Finding biomarkers for immunotherapy is an urgent issue in cancer treatment.Cellular retinoic acid-binding protein 2(CRABP2)is a controversial factor in the occurrence and development of human tumors.However,there is ...Finding biomarkers for immunotherapy is an urgent issue in cancer treatment.Cellular retinoic acid-binding protein 2(CRABP2)is a controversial factor in the occurrence and development of human tumors.However,there is limited research on the relationship between CRABP2 and immunotherapy response.This study found that negative correlations of CRABP2 and immune checkpoint markers(PD-1,PD-L1,and CTLA-4)were observed in breast invasive carcinoma(BRCA),skin cutaneous melanoma(SKCM),stomach adenocarcinoma(STAD)and testicular germ cell tumors(TGCT).In particular,in SKCM patients who were treated with PD-1 inhibitors,high levels of CRABP2 predicted poor prognosis.Additionally,CRABP2 expression was elevated in cancer-associated fibroblasts(CAFs)at the single-cell level.The expression of CRABP2 was positively correlated with markers of CAFs,such as MFAP5,PDPN,ITGA11,PDGFRα/βand THY1 in SKCM.To validate the tumor-promoting effect of CRABP2 in vivo,SKCM xenograft mice models with CRABP2 overexpression have been constructed.These models showed an increase in tumor weight and volume.Enrichment analysis indicated that CRABP2 may be involved in immunerelated pathways of SKCM,such as extracellular matrix(ECM)receptor interaction and epithelial-mesenchymal transition(EMT).The study suggests that CRABP2 may regulate immunotherapy in SKCM patients by influencing infiltration of CAFs.In conclusion,this study provides new insights into the role of CRABP2 in immunotherapy response.The findings suggest that CRABP2 may be a promising biomarker for PD-1 inhibitors in SKCM patients.Further research is needed to confirm these findings and to explore the clinical implications of CRABP2 in immunotherapy.展开更多
Within the intricate milieu of colorectal cancer(CRC)tissues,cancer-associated fibroblasts(CAFs)act as pivotal orchestrators,wielding considerable influence over tumor progression.This review endeavors to dissect the ...Within the intricate milieu of colorectal cancer(CRC)tissues,cancer-associated fibroblasts(CAFs)act as pivotal orchestrators,wielding considerable influence over tumor progression.This review endeavors to dissect the multifaceted functions of CAFs within the realm of CRC,thereby highlighting their indispensability in fostering CRC malignant microenvironment and indicating the development of CAFs-targeted therapeutic interventions.Through a comprehensive synthesis of current knowledge,this review delineates insights into CAFsmediated modulation of cancer cell proliferation,invasiveness,immune evasion,and neovascularization,elucidating the intricate web of interactions that sustain the pro-tumor metabolism and secretion of multiple factors.Additionally,recognizing the high level of heterogeneity within CAFs is crucial,as they encompass a range of subtypes,including myofibroblastic CAFs,inflammatory CAFs,antigen-presenting CAFs,and vessel-associated CAFs.Innovatively,the symbiotic relationship between CAFs and the intestinal microbiota is explored,shedding light on a novel dimension of CRC pathogenesis.Despite remarkable progress,the orchestrated dynamic functions of CAFs remain incompletely deciphered,underscoring the need for continued research endeavors for therapeutic advancements in CRC management.展开更多
Colorectal cancer(CRC)remains one of the most commonly diagnosed and deadliest types of cancer worldwide.CRC displays a desmoplastic reaction(DR)that has been inversely associated with poor prognosis;less DR is associ...Colorectal cancer(CRC)remains one of the most commonly diagnosed and deadliest types of cancer worldwide.CRC displays a desmoplastic reaction(DR)that has been inversely associated with poor prognosis;less DR is associated with a better prognosis.This reaction generates excessive connective tissue,in which cancer-associated fibroblasts(CAFs)are critical cells that form a part of the tumor microenvironment.CAFs are directly involved in tumorigenesis through different mechanisms.However,their role in immunosuppression in CRC is not well understood,and the precise role of signal transducers and activators of transcription(STATs)in mediating CAF activity in CRC remains unclear.Among the myriad chemical and biological factors that affect CAFs,different cytokines mediate their function by activating STAT signaling pathways.Thus,the harmful effects of CAFs in favoring tumor growth and invasion may be modulated using STAT inhibitors.Here,we analyze the impact of different STATs on CAF activity and their immunoregulatory role.展开更多
Colorectal cancer (CRC) is a major global health concern. Accumulation of cancer-associated fibroblasts(CAFs) in CRC is associated with poor prognosis and disease recurrence. CAFs are the main cellular component ofthe...Colorectal cancer (CRC) is a major global health concern. Accumulation of cancer-associated fibroblasts(CAFs) in CRC is associated with poor prognosis and disease recurrence. CAFs are the main cellular component ofthe tumor microenvironment. CAF-tumor cell interplay, which is facilitated by various secretomes, drives colorectalcarcinogenesis. The complexity of CAF populations contributes to the heterogeneity of CRC and influences patientsurvival and treatment response. Due to their significant roles in colorectal carcinogenesis, different clinicalapplications utilizing or targeting CAFs have been suggested. Circulating CAFs (cCAFs) which can be detected inblood samples, have been proposed to help in determining patient prognosis and enables the detection of cancerthrough liquid biopsy. Liquid biopsy is gaining traction as it is non-invasive, allows frequent and easy sampling, andshows concordance to tissue biopsy analysis. In addition, CAF-targeted therapy is currently being studied extensivelyto be used as one of the treatment avenues for CRC. Various mechanisms of CAF-targeted therapy have beenreported, including blocking the signaling pathways involving CAFs and cancer cells, thus abolishing the CAF-tumorcell crosstalk and subsequently hindering tumorigenesis. These translational applications of cCAFs and utilization ofCAFs as key targets for CRC therapy, although still in the early phases of development, will potentially improve CRCpatient management in the future.展开更多
