New Insights into Molecular Links Between Microbiota and Gastrointestinal Cancers: A Literature Review

Despite decades of exhaustive research on cancer, questions about cancer initiation, development, recurrence, and metastasis have still not been completely answered. One of the reasons is the plethora of factors acting simultaneously in a tumour microenvironment, of which not all have garnered attention. One such factor that has long remained understudied and has only recently received due attention is the host microbiota. Our sheer-sized microbiota exists in a state of symbiosis with the body and exerts significant impact on our body’s physiology, ranging from immune-system development and regulation to neurological and cognitive development. The presence of our microbiota is integral to our development, but a change in its composition (microbiota dysbiosis) can often lead to adverse effects, increasing the propensity of serious diseases like cancers. In the present review, we discuss environmental and genetic factors that cause changes in microbiota composition, disposing of the host towards cancer, and the molecular mechanisms (such as β-catenin signalling) and biochemical pathways (like the generation of oncogenic metabolites like N-nitrosamines and hydrogen sulphide) that the microbiota uses to initiate or accelerate cancers, with emphasis on gastrointestinal cancers. Moreover, we discuss how microbiota can adversely influence the success of colorectal-cancer chemotherapy, and its role in tumour metastasis. We also attempted to resolve conflicting results obtained for the butyrate effect on tumour suppression in the colon, often referred to as the ‘butyrate paradox’. In addition, we suggest the development of microbiota-based biomarkers for early cancer diagnosis, and a few target molecules of which the inhibition can increase the overall chances of cancer cure.

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Molecules from the Microbiome

Annual Review of Biochemistry ◽

10.1146/annurev-biochem-080320-115307 ◽

2021 ◽

Vol 90 (1) ◽

Author(s):

Emilee E. Shine ◽

Jason M. Crawford

Keyword(s):

Small Molecules ◽

Molecular Mechanisms ◽

System Development ◽

Human Microbiome ◽

Host Responses ◽

Annual Review ◽

Publication Date ◽

Mechanistic Studies ◽

Immune System Development ◽

Interdisciplinary Approaches

The human microbiome encodes a second genome that dwarfs the genetic capacity of the host. Microbiota-derived small molecules can directly target human cells and their receptors or indirectly modulate host responses through functional interactions with other microbes in their ecological niche. Their biochemical complexity has profound implications for nutrition, immune system development, disease progression, and drug metabolism, as well as the variation in these processes that exists between individuals. While the species composition of the human microbiome has been deeply explored, detailed mechanistic studies linking specific microbial molecules to host phenotypes are still nascent. In this review, we discuss challenges in decoding these interaction networks, which require interdisciplinary approaches that combine chemical biology, microbiology, immunology, genetics, analytical chemistry, bioinformatics, and synthetic biology. We highlight important classes of microbiota-derived small molecules and notable examples. An understanding of these molecular mechanisms is central to realizing the potential of precision microbiome editing in health, disease, and therapeutic responses. Expected final online publication date for the Annual Review of Biochemistry, Volume 90 is June 2021. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

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GIPC proteins negatively modulate Plexind1 signaling during vascular development

eLife ◽

10.7554/elife.30454 ◽

2019 ◽

Vol 8 ◽

Cited By ~ 3

Author(s):

Jorge Carretero-Ortega ◽

Zinal Chhangawala ◽

Shane Hunt ◽

Carlos Narvaez ◽

Javier Menéndez-González ◽

...

Keyword(s):

Cancer Biology ◽

Molecular Mechanisms ◽

System Development ◽

Drug Hypersensitivity ◽

Vascular Development ◽

Vascular Endothelial ◽

Neuropilin 1 ◽

Immune System Development ◽

Antiangiogenic Drug ◽

Endothelial Growth Factor

Semaphorins (SEMAs) and their Plexin (PLXN) receptors are central regulators of metazoan cellular communication. SEMA-PLXND1 signaling plays important roles in cardiovascular, nervous, and immune system development, and cancer biology. However, little is known about the molecular mechanisms that modulate SEMA-PLXND1 signaling. As PLXND1 associates with GIPC family endocytic adaptors, we evaluated the requirement for the molecular determinants of their association and PLXND1’s vascular role. Zebrafish that endogenously express a Plxnd1 receptor with a predicted impairment in GIPC binding exhibit low penetrance angiogenesis deficits and antiangiogenic drug hypersensitivity. Moreover, gipc mutant fish show angiogenic impairments that are ameliorated by reducing Plxnd1 signaling. Finally, GIPC depletion potentiates SEMA-PLXND1 signaling in cultured endothelial cells. These findings expand the vascular roles of GIPCs beyond those of the Vascular Endothelial Growth Factor (VEGF)-dependent, proangiogenic GIPC1-Neuropilin 1 complex, recasting GIPCs as negative modulators of antiangiogenic PLXND1 signaling and suggest that PLXND1 trafficking shapes vascular development.

