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How the interplay among the tumor microenvironment and the gut microbiota influences the stemness of colorectal cancer cells

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World Journal of Stem Cells 2023年第5期15卷 281-301页

作者： María Belén Novoa Díaz pedro carriere Claudia Gentili Departamento de Biología Bioquímica y FarmaciaUniversidad Nacional del SurBahía Blanca 8000Buenos AiresArgentina Instituto de Ciencias Biológicas y Biomédicas del Sur Consejo Nacional de Investigaciones Científicas y Técnicas(CONICET)-Universidad Nacional del Sur(UNS)Bahía Blanca 8000Buenos AiresArgentina

Colorectal cancer(CRC)remains the third most prevalent cancer disease and involves a multi-step process in which intestinal cells acquire malignant *** is well established that the appearance of distal metastasis in CRC patients is the cause of a poor prognosis and treatment ***,in the last decades,CRC aggressiveness and progression have been attributed to a specific cell population called CRC stem cells(CCSC)with features like tumor initiation capacity,self-renewal capacity,and acquired multidrug *** data highlight the concept of this cell subtype as a plastic entity that has a dynamic status and can be originated from different types of cells through genetic and epigenetic *** alterations are modulated by complex and dynamic crosstalk with environmental factors by paracrine *** is known that in the tumor niche,different cell types,structures,and biomolecules coexist and interact with cancer cells favoring cancer growth and ***,these components constitute the tumor microenvironment(TME).Most recently,researchers have also deepened the influence of the complex variety of microorganisms that inhabit the intestinal mucosa,collectively known as gut microbiota,on *** TME and microorganisms participate in inflammatory processes that can drive the initiation and evolution of *** in the last decade,crucial advances have been made concerning to the synergistic interaction among the TME and gut microorganisms that condition the identity of CCSC,the data exposed in this review could provide valuable insights into the biology of CRC and the development of new targeted therapies.

关键词： Colorectal cancer Colorectal cancer stem cells Tumor microenvironment factors Tumor stroma Gut microbiota Cancer progression

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Involvement of Met receptor pathway in aggressive behavior of colorectal cancer cells induced by parathyroid hormone-related peptide

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World Journal of Gastroenterology 2022年第26期28卷 3177-3200页

作者： María Belén Novoa Díaz pedro carriere Graciela Gigola Ariel Osvaldo Zwenger Natalia Calvo Claudia Gentili Departamento de Biología Bioquímica y FarmaciaUniversidad Nacional del Sur(UNS)-INBIOSUR(CONICET-UNS)Bahía Blanca 8000Buenos AiresArgentina Centro de Estudios Clínicos SAGA CEC SAGASantiago de Chile 8320000Chile

BACKGROUND Parathyroid hormone-related peptide(PTHrP)plays a key role in the development and progression of many *** found that in colorectal cancer(CRC)HCT116 cells,the binding of PTHrP to its receptor PTHR type 1(PTHR1)activates events associated with an aggressive *** HCT116 cell xenografts,PTHrP modulates the expression of molecular markers linked to tumor *** evidence suggests that the Met receptor is involved in the development and evolution of *** on these data,we hypothesized that the signaling pathway trigged by PTHrP could be involved in the transactivation of Met and consequently in the aggressive behavior of CRC *** To elucidate the relationship among PTHR1,PTHrP,and Met in CRC *** For in vitro assays,HCT116 and Caco-2 cells derived from human CRC were incubated in the absence or presence of PTHrP(1-34)(10-8 M).Where indicated,cells were pre-incubated with specific kinase inhibitors or dimethylsulfoxide,the vehicle of the *** protein levels were evaluated by Western blot ***-time polymerase chain reaction(RT-qPCR)was carried out to determine the changes in gene *** healing assay and morpho logical monitoring were performed to evaluate cell migration and changes related to the epithelialmesenchymal transition(EMT),*** number of viable HCT116 cells was counted by trypan blue dye exclusion test to evaluate the effects of irinotecan(CPT-11),oxaliplatin(OXA),or doxorubicin(DOXO)with or without *** in vivo tests,HCT116 cell xenografts on 6-wk-old male N:NIH(S)_nu mice received daily intratumoral injections of PTHrP(40μg/kg)in 100μL phosphate-buffered saline(PBS)or the vehicle(PBS)as a control during 20 *** slaughter was carried out and the tumors were removed,weighed,and fixed in a 4%formaldehyde solution for subsequent treatment by *** evaluate the expression of molecular markers in human tumor samples,we studied 23 specimens ob

关键词： PTHrP MET receptor tyrosine kinase Parathyroid hormone receptor type 1 Colorectal cancer Drug resistance

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Survival effect of probiotics in a rat model of colorectal cancer treated with capecitabine

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World Journal of Gastrointestinal Oncology 2021年第10期13卷 1518-1531页