Tumor microenvironment plays a very important role in the growth,invasion and metastasis of tumor cells.The tumor interstitial microenvironment is an important part of the tumor microenvironment,which includes two par...Tumor microenvironment plays a very important role in the growth,invasion and metastasis of tumor cells.The tumor interstitial microenvironment is an important part of the tumor microenvironment,which includes two parts:the non-cellular and cellular components of the tumor interstitium,specifically including the extracellular matrix,blood vessels,and interstitial cells.Among them,activated interstitial fibroblasts,namely cancer-associated fibroblasts(CAFs),are the main components of tumor interstitial cells,which are most closely related to tumor interstitial fibrosis and tumor progress,and are expected to become a new target for cancer treatment.展开更多
Pancreatic cancer(PC) is the most aggressive type of common cancers, and in 2014, nearly 40000 patients died from the disease in the United States. Pancreatic ductal adenocarcinoma, which accounts for the majority of ...Pancreatic cancer(PC) is the most aggressive type of common cancers, and in 2014, nearly 40000 patients died from the disease in the United States. Pancreatic ductal adenocarcinoma, which accounts for the majority of PC cases, is characterized by an intense stromal desmoplastic reaction surrounding the cancer cells. Cancer-associated fibroblasts(CAFs) are the main effector cells in the desmoplastic reaction, and pancreatic stellate cells are the most important source of CAFs. However, other important components of the PC stroma are inflammatory cells and endothelial cells. The aim of this review is to describe the complex interplay between PC cells and the cellular and noncellular components of the tumour stroma. Published data have indicated that the desmoplastic stroma protects PC cells against chemotherapy and radiation therapy and that it might promote the proliferation and migration of PC cells. However, in animal studies, experimental depletion of the desmoplastic stroma and CAFs has led to more aggressive cancers. Hence, the precise role of the tumour stroma in PC remains to be elucidated. However, it is likely that a contextdependent therapeutic modification, rather than pure depletion, of the PC stroma holds potential for the development of new treatment strategies for PC patients.展开更多
The significant influence of tumor stroma on malignant cells has been extensively investigated in this era of targeted therapy. The tumor microenvironment, as a dynamic system, is orchestrated by various cells includi...The significant influence of tumor stroma on malignant cells has been extensively investigated in this era of targeted therapy. The tumor microenvironment, as a dynamic system, is orchestrated by various cells including tumor vascular composing cells, inflammatory cells and fibroblasts. As a major and important component in tumor stroma, increasing evidence has shown that spindle-shaped cancer-associated fibroblasts (CAFs) are a significant modifier of cancer evolution, and promote tumorigenesis, tumor invasion and metastasis by stimulating angiogenesis, malignant cell survival, epithelial-mesenchymal transition (EMT) and proliferation via direct cell-to-cell contact or secretion of soluble factors in most digestive solid tumors. CAFs are thought to be activated, characterized by the expression of α-smooth muscle actin, fibroblast activated protein, fibroblast specific protein, vimentin, fibronectin, etc. They are hypothesized to originate from normal or aged fibroblasts, bone marrow-derived mesenchymal cells, or vascular endothelial cells. EMT may also be an important process generating CAFs, and most probably, CAFs may originate from multiple cells. A close link exists between EMT, tumor stem cells, and chemo-resistance of tumor cells, which is largely orchestrated by CAFs. CAFs significantly induce immunosuppression, and may be a prognostic marker in various malignancies. Targeted therapy toward CAFs has displayed promising anticancer efficacy, which further reinforces the necessity to explore the relationship between CAFs and their hosts.展开更多
Cancer-associated fibroblasts(CAFs) are important components of various types of tumors,including gastric cancer(GC).During tumorigenesis and progression,CAFs play critical roles in tumor invasion and metastasis via a...Cancer-associated fibroblasts(CAFs) are important components of various types of tumors,including gastric cancer(GC).During tumorigenesis and progression,CAFs play critical roles in tumor invasion and metastasis via a series of functions including extracellular matrix deposition,angiogenesis,metabolism reprogramming and chemoresistance.However,the mechanism of the interaction between gastric cancer cells and CAFs remains largely unknown.Micro RNAs(mi RNAs) are a class of non-coding small RNA molecules,and their expression in CAFs not only regulates the expression of a number of target genes but also plays an essential role in the communication between tumor cells and CAFs.In this review,we provide an overview of recent studies on CAF mi RNAs in GC and the relevant signaling pathways in gastrointestinal tumors.Focusing the attention on these signaling pathways may help us better understand their role in tumor invasion and metastasis and identify new molecular targets for therapeutic strategies.展开更多
AIM To investigate the inhibitory effect of astragaloside IV on the pathological functions of cancer-associated fibroblasts,and to explore the underlying mechanism.METHODS Paired gastric normal fibroblast(GNF) and gas...AIM To investigate the inhibitory effect of astragaloside IV on the pathological functions of cancer-associated fibroblasts,and to explore the underlying mechanism.METHODS Paired gastric normal fibroblast(GNF) and gastric cancer-associated fibroblast(GCAF) cultures were established from resected tissues. GCAFs were treated with vehicle control or different concentrations of astragaloside Ⅳ. Conditioned media were prepared from GNFs,GCAFs,control-treated GCAFs,and astragaloside Ⅳ-treated GCAFs,and used to culture BGC-823 human gastric cancer cells. Proliferation,migration and invasion capacities of BGC-823 cells were determined by MTT,wound healing,and Transwell invasion assays,respectively. The action mechanism of astragaloside Ⅳ was investigated by detecting the expression of micro RNAs and the expression and secretion of the oncogenic factor,macrophage colonystimulating factor(M-CSF),and the tumor suppressive factor,tissue inhibitor of metalloproteinase 2(TIMP2),in different groups of GCAFs. The expression of the oncogenic pluripotency factors SOX2 and NANOG in BGC-823 cells cultured with different conditioned media was