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Symbiont-induced odorant binding proteins mediate insect host hematopoiesis

eLife ◽

10.7554/elife.19535 ◽

2017 ◽

Vol 6 ◽

Cited By ~ 48

Author(s):

Joshua B Benoit ◽

Aurélien Vigneron ◽

Nichole A Broderick ◽

Yineng Wu ◽

Jennifer S Sun ◽

...

Keyword(s):

Immune System ◽

Molecular Mechanisms ◽

System Development ◽

Model Systems ◽

Tsetse Flies ◽

Immune System Development ◽

Indigenous Microbiota ◽

And Function ◽

Necessary And Sufficient ◽

Odorant Binding

Symbiotic bacteria assist in maintaining homeostasis of the animal immune system. However, the molecular mechanisms that underlie symbiont-mediated host immunity are largely unknown. Tsetse flies (Glossina spp.) house maternally transmitted symbionts that regulate the development and function of their host’s immune system. Herein we demonstrate that the obligate mutualist, Wigglesworthia, up-regulates expression of odorant binding protein six in the gut of intrauterine tsetse larvae. This process is necessary and sufficient to induce systemic expression of the hematopoietic RUNX transcription factor lozenge and the subsequent production of crystal cells, which actuate the melanotic immune response in adult tsetse. Larval Drosophila’s indigenous microbiota, which is acquired from the environment, regulates an orthologous hematopoietic pathway in their host. These findings provide insight into the molecular mechanisms that underlie enteric symbiont-stimulated systemic immune system development, and indicate that these processes are evolutionarily conserved despite the divergent nature of host-symbiont interactions in these model systems.

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Molecular Processes Involved in Pancreatic Cancer and Therapeutics

Current Chemical Biology ◽

10.2174/2212796814999201008130819 ◽

2020 ◽

Vol 14 ◽

Author(s):

Subhajit Makar ◽

Abhrajyoti Ghosh ◽

Divya ◽

Shalini Shivhare ◽

Ashok Kumar ◽

...

Keyword(s):

Pancreatic Cancer ◽

Molecular Mechanisms ◽

Early Stage ◽

Locally Advanced ◽

Therapeutic Strategies ◽

Screening Methods ◽

Pancreatic Cancer Cells ◽

Systemic Treatments ◽

Cancer Initiation ◽

Novel Therapeutic Strategies

: Despite advances in the development of cytotoxic and targeted therapies, pancreatic adenocarcinoma (PAC) remains a significant cause of cancer mortality worldwide. It is also difficult to detect it at an early stage due to numbers of factors. Most of the patients are present with locally advanced or metastatic disease, which precludes curative resection. In the absence of effective screening methods, considerable efforts have been made to identify better systemic treatments during the past decade. This review describes the recent advances in molecular mechanisms involved in pancreatic cancer initiation, progression, and metastasis. Additionally, the importance of deregulated cellular signalling pathways and various cellular proteins as potential targets for developing novel therapeutic strategies against incurable forms of pancreatic cancer is reported. The emphasis is on the critical functions associated with growth factors and their receptors viz. c-MET/HGF, CTHRC1, TGF-β, JAK-STAT, cyclooxygenase pathway, WNT, CCK, MAPK-RAS-RAF, PI3K-AKT, Notch, src, IGF-1R, CDK2NA and chromatin regulation for the sustained growth, survival, and metastasis of pancreatic cancer cells. It also includes various therapeutic strategies viz. immunotherapy, surgical therapy, radiation therapy and chemotherapy.

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Toxicology

10.1093/oso/9780190662677.003.0007 ◽

2017 ◽

Author(s):

Robert Laumbach ◽

Michael Gochfeld

Keyword(s):

Molecular Mechanisms ◽

Molecular Targets ◽

Toxicity Testing ◽

The Body ◽

Toxic Substances ◽

Basic Principles ◽

Practical Applications ◽

Mechanisms Of Toxicity ◽

Body Distribution ◽

Threshold Doses

This chapter describes the basic principles of toxicology and their application to occupational and environmental health. Topics covered include pathways that toxic substances may take from sources in the environment to molecular targets in the cells of the body where toxic effects occur. These pathways include routes of exposure, absorption into the body, distribution to organs and tissues, metabolism, storage, and excretion. The various types of toxicological endpoints are discussed, along with the concepts of dose-response relationships, threshold doses, and the basis of interindividual differences and interspecies differences in response to exposure to toxic substances. The diversity of cellular and molecular mechanisms of toxicity, including enzyme induction and inhibition, oxidative stress, mutagenesis, carcinogenesis, and teratogenesis, are discussed and the chapter concludes with examples of practical applications in clinical evaluation and in toxicity testing.

