Wnt/β-catenin signaling in cancers and targeted therapies

Signal Transduction and Targeted Therapy, Journal Year: 2021, Volume and Issue: 6(1)

Published: Aug. 30, 2021

Abstract Wnt/β-catenin signaling has been broadly implicated in human cancers and experimental cancer models of animals. Aberrant activation is tightly linked with the increment prevalence, advancement malignant progression, development poor prognostics, even ascendence cancer-associated mortality. Early investigations have proposed theoretical potential that efficient repression this might provide promising therapeutic choices managing various types cancers. Up to date, many therapies targeting developed, which assumed endow clinicians new opportunities developing more satisfactory precise remedies for patients aberrant signaling. However, current facts indicate clinical translations signaling-dependent targeted faced un-neglectable crises challenges. Therefore, study, we systematically reviewed most updated knowledge relatively generate a clearer accurate awareness both developmental stage underlying limitations Wnt/β-catenin-targeted Insights study will help readers better understand roles insights acknowledge challenges

Language: Английский

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Animal models to study acute and chronic intestinal inflammation in mammals

Gut Pathogens, Journal Year: 2015, Volume and Issue: 7(1)

Published: Nov. 10, 2015

Acute and chronic inflammatory diseases of the intestine impart a significant negative impact on health well-being human non-human mammalian animals. Understanding underlying mechanisms disease is mandatory to develop effective treatment prevention strategies. As etiologies are multifactorial, use appropriate animal models associated metrics essential. In this regard, used alone or in combination study acute paired with commonly inflammation-inducing agents reviewed. This includes both chemical biological incitants inflammation, non-mammalian (i.e. nematodes, insects, fish) rodents, rabbits, pigs, ruminants, dogs, primates) intestinal inflammation including germ-free, gnotobiotic, as well surgical, genetically modified Importantly, induce via multitude mechanisms, injury can vary greatly according incitant model used, allowing studies ascertain long-term short-term effects inflammation. Thus, researchers clinicians should be aware relative strengths limitations various intestine, scope relevance outcomes achievable based knowledge. The ability mimic common an important factor successful model, however other such amount infective agent disease, invasion effect physiologic changes have inducing damage also features. many cases, multiple necessary answer specific question being addressed regarding disease. Some responses certain while others responses; review aims illustrate weaknesses each guide choice facilitate

Language: Английский

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Mouse models of intestinal cancer

The Journal of Pathology, Journal Year: 2015, Volume and Issue: 238(2), P. 141 - 151

Published: Sept. 28, 2015

Abstract Murine models of intestinal cancer are powerful tools to recapitulate human cancer, understand its biology and test therapies. With recent developments identifying the importance tumour microenvironment potential for immunotherapy, autochthonous genetically engineered mouse ( GEMMs ) will remain an important part preclinical studies foreseeable future. This review provide overview current from Apc Min/+ mouse, which has been used over 25 years, latest ‘state‐of‐the‐art’ organoid models. We discuss here how these have define fundamental processes involved in initiation attempts generate metastatic models, is ultimate cause mortality. Together key insights this complex disease hopefully lead discovery new therapeutic strategies. © 2015 The Authors. Pathological Society Great Britain Ireland.

Language: Английский

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Sex disparity in colonic adenomagenesis involves promotion by male hormones, not protection by female hormones

Proceedings of the National Academy of Sciences, Journal Year: 2014, Volume and Issue: 111(46), P. 16514 - 16519

Published: Nov. 3, 2014

Significance The age-adjusted incidence of colonic adenomas and colorectal cancer is higher in men than women. In a careful analysis two established animal models, we found that castration reduced, testosterone supplementation restored, the number male rat mouse colon, whereas ovariectomy replacement female hormones had no measureable effect on adenomagenesis. Min mice, which most tumors arise small intestine, this testosterone-dependent sexual dimorphism mice was specific to colon. Our results support paradigm shift: Testosterone promotes early adenomagenesis through an indirect mechanism, explaining enhanced susceptibility males human, rat, mouse.

Language: Английский

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E. coli and colorectal cancer: a complex relationship that deserves a critical mindset

Critical Reviews in Microbiology, Journal Year: 2018, Volume and Issue: 44(5), P. 619 - 632

Published: June 17, 2018

To the multiple factors that may eventually result in colorectal cancer (CRC), strains of E. coli have now been added, particular producing colibactin from their polyketide synthesis (pks) locus. The evidence and mechanistic explanations for this unfortunate effect what is most cases a harmless commensal are discussed first part review. In second part, observations presented do not fit with hypothesis colibactin-producing produce CRC. last review reserved an alternative explanation function enigmatic colibactin, toxin has yet isolated. It hypothesized preferentially colonizes cancerous lesions as rather than cause production provides selective advantage to compete other bacteria.

Language: Английский

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Rat models of human diseases and related phenotypes: a systematic inventory of the causative genes

Journal of Biomedical Science, Journal Year: 2020, Volume and Issue: 27(1)

Published: Aug. 2, 2020

Abstract The laboratory rat has been used for a long time as the model of choice in several biomedical disciplines. Numerous inbred strains have isolated, displaying wide range phenotypes and providing many models human traits diseases. Rat genome mapping genomics was considerably developed last decades. availability these resources stimulated numerous studies aimed at discovering causal disease genes by positional identification. now identified that underlie monogenic or complex diseases remarkably, results translated to significant proportion cases, leading identification novel susceptibility genes, helping studying mechanisms underlying pathological abnormalities also suggesting new therapeutic approaches. In addition, reverse genetic tools developed. Several genome-editing methods were introduced generate targeted mutations function which could be clarified this manner [generally are knockout mutations]. Furthermore, even when gene causing had without resorting model, mutated (in particular KO strains) created analyze pathogenesis. Today, over 350 playing key role critical biological processes altered diseases, thereby rich resource models. This article is an update progress made research provides reader with inventory number similar effects humans.