also examined.RESULTS GCAFs displayed higher capacities to induce BGC-823 cell proliferation,migration,and invasion than GNFs(P < 0.01). Astragaloside Ⅳ treatment strongly inhibited the proliferation-,migration-and invasion-promoting capacities of GCAFs(P < 0.05 for 10 μmol/L,P < 0.01 for 20 μmol/L and 40 μmol/L). Compared with GNFs,GCAFs expressed a lower level of micro RNA-214(P < 0.01) and a higher level of micro RNA-301 a(P < 0.01). Astragaloside Ⅳ treatment significantly upregulated micro RNA-214 expression(P < 0.01) and down-regulated micro RNA-301 a expression(P < 0.01) in GCAFs. Reestablishing the micro RNA expression balance subsequently suppressed M-CSF production(P < 0.01) and secretion(P < 0.05),and elevated TIMP2 production(P < 0.01) and secretion(P < 0.05). Consequently,the ability of GCAFs to increase SOX2 and NANOG expression in BGC-823 cells was abolished by astragaloside Ⅳ.CONCLUSION Astragaloside Ⅳ can inhibit the pathological functions of GCAFs by correcting their dysregulation of micro RNA expression,and it is promisingly a potent therapeutic agent regulating tumor microenvironment.展开更多
The hepatic stellate cells in the liver are stimulated sustainably by chronic injury of the hepatocytes, activating myofibroblasts, which produce abundant collagen. Myofibroblasts are the major source of extracellular...The hepatic stellate cells in the liver are stimulated sustainably by chronic injury of the hepatocytes, activating myofibroblasts, which produce abundant collagen. Myofibroblasts are the major source of extracellular proteins during fibrogenesis, and may directly, or secreted products, contribute to carcinogenesis and tumor progression. Cancer-associated fibroblasts(CAFs) are one of the components of the tumor microenvironment that promote the proliferation and invasion of cancer cells by secreting various growth factors and cytokines. CAFs crosstalk with cancer cells stimulates tumor progression by creating a favorable microenvironment for progression, invasion, and metastasis through the epithelial-mesenchymal transition. Basic studies on CAFs have advanced, and the role of CAFs in tumors has been elucidated. In particular, for hepatocellular carcinoma, carcinogenesis from cirrhosis is a known fact, and participation of CAFs in carcinogenesis is supported. In this review, we discuss the current literature on the role of CAFs and CAF-related signaling in carcinogenesis, crosstalk with cancer cells, immunosuppressive effects, angiogenesis, therapeutic targets, and resistance to chemotherapy. The role of CAFs is important in cancer initiation and progression. CAF-targeted therapy may be effective for suppression not only of fibrosis but also cancer progression.展开更多
AIM To determine whether it is possible to identify different immune phenotypic subpopulations of cancer-associated fibroblasts (CAFs) in pancreatic cancer (PC). METHODS We defined four different stromal compartments ...AIM To determine whether it is possible to identify different immune phenotypic subpopulations of cancer-associated fibroblasts (CAFs) in pancreatic cancer (PC). METHODS We defined four different stromal compartments in surgical specimens with PC: The juxtatumoural, peripheral, lobular and septal stroma. Tissue microarrays were produced containing all pre-defined PC compartments, and the expression of 37 fibroblast (FB) and 8 extracellular matrix (ECM) markers was evaluated by immunohistochemistry, immunofluorescence (IF), double-IF, and/or in situ hybridization. The compartment-specific mean labelling score was determined for each marker using a four-tiered scoring system. DOG1 gene expression was examined byquantitative reverse transcription PCR (qPCR). RESULTS CD10, CD271, cytoglobin, DOG1, miR-21, nestin, and tenascin C exhibited significant differences in expression profiles between the juxtatumoural and peripheral compartments. The expression of CD10, cytoglobin, DOG1, nestin, and miR-21 was moderate/strong in juxtatumoural CAFs (j-CAFs) and barely perceptible/weak in peripheral CAFs (p-CAFs). The upregulation of DOG1 gene expression in PC compared to normal pancreas was verified by qPCR. Tenascin C expression was strong in the juxtatumoural ECM and barely perceptible/weak in the peripheral ECM. CD271 expression was barely perceptible in j-CAFs but moderate in the other compartments. Galectin-1 was stronger expressed in j-CAFs vs septal fibroblasts, PDGFRβ, tissue transglutaminase 2, and hyaluronic acid were stronger expressed in lobular fibroblasts vs p-CAFs, and plectin-1 was stronger expressed in j-CAFs vs l-FBs. The expression of the remaining 33 markers did not differ significantly when related to the quantity of CAFs/FBs or the amount of ECM in the respective compartments.CONCLUSION Different immune phenotypic CAF subpopulations can be identified in PC, using markers such as cytoglobin, CD271, and miR-21. Future studies should determine whether CAF subpopulations have different functional properties.展开更多
Inefficient drug penetration hurdled by the stroma in the tumor tissue leads to a diminished therapeutic effect for drugs and a reduced infiltration level of immune cells.Herein,we constructed a PEGylated dendritic ep...Inefficient drug penetration hurdled by the stroma in the tumor tissue leads to a diminished therapeutic effect for drugs and a reduced infiltration level of immune cells.Herein,we constructed a PEGylated dendritic epirubicin(Epi)prodrug(Epi-P4D)to regulate the metabolism of cancer-associated fibroblasts(CAFs),thus enhancing Epi penetration into both multicellular tumor spheroids(MTSs)and tumor tissues in mouse colon cancer(CT26),mouse breast cancer(4T1)and human breast cancer(MDA-MB-231)models.Enhanced cytotoxicity against CT26 MTSs and remarkable antitumor efficacy of Epi-P4D were ascribed to reduced fibronectin,α-SMA,and collagen secretion.Besides,thinning of the tumor tissue stroma and efficient eradication of tumor cells promoted the immunogenic cell death effect for dendritic cell(DC)maturation and subsequent immune activation,including elevating the CD4^(+)T cell population,reducing CD4^(+)and CD8^(+)T cell hyperactivation and exhaustion,and amplifying the natural killer(NK)cell proportion and effectively activating them.As a result,this dendritic nanomedicine thinned the stroma of tumor tissues to enhance drug penetration and facilitate immune cell infiltration for elevated antitumor efficacy.展开更多