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Consumption of Select Dietary Emulsifiers Exacerbates the Development of Spontaneous Intestinal Adenoma

International Journal of Molecular Sciences ◽

10.3390/ijms22052602 ◽

2021 ◽

Vol 22 (5) ◽

pp. 2602

Author(s):

Emilie Viennois ◽

Benoit Chassaing

Keyword(s):

Intestinal Inflammation ◽

Tumor Development ◽

Low Grade ◽

Gastrointestinal Cancers ◽

Cancer Initiation ◽

And Function ◽

The Impact ◽

Chronic Intestinal Inflammation ◽

Low Grade Inflammation ◽

Intestinal Adenoma

Inflammation is a well-characterized critical driver of gastrointestinal cancers. Previous findings have shown that intestinal low-grade inflammation can be promoted by the consumption of select dietary emulsifiers, ubiquitous component of processed foods which alter the composition and function of the gut microbiota. Using a model of colitis-associated cancer, we previously reported that consumption of the dietary emulsifiers carboxymethylcellulose or polysorbate-80 exacerbated colonic tumor development. Here, we investigate the impact of dietary emulsifiers consumption on cancer initiation and progression in a genetical model of intestinal adenomas. In APCmin mice, we observed that dietary emulsifiers consumption enhanced small-intestine tumor development in a way that appeared to be independent of chronic intestinal inflammation but rather associated with emulsifiers’ impact on the proliferative status of the intestinal epithelium as well as on intestinal microbiota composition in both male and female mice. Overall, our findings further support the hypothesis that emulsifier consumption may be a new modifiable risk factor for colorectal cancer (CRC) and that alterations in host–microbiota interactions can favor gastrointestinal carcinogenesis in individuals with a genetical predisposition to such disorders.

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Insights into how environment shapes post-mortem RNA transcription in mouse brain

Scientific Reports ◽

10.1038/s41598-021-92268-y ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Raphael Severino Bonadio ◽

Larissa Barbosa Nunes ◽

Patricia Natália S. Moretti ◽

Juliana Forte Mazzeu ◽

Stefano Cagnin ◽

...

Keyword(s):

Lipid Metabolism ◽

Mouse Brain ◽

Molecular Mechanisms ◽

Cell Communication ◽

Rna Degradation ◽

The Body ◽

Biological Processes ◽

Post Mortem ◽

Gene Expression Alterations ◽

Upregulated Genes

AbstractMost biological features that occur on the body after death were already deciphered by traditional medicine. However, the molecular mechanisms triggered in the cellular microenvironment are not fully comprehended yet. Previous studies reported gene expression alterations in the post-mortem condition, but little is known about how the environment could influence RNA degradation and transcriptional regulation. In this work, we analysed the transcriptome of mouse brain after death under three concealment simulations (air exposed, buried, and submerged). Our analyses identified 2,103 genes differentially expressed in all tested groups 48 h after death. Moreover, we identified 111 commonly upregulated and 497 commonly downregulated genes in mice from the concealment simulations. The gene functions shared by the individuals from the tested environments were associated with RNA homeostasis, inflammation, developmental processes, cell communication, cell proliferation, and lipid metabolism. Regarding the altered biological processes, we identified that the macroautophagy process was enriched in the upregulated genes and lipid metabolism was enriched in the downregulated genes. On the other hand, we also described a list of biomarkers associated with the submerged and buried groups, indicating that these environments can influence the post-mortem RNA abundance in its particular way.

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Zebrafish Models of Autosomal Recessive Ataxias

Cells ◽

10.3390/cells10040836 ◽

2021 ◽

Vol 10 (4) ◽

pp. 836

Author(s):

Ana Quelle-Regaldie ◽

Daniel Sobrido-Cameán ◽

Antón Barreiro-Iglesias ◽

María Jesús Sobrido ◽

Laura Sánchez

Keyword(s):

