emerged in the past few years. These advances, including an appreciation of the cross-talk between cancer cells and the patient's immune system, have led to the identification of new targets. In turn, potential antibody treatments with various mechanisms of action, including immune activation or toxin-delivery, that are directed at these targets have been developed. Here, we identify established as well as novel targets for antibodies in ovarian cancer, and discuss how they may provide fresh opportunities to identify interventions with enhanced therapeutic potential.     

Kinetic studies of lipoprotein metabolism in the metabolic syndrome including effects of nutritional interventions

Nutritional interventions may favourably regulate dyslipoproteinemia and, hence, decrease cardiovascular disease risk. Lipoprotein kinetic studies afford a powerful approach to understanding and defining the mechanisms by which such interventions modulate lipoprotein metabolism. Stable isotope tracers and compartment models are now commonly employed for such studies. We review the recent application of tracer methodologies to the study of dyslipoproteinemia in the metabolic syndrome. We also focus on the effects of nutritional intervention studies that have addressed the effects of weight loss, n-3 fatty acids, plant sterols and alcohol on very low density lipoprotein, LDL and HDL metabolism. The potential for statin treatment as an adjunct to dietary modification is also discussed. New tracer methodologies are discussed, specifically those referring to reverse cholesterol transport. The nutritional interventions discussed in this review are readily transferable into clinical preventive practice. The potential benefits to be gained by weight loss and fish oil supplementation in the metabolic syndrome extend beyond their specific and positive effects on lipoprotein metabolism. Furthermore, recent developments in tracer methodologies afford new tools for probing the in-vivo pathways of lipoprotein metabolism in future studies.     

Gut dysbacteriosis and intestinal disease: mechanism and treatment

The gut microbiome functions like an endocrine organ, generating bioactive metabolites, enzymes or small molecules that can impact host physiology. Gut dysbacteriosis is associated with many intestinal diseases including (but not limited to) inflammatory bowel disease, primary sclerosing cholangitis-IBD, irritable bowel syndrome, chronic constipation, osmotic diarrhoea and colorectal cancer. The potential pathogenic mechanism of gut dysbacteriosis associated with intestinal diseases includes the alteration of composition of gut microbiota as well as the gut microbiota–derived signalling molecules. The many correlations between the latter and the susceptibility for intestinal diseases has placed a spotlight on the gut microbiome as a potential novel target for therapeutics. Currently, faecal microbial transplantation, dietary interventions, use of probiotics, prebiotics and drugs are the major therapeutic tools utilized to impact dysbacteriosis and associated intestinal diseases. In this review, we systematically summarized the role of intestinal microbiome in the occurrence and development of intestinal diseases. The potential mechanism of the complex interplay between gut dysbacteriosis and intestinal diseases, and the treatment methods are also highlighted.     

Exploiting the Fanconi Anemia Pathway for Targeted Anti-Cancer Therapy

Genome instability, primarily caused by faulty DNA repair mechanisms, drives tumorigenesis. Therapeutic interventions that exploit deregulated DNA repair in cancer have made considerable progress by targeting tumor-specific alterations of DNA repair factors, which either induces synthetic lethality or augments the efficacy of conventional chemotherapy and radiotherapy. The study of Fanconi anemia (FA), a rare inherited blood disorder and cancer predisposition syndrome, has been instrumental in understanding the extent to which DNA repair defects contribute to tumorigenesis. The FA pathway functions to resolve blocked replication forks in response to DNA interstrand cross-links (ICLs), and accumulating knowledge of its activation by the ubiquitin-mediated signaling pathway has provided promising therapeutic opportunities for cancer treatment. Here, we discuss recent advances in our understanding of FA pathway regulation and its potential application for designing tailored therapeutics that take advantage of deregulated DNA ICL repair in cancer.     

