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signaling pathways in cancer-associated fibroblasts:recent advances and future perspectives

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Cancer Communications 2023年第1期43卷 3-41页

作者： Zengli Fang Qingcai Meng Jin Xu Wei Wang Bo Zhang Jiang Liu Chen Liang Jie Hua Yingjun Zhao Xianjun Yu Si Shi Department of Pancreatic Surgery Fudan University Shanghai Cancer CenterShanghai 200032P.R.China Department of Oncology Shanghai Medical CollegeFudan UniversityShanghai 200032P.R.China Shanghai Pancreatic Cancer Institute Shanghai 200032P.R.China Pancreatic Cancer Institute Fudan UniversityShanghai 200032P.R.China Institutes of Biomedical Sciences Shanghai Medical CollegeFudan UniversityShanghai 200032P.R.China

As a critical component of the tumor microenvironment(TME),cancerassociated fibroblasts(CAFs)play important roles in cancer initiation and ***-known signaling pathways,including the transforming growth factor-β(TGF-β),Hedgehog(Hh),Notch,Wnt,Hippo,nuclear factor kappa-B(NF-κB),Janus kinase(JAK)/signal transducer and activator of transcription(STAT),mitogen-activated protein kinase(MAPK),and phosphoinositide 3-kinase(PI3K)/AKT pathways,as well as transcription factors,including hypoxia-inducible factor(HIF),heat shock transcription factor 1(HSF1),P53,Snail,and Twist,constitute complex regulatory networks in theTMEtomodulate the formation,activation,heterogeneity,metabolic characteristics and malignant phenotype of *** CAFs remodel the TME and influence the malignant biological processes of cancer cells by altering the transcriptional and secretory characteristics,and this modulation partially depends on the regulation of signaling *** results of preclinical and clinical trials indicated that therapies targeting signaling pathways in CAFs demonstrated promising efficacy but were also accompanied by some failures(e.g.,NCT01130142 and NCT01064622).Hence,a comprehensive understanding of the signaling cascades in CAFs might help us better understand the roles of CAFs and the TME in cancer progression and may facilitate the development of more efficient and safer stroma-targeted cancer ***,we review recent advances in studies of signaling pathways in CAFs and briefly discuss some future perspectives on CAF research.

关键词： signaling pathways Cancer-associated fibroblasts Cell-cell interaction Tumor microenvironment Therapeutic targets

Molecular mechanism of pancreatic ductal adenocarcinoma:The heterogeneity of cancer-associated fibroblasts and key signaling pathways

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World Journal of Clinical Oncology 2025年第2期16卷 18-28页

作者： Zhong-Yuan Hu Ding Ding Yu Song Ya-Feng Deng Cheng-Ming Zhang Tao Yu First School of Clinical Medicine Shaanxi University of Chinese MedicineXianyang 712000Shaanxi ProvinceChina College of Acupuncture and Massage Shaanxi University of Chinese MedicineXianyang 712000Shaanxi ProvinceChina Graduate School Guangzhou University of Chinese MedicineGuangzhou 510000Guangdong ProvinceChina Digestive Department I Shaanxi Provincial Hospital of Traditional Chinese MedicineXi’an 710000Shaanxi ProvinceChina

Pancreatic ductal adenocarcinoma stands out as an exceptionally fatal cancer owing to the complexities associated with its treatment and diagnosis,leading to a notably low five-year survival *** study offers a detailed exploration of epidemiological trends in pancreatic cancer and key molecular drivers,such as mutations in CDKN2A,KRAS,SMAD4,and TP53,along with the influence of cancer-associated fibroblasts(CAFs)on disease *** particular,we focused on the pivotal roles of signaling pathways such as the transforming growth factor-βand Wnt/β-catenin pathways in the development of pancreatic cancer and investigated their application in emerging therapeutic *** study provides new scientific perspectives on pancreatic cancer treatment,especially in the development of precision medicine and targeted therapeutic strategies,and demonstrates the importance of signaling pathway research in the development of effective therapeutic *** studies should explore the subtypes of CAFs and their specific roles in the tumor microenvironment to devise more effective therapeutic methods.