Resistance to sorafenib,an effective first-line treatment for advanced hepatocellular carcinoma(HCC),greatly compromised the prognosis of patients.The extracellular matrix is one of the most abundant components of the...Resistance to sorafenib,an effective first-line treatment for advanced hepatocellular carcinoma(HCC),greatly compromised the prognosis of patients.The extracellular matrix is one of the most abundant components of the tumor microenvironment.Beyond acting as a physical barrier,it remains unclear whether cell interactions and signal transduction mediated by the extracellular matrix contribute to sorafenib resistance.With the analysis of primary HCC organoid RNA-seq data combined with in vivo and in vitro experiments validation,we discovered that fibronectin extra domain A(FN-EDA)derived from cancer-associated fibroblasts played a critical role in sorafenib resistance.Mechanistically,FN-EDA stimulates the up-regulation of the key one-carbon metabolism enzyme SHMT1 in HCC cells via the TLR4/NF-κB signaling pathway,thereby countering the oxidative stress induced by sorafenib.Moreover,we reinforced the clinical significance of our discoveries by conducting in vivo assays with an immunodeficiency subcutaneous xenograft tumor model,which was established using primary cancer-associated fibroblasts derived from clinical HCC tissues,and through the analysis of HCC samples obtained from The Cancer Genome Atlas(TCGA)database.Our findings suggest that targeting the FN-EDA/SHMT1 pathway could be a potential strategy to improve sorafenib responsiveness in HCC patients.展开更多
With the advancement of anticancer therapy,there is increasing interest in understanding the tumor microenvi-ronment(TME).Cancer-associated fibroblasts(CAFs)play a pivotal role in the TME and have been the focus of mu...With the advancement of anticancer therapy,there is increasing interest in understanding the tumor microenvi-ronment(TME).Cancer-associated fibroblasts(CAFs)play a pivotal role in the TME and have been the focus of much research in recent years.CAFs play an active role in cancer progression through complex interactions with other cells in the TME,releasing regulatory factors,synthesizing and remodeling the extracellular matrix.How-ever,research on the role of CAFs in renal cell carcinoma(RCC)is still in its nascent stages.Here,we describe the origins and subgroups of CAFs,the roles of CAFs in the development and progression of RCC,the impact of CAFs on RCC prognosis,and the potential of CAFs as treatment targets in RCC.By analyzing CAF subsets,biomarkers,and targeted therapies,we present the significance and contribution of CAFs in RCC research.Furthermore,we highlight the distinct contribution of CAFs in advanced RCC through horizontal comparison with other cancers.This paper provides a comprehensive perspective of recent and foundational studies on the role of CAFs in RCC and other types of cancers and new insights for further study of CAFs in RCC.展开更多
As a critical component of the tumor microenvironment(TME),cancerassociated fibroblasts(CAFs)play important roles in cancer initiation and progression.Well-known signaling pathways,including the transforming growth fa...As a critical component of the tumor microenvironment(TME),cancerassociated fibroblasts(CAFs)play important roles in cancer initiation and progression.Well-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.Activated 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 cascades.The 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 therapies.Here,we review recent advances in studies of signaling pathways in CAFs and briefly discuss some future perspectives on CAF research.展开更多
Cancer-associated fibroblasts(CAFs)play an important role in facilitating the progression of triple-negative breast cancer(TNBC)by deteriorating the tumor mechanical microenvironment(TMME).Herein,we designed a CAFs-ta...Cancer-associated fibroblasts(CAFs)play an important role in facilitating the progression of triple-negative breast cancer(TNBC)by deteriorating the tumor mechanical microenvironment(TMME).Herein,we designed a CAFs-targeting nanomedicine by conjugating doxorubicin(DOX)-loaded hydroxyethyl starch-IR780 nanoparticles(NPs)with Cys-Arg-Glu-Lys-Ala(CREKA)peptide,which had a special affinity for fibronectin overexpressed on CAFs.After systemic administration,the NPs efficiently targeted CAFs and generated hyperthermia upon light irradiation,decreasing CAFs through the combination of chemo-and photothermal-therapies.Thus,a series of changes in TMME were achieved by reducing CAFs,which further disrupted the niche of cancer stem cells(CSCs)to affect their survival.As a result,the tumor growth was significantly inhibited in 4T1 tumors.The strategy of TMME modulation and CSCs elimination through targeting and depleting CAFs provides a novel therapeutic treatment for desmoplastic solid tumors.展开更多
Background The interplay between gut microbiota and tumor microenvironment(TME)in the pathogenesis of colorectal cancer(CRC)is not well explored.Here,we elucidated the functional role of Bifidobacterium adolescentis(B...Background The interplay between gut microbiota and tumor microenvironment(TME)in the pathogenesis of colorectal cancer(CRC)is not well explored.Here,we elucidated the functional role of Bifidobacterium adolescentis(B.a)on CRC and investigated its possible mechanism on the manipulation of cancer-associated fibroblasts(CAFs)in CRC.Methods Different CRC animal models and various cell line models were established to explore the function of B.a on CRC.The single-cell RNA sequencing(scRNA-seq)or flow cytometry was used to detect the cell subsets in the TME of CRC.Western blot,quantitative real-time polymerase chain reaction(qRT-PCR),or immunofluorescence staining were performed to examine the activation of Wnt signaling and growth arrest specific 1(GAS1)on CD143+CAFs.Chromatin immunoprecipitation quantitative real-time PCR(CHIP-qPCR)was performed to investigate the regulation of transcription factor 4(TCF4)on GAS1.Multi-immunofluorescence assay examined the expression level of CD143 and GAS1 on tissue microarray.Results We found that B.a abundance was significantly reduced in CRC patients from two independent cohorts and the bacteria database of GMrepo.Supplementation with B.a suppressed ApcMin/+spontaneous or AOM/DSS-induced tumorigenesis in mice.scRNA-seq revealed that B.a facilitated a subset of CD143+CAFs by inhibiting the infiltration of Th2 cells,while promoting the TNF-alpha+B cells in TME.CD143+CAFs highly expressed GAS1 and exhibited tumor suppressive effect.Mechanistically,GAS1 was activated by the Wnt/β-catenin signaling in CD143+CAFs.B.a abundance was correlated with the expression level of CD143 and GAS1.The level of CD143+CAFs predicted the better survival outcome in CRC patients.Conclusions These results highlighted that B.a induced a new subset of CD143+CAFs by Wnt signaling-regulated GAS1 to suppress tumorigenesis and provided a novel therapeutic target for probiotic-based modulation of TME in CRC.展开更多