作者： Graciela Gigola pedro carriere María Belén Novoa Díaz Gabriela Perdigon Ariel Osvaldo Zwenger Claudia Gentili Biología Bioquímica y FarmaciaUniversidad Nacional del Sur(UNS)-INBIOSUR(CONICET-UNS)Bahía Blanca 8000Buenos Aires ProvinciaArgentina San Miguel de Tucumán 4000Argentina Centro de Estudios Clínicos SAGA CEC SAGASantiago de Chile 8320000Chile

BACKGROUND Probiotics are used to manage a number of gastrointestinal disorders due to their beneficial *** reports showed that probiotics also improve the life quality of patients with colorectal cancer(CRC)subjected to oncologic *** a CRC animal model,probiotics supplementation has the potential to decrease the formation of aberrant crypts and ameliorate tumor malignancy,enhancing the antitumor effect of 5-fluorouracil(5-FU)*** on these data,we hypothesize that the administration of probiotics impact positively in the overall survival and life quality of rats with CRC under the treatment of capecitabine,which is the pro drug of *** To evaluate the probiotics effects in a rat CRC model treated with capecitabine and followed until the end of *** 1,2-Dimethylhidrazine dihydrochloride(1,2-DMH)was employed as carcinogen inductor of *** male Wistar-Lewis rats were randomly assigned to one of five following groups:Control(n=5),Control+probiotics(Control-P group,n=5),1,2-DMH alone(DMH group,n=10),1,2-DMH+capecitabine(DMH-C group,n=10),1,2-DMH+probiotics(DMH-P group,n=10)and 1,2-DMH+capecitabine+probiotics(DMH-C-P group,n=10).All parametric data were expressed as the mean±*** statistical significance of differences was analyzed using one-way *** were analyzed with InfoStat *** results were considered statistically significant at P<*** survival was evaluated with the Kaplan-Meier estimator with the log-rank *** The data of mean overall survival for DMH,DMH-P,DMH-C,DMH-C-P,Control and Control-P groups were 250 d[95%confidence interval(CI):242.5-253.1],268 d(95%CI:246.3-271.4),380 d(95%CI:337.8-421.9),480 d(95%CI:436.9-530.7),588 d(95%CI:565.8-609.3)and 590 d(95%CI:564.3-612.9),respectively,with a significant difference between DMH-C and DMH-C-P groups(P=0.001).Comparing all groups by Kaplan-Meier estimator,we found a significantly different in the overall survival of DMH and DMH-

关键词： Colorectal cancer Capecitabine Probiotics Survival Life quality Animal experimentation

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Involvement of parathyroid hormone-related peptide in the aggressive phenotype of colorectal cancer cells

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World Journal of Gastroenterology 2021年第41期27卷 7025-7040页

作者： María Belén Novoa Díaz pedro Matías carriere María Julia Martín Natalia Calvo Claudia Gentili Departamento de Biología Bioquímica y FarmaciaUniversidad Nacional del Sur(UNS)-INBIOSUR(CONICET-UNS)Bahía Blanca 8000Buenos AiresArgentina Departamento de Química Universidad Nacional del Sur(UNS)-INQUISUR(CONICET-UNS)Bahía Blanca 8000Buenos AiresArgentina

Colorectal cancer(CRC)remains one of the leading causes of mortality from malignant diseases *** general terms,CRC presents high heterogeneity due to the influence of different genetic and environmental factors;also,the neoplastic cells are strongly influenced by the extracellular matrix and several surrounding cells,known together as the tumor microenvironment(TME).Bidirectional communication takes place between the tumor and the TME through the release of autocrine and paracrine *** hormone-related peptide(PTHrP)is a cytokine secreted by a wide variety of tissues and is able to regulate several cellular functions both in physiological as well as in pathological *** exerts its effects as a paracrine/autocrine factor,although its mode of action is mainly *** has been shown that this peptide is expressed by several tumors and that the tumor secretion of PTHrP is responsible for the malignant humoral *** years ago,when our research group started studying PTHrP effects in the experimental models derived from intestinal tumors,the literature available at the time addressing the effects of PTHrP on colorectal tumors was limited,and no articles had been published regarding to the paracrine action of PTHrP in CRC *** on this and on our previous findings regarding the role of PTH in CRC cells,our purpose in recent years has been to explore the role of PTHrP in *** analyzed the behavior of CRC cells treated with exogenous PTHrP,focalizing in the study of the following events:Survival,cell cycle progression and proliferation,migration,chemoresistance,tumor-associated angiogenesis,epithelial to mesenchymal transition program and other events also associated with invasion,such us the induction of cancer stem cells *** work summarizes the major findings obtained by our investigation group using in vitro and in vivo CRC models that evidence the participation of PTHrP in the acquisition of an aggressiv

关键词： Parathyroid hormone-related protein Colorectal cancer Tumor biomarkers Neoplastic processes Drug resistance Tumor microenvironment

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