Animal Models ◽

Autosomal Recessive ◽

Molecular Mechanisms ◽

System Development ◽

Rapid Development ◽

Nervous System Development ◽

Central Nervous System Development ◽

Cellular Processes ◽

Recessive Disorders

Autosomal recessive ataxias are much less well studied than autosomal dominant ataxias and there are no clearly defined systems to classify them. Autosomal recessive ataxias, which are characterized by neuronal and multisystemic features, have significant overlapping symptoms with other complex multisystemic recessive disorders. The generation of animal models of neurodegenerative disorders increases our knowledge of their cellular and molecular mechanisms and helps in the search for new therapies. Among animal models, the zebrafish, which shares 70% of its genome with humans, offer the advantages of being small in size and demonstrating rapid development, making them optimal for high throughput drug and genetic screening. Furthermore, embryo and larval transparency allows to visualize cellular processes and central nervous system development in vivo. In this review, we discuss the contributions of zebrafish models to the study of autosomal recessive ataxias characteristic phenotypes, behavior, and gene function, in addition to commenting on possible treatments found in these models. Most of the zebrafish models generated to date recapitulate the main features of recessive ataxias.

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Comprehensive Analysis of SFRP Family Members Prognostic Value and Immune Infiltration in Gastric Cancer

Life ◽

10.3390/life11060522 ◽

2021 ◽

Vol 11 (6) ◽

pp. 522

Author(s):

Dehua Liu ◽

Chenyu Sun ◽

Nahyun Kim ◽

Chandur Bhan ◽

John Pocholo Whitaker Tuason ◽

...

Keyword(s):

Gastric Cancer ◽

Wnt Signaling ◽

Signaling Pathway ◽

Prognostic Value ◽

Immune Cell ◽

System Development ◽

Wnt Signaling Pathway ◽

Immune System Development ◽

Precision Therapy ◽

Gastric Cancer Patients

Gastric cancer (GC) is the fifth most common cancer globally. Secreted frizzled-related proteins (SFRP) are important elements associated with the Wnt signaling pathway, and its dysregulated expression is found in multiple cancers. However, the function of distinct SFRPs in GC remains poorly understood. We investigated the differential expression, prognostic value, and immune cell infiltration of SFRPs in gastric cancer patients from the Oncomine, Gene Expression Profiling Interactive Analysis (GEPIA), UALCAN, Kaplan–Meier plotter, cBioPortal, STRING, Gene-MANIA, DAVID, MethSurv, and TIMER databases. We found that the expression levels of SFRP2 and SFRP4 were significantly increased in GC tissues, whereas the SFRP1 and SFRP5 expressions were reduced. SFRP1, SFRP2, and SFRP5 were significantly correlated with the clinical cancer stage in GC patients. Higher expression of SFRPs was associated with short overall survival (OS) in GC patients. Besides, high SFRPs methylation showed favorable OS in GC patients. The functions of SFRPs were primarily related to the Wnt signaling pathway, immune system development, and basal cell carcinoma. The expression of SFRPs was strongly correlated with immune infiltrating cells, including CD4+ T cells and macrophages in GC. Our study indicated that SFRPs could be potential targets of precision therapy and prognostic biomarkers for the survival of GC patients.

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Strategies for the Development of pH-Responsive Synthetic Polypeptides and Polymer-Peptide Hybrids: Recent Advancements

Polymers ◽

10.3390/polym13040624 ◽

2021 ◽

Vol 13 (4) ◽

pp. 624

Author(s):

Cintya Dharmayanti ◽

Todd A. Gillam ◽

Manuela Klingler-Hoffmann ◽

Hugo Albrecht ◽

Anton Blencowe

Keyword(s):

Functional Groups ◽

Hybrid Materials ◽

Tumour Microenvironment ◽

The Body ◽

Supramolecular Interactions ◽

Biological Interactions ◽

Ph Responsive ◽

Form Complex ◽

Synthetic Polypeptides ◽

External Stimuli

Synthetic polypeptides and polymer-peptide hybrid materials have been successfully implemented in an array of biomedical applications owing to their biocompatibility, biodegradability and ability to mimic natural proteins. In addition, these materials have the capacity to form complex supramolecular structures, facilitate specific biological interactions, and incorporate a diverse selection of functional groups that can be used as the basis for further synthetic modification. Like conventional synthetic polymers, polypeptide-based materials can be designed to respond to external stimuli (e.g., light and temperature) or changes in the environmental conditions (e.g., redox reactions and pH). In particular, pH-responsive polypeptide-based systems represent an interesting avenue for the preparation of novel drug delivery systems that can exploit physiological or pathological pH variations within the body, such as those that arise in the extracellular tumour microenvironment, intracellularly within endosomes/lysosomes, or during tissue inflammation. Here, we review the significant progress made in advancing pH-responsive polypeptides and polymer-peptide hybrid materials during the last five years, with a particular emphasis on the manipulation of ionisable functional groups, pH-labile linkages, pH-sensitive changes to secondary structure, and supramolecular interactions.

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