The tumor microenvironment is proposed to contribute substantially to the progression of cancers,including breast cancer.Cancer-associated fibroblasts(CAFs)are the most abundant components of the tumor microenvironmen...The tumor microenvironment is proposed to contribute substantially to the progression of cancers,including breast cancer.Cancer-associated fibroblasts(CAFs)are the most abundant components of the tumor microenvironment.Studies have revealed that CAFs in breast cancer originate from several types of cells and promote breast cancer malignancy by secreting factors,generating exosomes,releasing nutrients,reshaping the extracellular matrix,and suppressing the function of immune cells.CAFs are also becoming therapeutic targets for breast cancer due to their specific distribution in tumors and their unique biomarkers.Agents interrupting the effect of CAFs on surrounding cells have been developed and applied in clinical trials.Here,we reviewed studies examining the heterogeneity of CAFs in breast cancer and expression patterns of CAF markers in different subtypes of breast cancer.We hope that summarizing CAFrelated studies from a historical perspective will help to accelerate the development of CAF-targeted therapeutic strategies for breast cancer.展开更多
Desmoplastic tumors have an abundance of stromal cells and the extracellular matrix which usually result in therapeutic resistance.Current treatment prescriptions for desmoplastic tumors are usually not sufficient to ...Desmoplastic tumors have an abundance of stromal cells and the extracellular matrix which usually result in therapeutic resistance.Current treatment prescriptions for desmoplastic tumors are usually not sufficient to eliminate the malignancy.Recently,through modulating cancer-associated fibroblasts(CAFs)which are the most abundant cell type among all stromal cells,natural products have improved chemotherapies and the delivery of nanomedicines to the tumor cells,showing promising ability to improve treatment effects on desmoplastic tumors.In this review,we discussed the latest advances in inhibiting desmoplastic tumors by modeling CAFs using natural products,highlighting the potential therapeutic abilities of natural products in targeting CAFs for cancer treatment.展开更多
Objective： Cancer-associated fibroblasts （CAFs） are one of the hallmarks of the cancer microenvironment. Recent evidence has indicated that CAFs are more competent in enhancing cancer cell growth and migration than...Objective： Cancer-associated fibroblasts （CAFs） are one of the hallmarks of the cancer microenvironment. Recent evidence has indicated that CAFs are more competent in enhancing cancer cell growth and migration than normal fibroblasts. However, the unique protein expression of CAFs has not been fully elucidated. This study aims to investigate the characterizations of colon CAFs by comparing the differential protein expression between CAFs and normal fibroblasts. Methods： Primary fibroblasts were isolated from surgical specimen of human colon cancer and matched normal colonic tissue. Purity of the cell population was verified through immunostain analysis. Total cell lysates and conditioned media from each group of cells were extracted, and protein expression analysis was con- ducted using the surface-enhanced laser desorption/ionization time-of-flight mass spectrometry （SELDI-TOF-MS） ProteinChip platform. Results： Most primary cells showed typical fibroblast-like features after two weeks. Increased proportion of a-smooth muscle actin-positive myofibroblasts was detected within the CAFs in four of the six pairs of primary cells. Fibroblast activation protein was weakly expressed in most cells without differences. Using SELDI-TOF-MS ProteinChip platform, four protein peaks mass over charge ratio （m/z） 1142, 3011, 4035, and 4945 were detected in the total cell lysates, and two protein peaks m/z 1368 and 1389 were detected in the conditioned media. The potential candidate proteins found in the Swiss-Prot database include morphogenetic neuropeptides, FMRFamide-related peptides, insulin-like growth factor II, thymosin 13-4-like protein 3, and tight junction-associated protein 1. Conclusions： Using the SELDI-ProteinChip platform, differential protein expressions were identified in colon CAFs compared with normal colonic stromal fibroblasts. The complex proteomic alternations in colon CAFs may play important roles related to the colon cancer microenvironment.展开更多
基金supported by grants from the Natural Science Foundation of Hunan Province(2022JJ80044)the Youth Science Foundation of Xiangya Hospital(2019Q13).
文摘Finding biomarkers for immunotherapy is an urgent issue in cancer treatment.Cellular retinoic acid-binding protein 2(CRABP2)is a controversial factor in the occurrence and development of human tumors.However,there is limited research on the relationship between CRABP2 and immunotherapy response.This study found that negative correlations of CRABP2 and immune checkpoint markers(PD-1,PD-L1,and CTLA-4)were observed in breast invasive carcinoma(BRCA),skin cutaneous melanoma(SKCM),stomach adenocarcinoma(STAD)and testicular germ cell tumors(TGCT).In particular,in SKCM patients who were treated with PD-1 inhibitors,high levels of CRABP2 predicted poor prognosis.Additionally,CRABP2 expression was elevated in cancer-associated fibroblasts(CAFs)at the single-cell level.The expression of CRABP2 was positively correlated with markers of CAFs,such as MFAP5,PDPN,ITGA11,PDGFRα/βand THY1 in SKCM.To validate the tumor-promoting effect of CRABP2 in vivo,SKCM xenograft mice models with CRABP2 overexpression have been constructed.These models showed an increase in tumor weight and volume.Enrichment analysis indicated that CRABP2 may be involved in immunerelated pathways of SKCM,such as extracellular matrix(ECM)receptor interaction and epithelial-mesenchymal transition(EMT).The study suggests that CRABP2 may regulate immunotherapy in SKCM patients by influencing infiltration of CAFs.In conclusion,this study provides new insights into the role of CRABP2 in immunotherapy response.The findings suggest that CRABP2 may be a promising biomarker for PD-1 inhibitors in SKCM patients.Further research is needed to confirm these findings and to explore the clinical implications of CRABP2 in immunotherapy.