关键词： Pancreatic cancer Fibroblasts signaling pathways Tumor microenvironment

signaling pathways downstream to receptor tyrosine kinases:targets for cancer treatment

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Journal of Cancer Metastasis and Treatment 2020年第1期6卷 556-574页

作者： Emma Cordover Audrey Minden Susan Lehman Cullman Laboratory for Cancer Research Department of Chemical BiologyErnest Mario School of PharmacyRutgersThe State University of New JerseyPiscatawayNJ 08854USA

Mammalian cells have the ability to respond to a myriad of diverse extracellular stimuli that modulate cell *** often involves ligands binding to cell surface receptors and subsequent activation of intracellular signaling *** pathways can lead to changes in gene expression patterns that in turn regulate cell growth,differentiation,migration,and *** important type of cell surface receptor is the receptor tyrosine kinase(RTK).In response to in response to ligand binding,RTKs dimerize,then trans-phosphorylate each other,leading to activation of downstream *** the signaling proteins in these pathways are important for normal cell growth control,when improperly regulated they can lead to uncontrolled growth and sometimes *** this reason,they are often considered to be good candidates for drug targets for chemotherapeutic *** can activate multiple different signaling *** of the signaling proteins in these pathways can have crosstalk with other RTK activated pathways,and some of them can be activated by multiple mechanisms in addition to activation by *** there is a wide array of different signaling proteins and pathways activated by RTKs,in this review we will discuss components of several key pathways including the MAPK pathway,the Her2/Neu pathway,mTOR,and Pak *** provide an overview of the roles for these pathways in cell signaling and discuss how different components of these pathways are being considered as targets for cancer treatment.

关键词： Receptor tyrosine kinases signaling pathways targeted cancer therapeutics oncogenes cell signaling

On signaling pathways: hematopoietic stem cell specification from hemogenic endothelium

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Science China(Life Sciences) 2015年第12期58卷 1256-1261页

作者： LONG Yan HUANG He Bone Marrow Transplantation Center The First Affiliated Hospital School of Medicine Zhejiang University

Hematopoietic stem cells(HSCs) are specified and generated during the embryonic development and have remarkable potential to replenish the full set of blood cell lineages. Researchers have long been interested in clarifying the molecular events involved in HSC specification. Many studies have reported the development of methods for generating functional hematopoietic cells from pluripotent stem cells(PSCs-embryonic stem cells(ESCs) and induced pluripotent stem cells(i PSCs)) for decades. However, the generation of HSCs with robust long-term repopulation potential remains a swingeing challenge, of which a major factor contributing to this failure is the difficulty to define the intraembryonic signals related to the specification of HSCs. Since HSCs directly derive from hemogenic endothelium, in this review, we summarize both in vivo and in vitro studies on conserved signaling pathways that control the specification of HSCs from hemogenic endothelial cells.

关键词： HSCs hemogenic endothelium signaling pathways

*** ZJ617 inhibits inflammatory and autophagy signaling pathways in gut-liver axis in piglet induced by lipopolysaccharide

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Journal of Animal Science and Biotechnology 2022年第2期13卷 551-566页

作者： Tao Zhu Jiangdi Mao Yifan Zhong Congxiang Huang Zhaoxi Deng Yanjun Cui Jianxin Liu Haifeng Wang The Key Laboratory of Molecular Animal Nutrition Ministry of EducationCollege of Animal ScienceZhejiang UniversityHangzhou 310058China Xixi Hospital of Hangzhou Hangzhou 310023China