Nutrigenomic Analysis of Diet-Gene Interactions on Functional Supplements for Weight Management

Recent advances in molecular biology combined with the wealth of information generated by the Human Genome Project have fostered the emergence of nutrigenomics, a new discipline in the field of nutritional research. Nutrigenomics may provide the strategies for the development of safe and effective dietary interventions against the obesity epidemic. According to the World Health Organization, more than 60% of the global disease burden will be attributed to chronic disorders associated with obesity by 2020. Meanwhile in the US, the prevalence of obesity has doubled in adults and tripled in children during the past three decades. In this regard, a number of natural dietary supplements and micronutrients have been studied for their potential in weight management. Among these supplements, (–)-hydroxycitric acid (HCA), a natural extract isolated from the dried fruit rind of Garcinia cambogia, and the micronutrient niacin-bound chromium(III) (NBC) have been shown to be safe and efficacious for weight loss. Utilizing cDNA microarrays, we demonstrated for the first time that HCA-supplementation altered the expression of genes involved in lipolytic and adipogenic pathways in adipocytes from obese women and up-regulated the expression of serotonin receptor gene in the abdominal fat of rats. Similarly, we showed that NBC-supplementation up-regulated the expression of myogenic genes while suppressed the expression of genes that are highly expressed in brown adipose tissue in diabetic obese mice. The potential biological mechanisms underlying the observed beneficial effects of these supplements as elucidated by the state-of-the-art nutrigenomic technologies will be systematically discussed in this review.Key Words: Insulin resistance, glucose tolerance factor, supplemental chromium, Garcinia cambogia, (-)-hydroxycitric acid, overweight, obesity, diabetes, cardiovascular disease, nutritional interventions, microarrays, nutrigenomics.     

The challenges for molecular nutrition research 2: quantification of the nutritional phenotype

In quantifying the beneficial effect of dietary interventions in healthy subjects, nutrition research meets a number of new challenges. Inter individual variation in biomarker values often is larger than the effect related to the intervention. Healthy subjects have a remarkable capacity to maintain homeostasis, both through direct metabolic regulation, metabolic compensation of altered diets, and effective defence and repair mechanisms in oxidative and inflammatory stress. Processes involved in these regulatory activities essentially different from processes involved in early onset of diet related diseases. So, new concepts and approaches are needed to better quantify the subtle effects possibly achieved by dietary interventions in healthy subjects. Apart from quantification of the genotype and food intake (these are discussed in separate reviews in this series), four major areas of innovation are discussed: the biomarker profile concept, perturbation of homeostasis combined with omics analysis, imaging, modelling and fluxes. All of these areas contribute to a better understanding and quantification of the nutritional phenotype.     

Malnutrition and cachexia in patients with head and neck cancer treated with (chemo)radiotherapy

AimTo highlight the problems associated with nutrition that occur in patients with squamous cell carcinoma of the head and neck (SCCHN).BackgroundSCCHN is associated with weight loss before, during and after radiotherapy or concurrent chemoradiotherapy. Because of serious consequences of malnutrition and cachexia on treatment outcome, mortality, morbidity, and quality of life, it is important to identify SCCHN patients with increased risk for the development of malnutrition and cachexia.Materials and methodsCritical review of the literature.ResultsThis review describes pathogenesis, diagnosis and treatment of malnutrition and cancer cachexia. Treatment of malnutrition and cancer cachexia includes nutritional interventions and pharmacological therapy. Advantages and disadvantages of different nutritional interventions and their effect on the nutritional status, quality of life and specific oncological treatment are presented.ConclusionsNutritional management is an essential part of care of these patients, including early screening, assessment of nutritional status and appropriate intervention.     

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.     

Screening of natural products for therapeutic activity against solid tumors

Most of the currently used cancer therapeutics are natural products. These agents were generally discovered based on their toxicity to tumour cells using various bioassays. Although the exact mechanisms of action of the most commonly used cancer therapeutics such as anthracyclins, podophyllotoxins and camptothecin are incompletely understood, it is becoming increasingly clear that these agents often show complex modes of action at the cellular level, interacting with numerous targets. Such complex modes of action may be the very reason for clinical efficacy. For discovering new cytotoxic anticancer drugs sophisticated screening methods were used. The principles of such screening projects conducted, using collections of purified natural products or extracts from plants have been described. By performing simple but robust prescreening tests such as the brine shrimp assay, bioactive extracts can be identified. Extracts (65) prepared from a collection of Egyptian plants were identified that showed cytotoxity on HepG2 cells. Interestingly, 22 (33%) of these raw extracts, induced > 2-fold induction of caspase-cleavage activity in a colon carcinoma cell line, consistent with induction of apoptosis. Only a fraction of the diversity of the biosphere has been tested for biological activity and novel cancer therapeutics remains to be discovered.     