文摘Within the intricate milieu of colorectal cancer(CRC)tissues,cancer-associated fibroblasts(CAFs)act as pivotal orchestrators,wielding considerable influence over tumor progression.This review endeavors to dissect the multifaceted functions of CAFs within the realm of CRC,thereby highlighting their indispensability in fostering CRC malignant microenvironment and indicating the development of CAFs-targeted therapeutic interventions.Through a comprehensive synthesis of current knowledge,this review delineates insights into CAFsmediated modulation of cancer cell proliferation,invasiveness,immune evasion,and neovascularization,elucidating the intricate web of interactions that sustain the pro-tumor metabolism and secretion of multiple factors.Additionally,recognizing the high level of heterogeneity within CAFs is crucial,as they encompass a range of subtypes,including myofibroblastic CAFs,inflammatory CAFs,antigen-presenting CAFs,and vessel-associated CAFs.Innovatively,the symbiotic relationship between CAFs and the intestinal microbiota is explored,shedding light on a novel dimension of CRC pathogenesis.Despite remarkable progress,the orchestrated dynamic functions of CAFs remain incompletely deciphered,underscoring the need for continued research endeavors for therapeutic advancements in CRC management.
基金Supported by the Programa de Apoyo a Proyectos de Investigación e Innovación Tecnológica(PAPIIT)de la Dirección General de Asuntos de Personal Académico,No.IN212722 and No.IA208424Consejo Mexiquense de Ciencia y Tecnología,No.CS000132Consejo Nacional de Humanidades,Ciencia y Tecnología,No.CF-2023-I-563.
文摘Colorectal cancer(CRC)remains one of the most commonly diagnosed and deadliest types of cancer worldwide.CRC displays a desmoplastic reaction(DR)that has been inversely associated with poor prognosis;less DR is associated with a better prognosis.This reaction generates excessive connective tissue,in which cancer-associated fibroblasts(CAFs)are critical cells that form a part of the tumor microenvironment.CAFs are directly involved in tumorigenesis through different mechanisms.However,their role in immunosuppression in CRC is not well understood,and the precise role of signal transducers and activators of transcription(STATs)in mediating CAF activity in CRC remains unclear.Among the myriad chemical and biological factors that affect CAFs,different cytokines mediate their function by activating STAT signaling pathways.Thus,the harmful effects of CAFs in favoring tumor growth and invasion may be modulated using STAT inhibitors.Here,we analyze the impact of different STATs on CAF activity and their immunoregulatory role.
基金supported by the Ministry of Higher Education Malaysia for Fundamental Research Grant Scheme with Project Code:FRGS/1/2020/SKK0/USM/03/10 and USM.
文摘Colorectal cancer (CRC) is a major global health concern. Accumulation of cancer-associated fibroblasts(CAFs) in CRC is associated with poor prognosis and disease recurrence. CAFs are the main cellular component ofthe tumor microenvironment. CAF-tumor cell interplay, which is facilitated by various secretomes, drives colorectalcarcinogenesis. The complexity of CAF populations contributes to the heterogeneity of CRC and influences patientsurvival and treatment response. Due to their significant roles in colorectal carcinogenesis, different clinicalapplications utilizing or targeting CAFs have been suggested. Circulating CAFs (cCAFs) which can be detected inblood samples, have been proposed to help in determining patient prognosis and enables the detection of cancerthrough liquid biopsy. Liquid biopsy is gaining traction as it is non-invasive, allows frequent and easy sampling, andshows concordance to tissue biopsy analysis. In addition, CAF-targeted therapy is currently being studied extensivelyto be used as one of the treatment avenues for CRC. Various mechanisms of CAF-targeted therapy have beenreported, including blocking the signaling pathways involving CAFs and cancer cells, thus abolishing the CAF-tumorcell crosstalk and subsequently hindering tumorigenesis. These translational applications of cCAFs and utilization ofCAFs as key targets for CRC therapy, although still in the early phases of development, will potentially improve CRCpatient management in the future.
文摘Tumor microenvironment plays a very important role in the growth,invasion and metastasis of tumor cells.The tumor interstitial microenvironment is an important part of the tumor microenvironment,which includes two parts:the non-cellular and cellular components of the tumor interstitium,specifically including the extracellular matrix,blood vessels,and interstitial cells.Among them,activated interstitial fibroblasts,namely cancer-associated fibroblasts(CAFs),are the main components of tumor interstitial cells,which are most closely related to tumor interstitial fibrosis and tumor progress,and are expected to become a new target for cancer treatment.
基金Supported by University of Southern DenmarkOdense University Hospital Research Fund
文摘Pancreatic cancer(PC) is the most aggressive type of common cancers, and in 2014, nearly 40000 patients died from the disease in the United States. Pancreatic ductal adenocarcinoma, which accounts for the majority of PC cases, is characterized by an intense stromal desmoplastic reaction surrounding the cancer cells. Cancer-associated fibroblasts(CAFs) are the main effector cells in the desmoplastic reaction, and pancreatic stellate cells are the most important source of CAFs. However, other important components of the PC stroma are inflammatory cells and endothelial cells. The aim of this review is to describe the complex interplay between PC cells and the cellular and noncellular components of the tumour stroma. Published data have indicated that the desmoplastic stroma protects PC cells against chemotherapy and radiation therapy and that it might promote the proliferation and migration of PC cells. However, in animal studies, experimental depletion of the desmoplastic stroma and CAFs has led to more aggressive cancers. Hence, the precise role of the tumour stroma in PC remains to be elucidated. However, it is likely that a contextdependent therapeutic modification, rather than pure depletion, of the PC stroma holds potential for the development of new treatment strategies for PC patients.
文摘The significant influence of tumor stroma on malignant cells has been extensively investigated in this era of targeted therapy. The tumor microenvironment, as a dynamic system, is orchestrated by various cells including tumor vascular composing cells, inflammatory cells and fibroblasts. As a major and important component in tumor stroma, increasing evidence has shown that spindle-shaped cancer-associated fibroblasts (CAFs) are a significant modifier of cancer evolution, and promote tumorigenesis, tumor invasion and metastasis by stimulating angiogenesis, malignant cell survival, epithelial-mesenchymal transition (EMT) and proliferation via direct cell-to-cell contact or secretion of soluble factors in most digestive solid tumors. CAFs are thought to be activated, characterized by the expression of α-smooth muscle actin, fibroblast activated protein, fibroblast specific protein, vimentin, fibronectin, etc. They are hypothesized to originate from normal or aged fibroblasts, bone marrow-derived mesenchymal cells, or vascular endothelial cells. EMT may also be an important process generating CAFs, and most probably, CAFs may originate from multiple cells. A close link exists between EMT, tumor stem cells, and chemo-resistance of tumor cells, which is largely orchestrated by CAFs. CAFs significantly induce immunosuppression, and may be a prognostic marker in various malignancies. Targeted therapy toward CAFs has displayed promising anticancer efficacy, which further reinforces the necessity to explore the relationship between CAFs and their hosts.