Background:This study investigated the protective effects of *** ZJ617 on intestinal and liver injury and the underlying mechanisms in modulating inflammatory,autophagy,and apoptosis signaling pathways in a piglet challenged with lipopolysaccharide(LPS).Methods:Duroc×Landrace×Large White piglets were assigned to 3 groups(n=6/group):control(CON)and LPS groups received oral phosphate-buffered saline for 2 weeks before intraperitoneal injection(i.p.)of physiological saline or LPS(25μg/kg body weight),respectively,while the ZJ617+LPS group was orally inoculated with ZJ617 for 2 weeks before *** *** were sacrificed 4 h after LPS injection to determine intestinal integrity,serum biochemical parameters,inflammatory signaling involved in molecular and liver injury ***:Compared with controls,LPS stimulation significantly increased intestinal phosphorylated-p38 MAPK,phosphorylated-ERK and JNK protein levels and decreased IκBαprotein expression,while serum LPS,TNF-α,and IL-6 concentrations(P<0.05)***617 pretreatment significantly countered the effects induced by LPS alone,with the exception of p-JNK protein *** with controls,LPS stimulation significantly increased LC3,Atg5,and Beclin-1 protein expression(P<0.05)but decreased ZO-1,claudin-3,and occludin protein expression(P<0.05)and increased serum DAO and D-xylose levels,effects that were all countered by ZJ617 *** induced significantly higher hepatic LC3,Atg5,Beclin-1,SOD-2,and Bax protein expression(P<0.05)and lower hepatic total bile acid(TBA)levels(P<0.05)compared with ***617 pretreatment significantly decreased hepatic Beclin-1,SOD2,and Bax protein expression(P<0.05)and showed a tendency to decrease hepatic TBA(P=0.0743)induced by LPS *** of ZJ617 before LPS injection induced the production of 5 significant metabolites in the intestinal contents:capric acid,isoleucine 1TMS,glycerol-1-phosphate byproduct,linoleic acid,alanine-alanine

关键词： Gut-liver axis Hepatic injury Intestinal barrier Lactobacillus Piglet signaling pathways

Auricularia polytricha and Flammulina velutipes ameliorate inflammation and modulate the gut microbiota via regulation of NF-κB and Keap1/Nrf2 signaling pathways on DSS-induced inflammatory bowel disease

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Food Bioscience 2022年第3期47卷 356-370页

作者： Ivan Stève Nguepi Tsopmejio Miao Ding Jiali Wei Cong Zhao Yu Jiang Yuting Li Hui Song School of Life Science Jilin Agricultural UniversityJilinPR China Department of Animal Biology and Physiology University of Yaoundé ICameroon Engineering Research Center of Chinese Ministry of Education for Edible and Medicinal Fungi ChangchunPR China

Flammulina velutipes and Auricularia polytricha are two popular dietary mushrooms,especially in the Northeast of *** have revealed many pharmacological effects due to their bioactive compounds,but their possible mechanism of action involved in inflammation remains poorly ***,Inflammatory bowel disease(IBD)which is a chronic disease and progressive inflammation in the gastrointestinal tract were used to evaluate their anti-inflammatory and modulatory properties on the intestinal microbiota via the signaling pathways involved by oral administration of ***(FVE)and ***(APE).Mice were daily received 3%DSS in the drinking water followed by the daily administration of FVE and *** food consumption,weight variation and DAI score were assessed during the experiment and inflammatory parameters,mRNA and protein expressions to determine the possible signaling pathways involved,and the gut microbiota from the cecum by high-throughput *** showed that APE and FVE improved clinical symptoms,inflammatory cytokines and oxidative *** also attenuated the mRNA and proteins expressions in colon ***,APE and FVE regulated DSS-induced intestinal dysbiosis and stimulated the SCFAs ***,APE and FVE could improve DSS-induced IBD in mice suggesting that they represent novels therapeutic drugs and could be used as prebiotic to modulate the gut microbiota and preserve intestinal integrity.