Unlocking the potential of non-coding RNAs in cancer research and therapy

Non-coding RNAs (ncRNAs) have emerged as key regulators of gene expression, with growing evidence implicating their involvement in cancer development and progression. The potential of ncRNAs as diagnostic and prognostic biomarkers for cancer is promising, with emphasis on their use in liquid biopsy and tissue-based diagnostics. In a nutshell, the review comprehensively summarizes the diverse classes of ncRNAs implicated in cancer, including microRNAs, long non-coding RNAs, and circular RNAs, and their functions and mechanisms of action. Furthermore, we describe the potential therapeutic applications of ncRNAs, including anti-miRNA oligonucleotides, siRNAs, and other RNA-based therapeutics in cancer treatment. However, significant challenges remain in developing effective ncRNA-based diagnostics and therapeutics, including the lack of specificity, limited understanding of mechanisms, and delivery challenges. This review also covers the current state-of-the-art non-coding RNA research technologies and bioinformatic analysis tools. Lastly, we outline future research directions in non-coding RNA research in cancer, including developing novel biomarkers, therapeutic targets, and modalities. In summary, this review provides a comprehensive understanding of non-coding RNAs in cancer and their potential clinical applications, highlighting both the opportunities and challenges in this rapidly evolving field.     

Therapeutic strategies of dual-target small molecules to overcome drug resistance in cancer therapy

Despite some advances in targeted therapeutics of human cancers, curative cancer treatment still remains a tremendous challenge due to the occurrence of drug resistance. A variety of underlying resistance mechanisms to targeted cancer drugs have recently revealed that the dual-target therapeutic strategy would be an attractive avenue. Compared to drug combination strategies, one agent simultaneously modulating two druggable targets generally shows fewer adverse reactions and lower toxicity. As a consequence, the dual-target small molecule has been extensively explored to overcome drug resistance in cancer therapy. Thus, in this review, we focus on summarizing drug resistance mechanisms of cancer cells, such as enhanced drug efflux, deregulated cell death, DNA damage repair, and epigenetic alterations. Based upon the resistance mechanisms, we further discuss the current therapeutic strategies of dual-target small molecules to overcome drug resistance, which will shed new light on exploiting more intricate mechanisms and relevant dual-target drugs for future cancer therapeutics.     

MicroRNA replacement therapy in cancer

Despite the recent progress in cancer management approaches, the mortality rate of cancer is still growing and there are lots of challenges in the clinics in terms of novel therapeutics. MicroRNAs (miRNA) are regulatory small noncoding RNAs and are already confirmed to have a great role in regulating gene expression level by targeting multiple molecules that affect cell physiology and disease development. Recently, miRNAs have been introduced as promising therapeutic targets for cancer treatment. Regulatory potential of tumor suppressor miRNAs, which enables regulation of entire signaling networks within the cells, makes them an interesting option for developing cancer therapeutics. In this regard, over recent decades, scientists have aimed at developing powerful and safe targeting approaches to restore these suppressive miRNAs in cancerous cells. The present review summarizes the function of miRNAs in tumor development and presents recent findings on how miRNAs have served as therapeutic agents against cancer, with a special focus on tumor suppressor miRNAs (mimics). Moreover, the latest investigations on the therapeutic strategies of miRNA delivery have been presented.     