文摘Cancer-associated fibroblasts(CAFs) are important components of various types of tumors,including gastric cancer(GC).During tumorigenesis and progression,CAFs play critical roles in tumor invasion and metastasis via a series of functions including extracellular matrix deposition,angiogenesis,metabolism reprogramming and chemoresistance.However,the mechanism of the interaction between gastric cancer cells and CAFs remains largely unknown.Micro RNAs(mi RNAs) are a class of non-coding small RNA molecules,and their expression in CAFs not only regulates the expression of a number of target genes but also plays an essential role in the communication between tumor cells and CAFs.In this review,we provide an overview of recent studies on CAF mi RNAs in GC and the relevant signaling pathways in gastrointestinal tumors.Focusing the attention on these signaling pathways may help us better understand their role in tumor invasion and metastasis and identify new molecular targets for therapeutic strategies.
基金Supported by the National Natural Science Foundation of China,No.81760552the Program of the Inner Mongolia Natural Science Foundation,No.2016MS0824 and No.2015MS0896+1 种基金the Program of“Keji Baiwan Gongcheng”of Inner Mongolia Medical University,No.YKD2015KJBW008the Supporting Program for Outstanding Youth in Science and Technology of Inner Mongolia Autonomous Region,No.NJYT-17-B30
文摘AIM To investigate the inhibitory effect of astragaloside IV on the pathological functions of cancer-associated fibroblasts,and to explore the underlying mechanism.METHODS Paired gastric normal fibroblast(GNF) and gastric cancer-associated fibroblast(GCAF) cultures were established from resected tissues. GCAFs were treated with vehicle control or different concentrations of astragaloside Ⅳ. Conditioned media were prepared from GNFs,GCAFs,control-treated GCAFs,and astragaloside Ⅳ-treated GCAFs,and used to culture BGC-823 human gastric cancer cells. Proliferation,migration and invasion capacities of BGC-823 cells were determined by MTT,wound healing,and Transwell invasion assays,respectively. The action mechanism of astragaloside Ⅳ was investigated by detecting the expression of micro RNAs and the expression and secretion of the oncogenic factor,macrophage colonystimulating factor(M-CSF),and the tumor suppressive factor,tissue inhibitor of metalloproteinase 2(TIMP2),in different groups of GCAFs. The expression of the oncogenic pluripotency factors SOX2 and NANOG in BGC-823 cells cultured with different conditioned media was also examined.RESULTS GCAFs displayed higher capacities to induce BGC-823 cell proliferation,migration,and invasion than GNFs(P < 0.01). Astragaloside Ⅳ treatment strongly inhibited the proliferation-,migration-and invasion-promoting capacities of GCAFs(P < 0.05 for 10 μmol/L,P < 0.01 for 20 μmol/L and 40 μmol/L). Compared with GNFs,GCAFs expressed a lower level of micro RNA-214(P < 0.01) and a higher level of micro RNA-301 a(P < 0.01). Astragaloside Ⅳ treatment significantly upregulated micro RNA-214 expression(P < 0.01) and down-regulated micro RNA-301 a expression(P < 0.01) in GCAFs. Reestablishing the micro RNA expression balance subsequently suppressed M-CSF production(P < 0.01) and secretion(P < 0.05),and elevated TIMP2 production(P < 0.01) and secretion(P < 0.05). Consequently,the ability of GCAFs to increase SOX2 and NANOG expression in BGC-823 cells was abolished by astragaloside Ⅳ.CONCLUSION Astragaloside Ⅳ can inhibit the pathological functions of GCAFs by correcting their dysregulation of micro RNA expression,and it is promisingly a potent therapeutic agent regulating tumor microenvironment.
基金Supported by Research Program on Hepatitis from Japan Agency for Medical Research and development,AMED
文摘The hepatic stellate cells in the liver are stimulated sustainably by chronic injury of the hepatocytes, activating myofibroblasts, which produce abundant collagen. Myofibroblasts are the major source of extracellular proteins during fibrogenesis, and may directly, or secreted products, contribute to carcinogenesis and tumor progression. Cancer-associated fibroblasts(CAFs) are one of the components of the tumor microenvironment that promote the proliferation and invasion of cancer cells by secreting various growth factors and cytokines. CAFs crosstalk with cancer cells stimulates tumor progression by creating a favorable microenvironment for progression, invasion, and metastasis through the epithelial-mesenchymal transition. Basic studies on CAFs have advanced, and the role of CAFs in tumors has been elucidated. In particular, for hepatocellular carcinoma, carcinogenesis from cirrhosis is a known fact, and participation of CAFs in carcinogenesis is supported. In this review, we discuss the current literature on the role of CAFs and CAF-related signaling in carcinogenesis, crosstalk with cancer cells, immunosuppressive effects, angiogenesis, therapeutic targets, and resistance to chemotherapy. The role of CAFs is important in cancer initiation and progression. CAF-targeted therapy may be effective for suppression not only of fibrosis but also cancer progression.