Language: Английский

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Traditional Processed Meat Products Re-designed Towards Inulin-rich Functional Foods Reduce Polyps in Two Colorectal Cancer Animal Models

Scientific Reports, Journal Year: 2019, Volume and Issue: 9(1)

Published: Oct. 15, 2019

Abstract Inulin-rich foods exert a prebiotic effect, as this polysaccharide is able to enhance beneficial colon microbiota populations, giving rise the in situ production of short-chain fatty acids (SCFAs) such propionic and butyric acids. These SCFAs are potent preventive agents against colorectal cancer due their histone deacetylases inhibitory properties, which induce apoptosis tumor colonocytes. As fourth most common neoplasia Europe with 28.2 new cases per 100,000 inhabitants, cost-effective strategy has been tested work by redesigning porcine meat products ( chorizo sausages cooked ham) consumed substantial proportion population towards potential functional foods. In order test effect these inulin-rich cancer, an animal model Rattus norvegicus F344) was used, involving two doses azoxymethane (10 mg/kg) treatments dextran sodium sulfate (DSS) during 20-week assay period. Control feed, control sausages, (15.7% inulin), ham (10% inulin) were used feed corresponding cohorts. Then, animals sacrificed digestive tract tissues analyzed. The results showed statistically significant 49% reduction number polyps cohorts respect animals, well increase cecum weight (an indicator diet rich fiber), 51.8% propionate production, 39.1% butyrate concentrations, hyperplastic Peyer’s patches. Metagenomics studies also demonstrated differences, revealing Bacteroidetes populations (mainly Bacteroidaceae Prevotellaceae families, include prominent producers), together Firmicutes (especially lower Lachnospiraceae populations). However, remarkable anti-inflammatory fiber-fermentative Blautia genus, belongs family. presented important pro-inflammatory bacterial those genus Desulfovibrio Bilophila . corroborated genetic CRC (F344/NSlc-Apc 1588/kyo ) that produced similar results. Therefore, processed can be redesigned interest dietary for preventing human populations.

Language: Английский

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A RATional choice for translational research?

Disease Models & Mechanisms, Journal Year: 2016, Volume and Issue: 9(10), P. 1069 - 1072

Published: Oct. 1, 2016

ABSTRACT Future prospects continue to be strong for research using the rat as a model organism. New technology has enabled proliferation of many new transgenic and knockout strains, genomes more than 40 strains have been sequenced, publications produced at steady rate, discoveries disease-associated genes mechanisms from experiments abound, frequently with conservation function between rats humans. However, advances in genome led increasing insights into human disease directly genetic studies, pulling researchers genetics arena placing funding organisms their databases under threat. This, therefore, is pivotal time rat-based biomedical – timely moment review progress providing inspiration Special Collection focused on impact translational science, launched this issue Disease Models & Mechanisms. What areas are most appropriate rats? Why should favoured over other organisms, present levels continued? Which approaches we expect yield biologically medically useful coming years? These key issues that addressed original Research Articles reviews published Collection, introductory Editorial. exemplar articles serve landmark status quo after decade major could help guide direction decade.

Language: Английский

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TALEN-mediated apc mutation in Xenopus tropicalis phenocopies familial adenomatous polyposis

Oncoscience, Journal Year: 2015, Volume and Issue: 2(5), P. 555 - 566

Published: May 19, 2015

Truncating mutations in the tumor suppressor gene adenomatous polyposis coli (APC) are initiating step vast majority of sporadic colorectal cancers, and they underlie familial (FAP) syndromes. Modeling APC- driven formation mouse has contributed substantially to our mechanistic understanding associated disease, but additional models needed explore therapeutic opportunities overcome current limitations models. We report on a novel penetrant genetic cancer model Xenopus tropicalis, an aquatic tetrapod vertebrate with external development, diploid genome short life cycle. Tadpoles froglets derived from embryos injected TAL effector nucleases targeting apc rapidly developed intestinal hyperplasia other neoplasms observed FAP patients, including desmoid tumors medulloblastomas. Bi-allelic causing frame shifts were detected tumors, which displayed activation Wnt/β-catenin pathway showed increased cellular proliferation. further demonstrate that simultaneous double bi-allelic mutation non-relevant is possible neoplasias, opening door for identification characterization or modifier genes expressing truncated apc. Our results power modeling human tropicalis using mosaic TALEN-mediated disruption.

Language: Английский

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Cancer Exacerbates Chemotherapy-Induced Sensory Neuropathy

Cancer Research, Journal Year: 2020, Volume and Issue: 80(13), P. 2940 - 2955

Published: April 28, 2020

For the constellation of neurologic disorders known as chemotherapy-induced peripheral neuropathy, mechanistic understanding and treatment remain deficient. Here, we present first evidence that chronic sensory neuropathy depends on nonlinear interactions between cancer chemotherapy. Global transcriptional profiling dorsal root ganglia revealed differential expression, notably in regulators neuronal excitability, metabolism, inflammatory responses, all which were unpredictable from effects observed with either chemotherapy or alone. Systemic also determined extent deficits encoding ion channel protein expression by single mechanosensory neurons, potassium Kv3.3 emerging one potential contributor to neuron dysfunction. Validated measures sensorimotor behavior awake, behaving animals dysfunction after was exacerbated cancer. Notably, errors precise forelimb placement emerged a novel behavioral deficit unpredicted our previous study These original findings identify contributors emphasize fundamental dependence systemic interaction SIGNIFICANCE: highlight need account for pathobiological major will have significant immediate impact future investigations this field.

Language: Английский

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