PARP-1 抑制剂靶向治疗上皮性卵巢癌的研究进展

简介聚二磷酸腺苷核糖聚合酶-1（PARP-1）及其功能和在DNA 损伤修复中的作用,综述PARP-1 抑制剂的作用机制、发展现状以及在上皮性卵巢癌治疗中的应用,并探讨PARP-1 抑制剂靶向治疗上皮性卵巢癌的临床试验失败原因,展望PARP-1 抑制剂的应用前景,提出需对PARP-1 抑制剂在用于治疗上皮性卵巢癌中的耐药机制和选择性展开深入研究。     

Mechanisms linking obesity and cancer

The incidence of obesity in US adults has been steadily increasing over the past few decades. Many comorbidities associated with obesity have been well-established such as type 2 diabetes and cardiovascular diseases. However, more recently an epidemiological relationship between obesity and the prevalence of a variety of cancers has also been uncovered. The shift of the paradigm surrounding white adipose tissue function from purely an energy storage tissue, to one that has both endocrine and metabolic relevance, has led to several mechanisms implicated in how obesity drives cancer prevalence and cancer deaths. Currently, there are four categories into which these mechanisms fall — increased lipids and lipid signaling, inflammatory responses, insulin resistance, and adipokines. In this review, we examine each of these categories and the mechanisms through which they drive cancer pathogenesis. Understanding the relationship(s) between obesity and cancer and especially the nodal points of control in these cascades will be essential in developing effective therapeutics or interventions for combating this deadly combination. This article is part of a Special Issue entitled Lipid Metabolism in Cancer.     

RAN GTPase as a target for cancer therapy: Ran binding proteins

The identification of a relevant effector of Ran GTPase (Ran) signaling and its pathways could provide a novel approach to cancer therapeutics. With recent research highlighting the significant relationship between Ran expression and the occurrence and progression of cancer, the development of a small molecule compound that would decrease the endogenous levels of Ran in the cell would have anti-mitotic effects and could lead to the development of new types of cancer therapeutics. In the absence of Ran binding proteins, Ran is expected to remain locked up in non-productive complexes with importins and is effectively removed from the system. Thus, Ran binding proteins present as a logical molecular target for the inhibition of Ran signaling within the cancer cell. Moreover, this family of proteins has been shown to have various other functions within the cell, some of which are also anti-neoplastic. The purpose of this review is to discuss Ran binding proteins and how their pathways may be exploited to provide an effective cancer treatment.     

Role of the Wnt and GTPase pathways in breast cancer tumorigenesis and treatment

Breast cancer (BC) is the most frequently diagnosed cancer among women in all the populations of the world. Although the BC mortality rate has declined, resistance to treatment is still a significant challenge for patient survival. Various cellular signaling pathways, such as Wnt and Rho/GTPase have been linked to the development, migration, and metastasis of BC, and also in treatment resistance mechanisms. Some studies have shown an association between two important cellular pathways, Wnt and Rho/GTPase, in cytoskeleton activation and cancer invasion. However, their involvement in BC has received little attention. This review summarizes the Wnt and Rho/GTPases signaling pathway functions, and also the crosstalk between these pathways in the progression, metastasis, and drug resistance mechanisms in BC. Considering the signaling pathways involved in BC tumorigenesis, future studies will need to investigate possible molecular interventions and new opportunities for the development of personalized strategies for BC treatment in order to improve overall outcomes.     

MicroRNAs as important players in regulating cancer through PTEN/PI3K/AKT signalling pathways

Cancer being the leading cause of mortality has become a great threat worldwide. Current cancer therapeutics lack specificity and have side effects due to a lack of understanding of the molecular mechanisms and signalling pathways involved in carcinogenesis. In recent years, researchers have been focusing on several signalling pathways to pave the way for novel therapeutics. The PTEN/PI3K/AKT pathway is one of the important pathways involved in cell proliferation and apoptosis, leading to tumour growth. In addition, the PTEN/PI3K/AKT axis has several downstream pathways that could lead to tumour malignancy, metastasis and chemoresistance. On the other hand, microRNAs (miRNAs) are important regulators of various genes leading to disease pathogenesis. Hence studies of the role of miRNAs in regulating the PTEN/PI3K/AKT axis could lead to the development of novel therapeutics for cancer. Thus, in this review, we have focused on various miRNAs involved in the carcinogenesis of various cancer via the PTEN/PI3K/AKT axis.