关键词： Flammulina velutipes Auricularia polytricha Inflammatory bowel disease signaling pathways Intestinal microbiota

Regulation of signaling pathways in hair follicle stem cells

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Burns & Trauma 2022年第1期10卷 306-324页

作者： Xiaoxiang Wang Yinghui Liu Jia He Jingru Wang Xiaodong Chen Ronghua Yang Department of Burn Surgery The First People’s Hospital of FoshanFoshan 528000China Guangdong Medical University Zhanjiang524000China Department of Dermatology Dermatology HospitalSouthern Medical UniversityGuangzhou510091China

Hair follicle stem cells(HFSCs)reside in the bulge region of the outer root sheath of the hair *** are considered slow-cycling cells that are endowed with multilineage differentiation potential and superior proliferative *** normal morphology and periodic growth of HFSCs play a significant role in normal skin functions,wound repair and skin *** HFSCs involved in these pathophysiological processes are regulated by a series of cell signal transduction pathways,such as lymphoid enhancer factor/T-cell factor,Wnt/β-catenin,transforming growth factor-β/bone morphogenetic protein,Notch and *** mechanisms of the interactions among these signaling pathways and their regulatory effects on HFSCs have been previously studied,but many mechanisms are still *** article reviews the regulation of hair follicles,HFSCs and related signaling pathways,with the aims of summarizing previous research results,revealing the regulatory mechanisms of HFSC proliferation and differentiation and providing important references and new ideas for treating clinical diseases.

关键词： Hair follicle stem cells signaling pathways Proliferation Differentiation Regenerative Repair

Mesenchymal stromal cells' role in tumor microenvironment:involvement of signaling pathways

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Cancer Biology & Medicine 2017年第2期14卷 129-141页

作者： Armel Herve Nwabo Kamdje Paul Takam Kamga Richard Tagne Simo Lorella Vecchio Paul Faustin Seke Etet Jean Marc Muller Giulio Bassi Erique Lukong Raghuveera Kumar Goel Jeremie Mbo Amvene Mauro Krampera Department of Biomedical Sciences University of Ngaoundere Laboratory University of Verona Department of Basic Health SciencesCollege of Applied Medical SciencesQassim University Faculty of Science University of Poitiers Department of Biochemistry College of MedicineUniversity of Saskatchewan

Mesenchymal stromal cells(MSCs) are adult multipotent stem cells residing as pericytes in various tissues and organs where they can differentiate into specialized cells to replace dying cells and damaged tissues. These cells are commonly found at injury sites and in tumors that are known to behave like "wounds that do not heal." In this article, we discuss the mechanisms of MSCs in migrating, homing, and repairing injured tissues. We also review a number of reports showing that tumor microenvironment triggers plasticity mechanisms in MSCs to induce malignant neoplastic tissue formation, maintenance, and chemoresistance, as well as tumor growth. The antitumor properties and therapeutic potential of MSCs are also discussed.

关键词： Mesenchymal stromal cells systemic circulation migration homing tumor modulation signaling pathways chemoresistance

Targeting stem cell signaling pathways for drug discovery:advances in the Notch and Wnt pathways

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Science China(Life Sciences) 2014年第6期57卷 575-580页

作者： AN Songzhu Michael DING Qiang ZHANG Jie XIE JingYi LI LingSong Curegenix Inc. Center for Stem Cell and NanoMedicine Shanghai Advanced Research InstituteChinese Academy of Sciences

signaling pathways transduce extracellular stimuli into cells through molecular cascades to regulate cellular *** stem cells,a small number of pathways,notably those of TGF-?/BMP,Hedgehog,Notch,and Wnt,are responsible for the regulation of pluripotency and *** embryonic development,these pathways govern cell fate specifications as well as the formation of tissues and *** adulthood,their normal functions are important for tissue homeostasis and regeneration,whereas aberrations result in diseases,such as cancer and degenerative *** complex biological systems,stem cell signaling pathways work in concert as a network and exhibit crosstalk,such as the negative crosstalk between Wnt and *** the past decade,genetic and genomic studies have identified a number of potential drug targets that are involved in stem cell signaling ***,discovery of new targets and drugs for these pathways has become one of the most active areas in both the research community and pharmaceutical *** progress has been made and several promising drug candidates have entered into clinical *** review focuses on recent advances in the discovery of novel drugs which target the Notch and Wnt pathways.

关键词： stem cell drug discovery signaling pathways Notch Wnt cancer