Background and aims: Microbiota heterogeneity among humans is mainly due to genetic background, age, dietary habits, lifestyle and local environments. In this study we investigated whether the gut microbiota profile of Italian healthy volunteers could differ based on their geographical origin. Materials and Methods: 16S rRNA gene sequencing was employed to analyze the gut microbiota of 31 healthy volunteers from three different Italian regions: Apulia (South), Lazio (Center) and Lombardy (North). Results: Differences in microbiota composition were detected when the study participants were grouped by their region of origin and when they were classified based on age classes (p-values < 0.05). Also species richness was significantly different both according to Italian Regions (median richness: 177.8 vs. 140.7 vs. 168.0 in Apulia, Lazio and Lombardy; p < 0.001) and according to age classes (median richness: 140.1 vs. 177.8 vs. 160.0 in subjects < 32, 32–41 and > 41 years; p < 0.001), whereas the Shannon index and beta diversity did not change. Conclusions: This study identified differences in the gut microbiota composition and richness among individuals with the same ethnicity coming from three different Italian regions. Our results underline the importance of studies on population-specific variations in human microbiota composition leading to geographically tailored approaches to microbiota engineering.
Background Despite their lethality and ensuing clinical and therapeutic relevance, circulating tumor cells (CTCs) from colorectal carcinoma (CRC) remain elusive, poorly characterized biological entities. Methods and findings We perfected a cell system of stable, primary lines from human CRC showing that they possess the full complement of ex- and in-vivo , in xenogeneic models, characteristics of CRC stem cells (CCSCs). Here we show how tumor-initiating, CCSCs cells can establish faithful orthotopic phenocopies of the original disease, which contain cells that spread into the circulatory system. While in the vascular bed, these cells retain stemness, thus qualifying as circulating CCSCs (cCCSCs). This is followed by the establishment of lesions in distant organs, which also contain resident metastatic CCSCs (mCCSCs). Interpretation Our results support the concept that throughout all the stages of CRC, stemness is retained as a continuous property by some of their tumor cells. Importantly, we describe a useful standardized model that can enable isolation and stable perpetuation of human CRC's CCSCs, cCCSCs and mCCSCs, providing a useful platform for studies of CRC initiation and progression that is suitable for the discovery of reliable stage-specific biomarkers and the refinement of new patient-tailored therapies. Fund This work was financially supported by grants from “Ministero della Salute Italiano”(GR-2011-02351534, RC1703IC36 and RC1803IC35) to Elena Binda and from “Associazione Italiana Cancro” (IG-14368) Angelo L. Vescovi. None of the above funders have any role in study design, data collection, data analysis, interpretation, writing the project.
Background Glioblastoma multiforme (GBM) is an incurable tumor, with a median survival rate of only 14–15 months. Along with heterogeneity and unregulated growth, a central matter in dealing with GBMs is cell invasiveness. Thus, improving prognosis requires finding new agents to inhibit key multiple pathways, even simultaneously. A subset of GBM stem-like cells (GSCs) may account for tumorigenicity, representing, through their pathways, the proper cellular target in the therapeutics of glioblastomas. GSCs cells are routinely enriched and expanded due to continuous exposure to specific growth factors, which might alter some of their intrinsic characteristic and hide therapeutically relevant traits. Methods By removing exogenous growth factors stimulation, here we isolated and characterized a subset of GSCs with a “mitogen-independent” phenotype (I-GSCs) from patient’s tumor specimens. Differential side-by-side comparative functional and molecular analyses were performed either in vitro or in vivo on these cells versus their classical growth factor (GF)-dependent counterpart (D-GSCs) as well as their tissue of origin. This was performed to pinpoint the inherent GSCs’ critical regulators, with particular emphasis on those involved in spreading and tumorigenic potential. Transcriptomic fingerprints were pointed out by ANOVA with Benjamini-Hochberg False Discovery Rate (FDR) and association of copy number alterations or somatic mutations was determined by comparing each subgroup with a two-tailed Fisher’s exact test. The combined effects of interacting in vitro and in vivo with two emerging GSCs’ key regulators, such as Wnt5a and EphA2, were then predicted under in vivo experimental settings that are conducive to clinical applications. In vivo comparisons were carried out in mouse-human xenografts GBM model by a hierarchical linear model for repeated measurements and Dunnett’s multiple comparison test with the distribution of survival compared by Kaplan–Meier method. Results Here, we assessed that a subset of GSCs from high-grade gliomas is self-sufficient in the activation of regulatory growth signaling. Furthermore, while constitutively present within the same GBM tissue, these GF-independent GSCs cells were endowed with a distinctive functional and molecular repertoire, defined by highly aggressive Wnt5aHigh/EphA2Low profile, as opposed to Wnt5aLow/EphA2High expression in sibling D-GSCs. Regardless of their GBM subtype of origin, I-GSCs, are endowed with a raised in vivo tumorigenic potential than matched D-GSCs, which were fast-growing ex-vivo but less lethal and invasive in vivo. Also, the malignant I-GSCs’ transcriptomic fingerprint faithfully mirrored the original tumor, bringing into evidence key regulators of invasiveness, angiogenesis and immuno-modulators, which became candidates for glioma diagnostic/prognostic markers and therapeutic targets. Particularly, simultaneously counteracting the activity of the tissue invasive mediator Wnt5a and EphA2 tyrosine kinase receptor addictively hindered GSCs’ tumorigenic and invasive ability, thus increasing survival. Conclusion We show how the preservation of a mitogen-independent phenotype in GSCs plays a central role in determining the exacerbated tumorigenic and high mobility features distinctive of GBM. The exploitation of the I-GSCs' peculiar features shown here offers new ways to identify novel, GSCs-specific effectors, whose modulation can be used in order to identify novel, potential molecular therapeutic targets. Furthermore, we show how the combined use of PepA, the anti-Wnt5a drug, and of ephrinA1-Fc to can hinder GSCs’ lethality in a clinically relevant xenogeneic in vivo model thus being conducive to perspective, novel combinatorial clinical application.
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