基金Supported by Aase-and-Ejnar Danielsen’s Foundation,No.10-001452Brodrene Hartmann’s Foundation,No.A28308+5 种基金the Foundation of 17.12.1981,No.19024005Karen S.Jensens Grant,No.27-A1433University of Southern Denmark Faculty ScholarshipOdense University Hospital Free Research Fund,No.29-A1500,22-A1133 and 49-A2379Odense University Hospital Ph.D.stipend,No.1032Odense Pancreas Center(OPAC)
文摘AIM To determine whether it is possible to identify different immune phenotypic subpopulations of cancer-associated fibroblasts (CAFs) in pancreatic cancer (PC). METHODS We defined four different stromal compartments in surgical specimens with PC: The juxtatumoural, peripheral, lobular and septal stroma. Tissue microarrays were produced containing all pre-defined PC compartments, and the expression of 37 fibroblast (FB) and 8 extracellular matrix (ECM) markers was evaluated by immunohistochemistry, immunofluorescence (IF), double-IF, and/or in situ hybridization. The compartment-specific mean labelling score was determined for each marker using a four-tiered scoring system. DOG1 gene expression was examined byquantitative reverse transcription PCR (qPCR). RESULTS CD10, CD271, cytoglobin, DOG1, miR-21, nestin, and tenascin C exhibited significant differences in expression profiles between the juxtatumoural and peripheral compartments. The expression of CD10, cytoglobin, DOG1, nestin, and miR-21 was moderate/strong in juxtatumoural CAFs (j-CAFs) and barely perceptible/weak in peripheral CAFs (p-CAFs). The upregulation of DOG1 gene expression in PC compared to normal pancreas was verified by qPCR. Tenascin C expression was strong in the juxtatumoural ECM and barely perceptible/weak in the peripheral ECM. CD271 expression was barely perceptible in j-CAFs but moderate in the other compartments. Galectin-1 was stronger expressed in j-CAFs vs septal fibroblasts, PDGFRβ, tissue transglutaminase 2, and hyaluronic acid were stronger expressed in lobular fibroblasts vs p-CAFs, and plectin-1 was stronger expressed in j-CAFs vs l-FBs. The expression of the remaining 33 markers did not differ significantly when related to the quantity of CAFs/FBs or the amount of ECM in the respective compartments.CONCLUSION Different immune phenotypic CAF subpopulations can be identified in PC, using markers such as cytoglobin, CD271, and miR-21. Future studies should determine whether CAF subpopulations have different functional properties.
基金supported by the National Science and Technology Major Project of China(2023YFB3810004)the National Natural Science Foundation of China(32271445,52103175,32271382,32101145)+4 种基金the National Key Research and Development Program of China(2022YFC2009900)Department of Science and Technology of Sichuan Province(24NSFJQ0167,China)1·3·5 Project for Disciplines of Excellence,West China Hospital,Sichuan University(ZYJC21013,China)Post-Doctor Research Project,West China Hospital,Sichuan University(2021HXBH055,2021HXBH057,China)China Postdoctoral Science Foundation(2021M692314).
文摘Inefficient drug penetration hurdled by the stroma in the tumor tissue leads to a diminished therapeutic effect for drugs and a reduced infiltration level of immune cells.Herein,we constructed a PEGylated dendritic epirubicin(Epi)prodrug(Epi-P4D)to regulate the metabolism of cancer-associated fibroblasts(CAFs),thus enhancing Epi penetration into both multicellular tumor spheroids(MTSs)and tumor tissues in mouse colon cancer(CT26),mouse breast cancer(4T1)and human breast cancer(MDA-MB-231)models.Enhanced cytotoxicity against CT26 MTSs and remarkable antitumor efficacy of Epi-P4D were ascribed to reduced fibronectin,α-SMA,and collagen secretion.Besides,thinning of the tumor tissue stroma and efficient eradication of tumor cells promoted the immunogenic cell death effect for dendritic cell(DC)maturation and subsequent immune activation,including elevating the CD4^(+)T cell population,reducing CD4^(+)and CD8^(+)T cell hyperactivation and exhaustion,and amplifying the natural killer(NK)cell proportion and effectively activating them.As a result,this dendritic nanomedicine thinned the stroma of tumor tissues to enhance drug penetration and facilitate immune cell infiltration for elevated antitumor efficacy.
基金supported in part by the National Natural Science Foundation of China (No.81672856,82203669,81803028)the General Program of Chongqing Natural Science Foundation (China) (No.cstc2021jcyj-msxmX0687).
文摘Resistance to sorafenib,an effective first-line treatment for advanced hepatocellular carcinoma(HCC),greatly compromised the prognosis of patients.The extracellular matrix is one of the most abundant components of the tumor microenvironment.Beyond acting as a physical barrier,it remains unclear whether cell interactions and signal transduction mediated by the extracellular matrix contribute to sorafenib resistance.With the analysis of primary HCC organoid RNA-seq data combined with in vivo and in vitro experiments validation,we discovered that fibronectin extra domain A(FN-EDA)derived from cancer-associated fibroblasts played a critical role in sorafenib resistance.Mechanistically,FN-EDA stimulates the up-regulation of the key one-carbon metabolism enzyme SHMT1 in HCC cells via the TLR4/NF-κB signaling pathway,thereby countering the oxidative stress induced by sorafenib.Moreover,we reinforced the clinical significance of our discoveries by conducting in vivo assays with an immunodeficiency subcutaneous xenograft tumor model,which was established using primary cancer-associated fibroblasts derived from clinical HCC tissues,and through the analysis of HCC samples obtained from The Cancer Genome Atlas(TCGA)database.Our findings suggest that targeting the FN-EDA/SHMT1 pathway could be a potential strategy to improve sorafenib responsiveness in HCC patients.
基金supported by grants from the Natural Science Founda-tion of Shanghai(graft number:20ZR1413100)Beijing Xisike Clinical Oncology Research Foundation(graft number:Y-HR2020MS-0948)+1 种基金the Shanghai Anti-Cancer Association Eyas Project(graft numbers:SACA-CY21A06,SACA-CY21B01)Shanghai Municipal Health Bureau(graft number:2020CXJQ03).
文摘With the advancement of anticancer therapy,there is increasing interest in understanding the tumor microenvi-ronment(TME).Cancer-associated fibroblasts(CAFs)play a pivotal role in the TME and have been the focus of much research in recent years.CAFs play an active role in cancer progression through complex interactions with other cells in the TME,releasing regulatory factors,synthesizing and remodeling the extracellular matrix.How-ever,research on the role of CAFs in renal cell carcinoma(RCC)is still in its nascent stages.Here,we describe the origins and subgroups of CAFs,the roles of CAFs in the development and progression of RCC,the impact of CAFs on RCC prognosis,and the potential of CAFs as treatment targets in RCC.By analyzing CAF subsets,biomarkers,and targeted therapies,we present the significance and contribution of CAFs in RCC research.Furthermore,we highlight the distinct contribution of CAFs in advanced RCC through horizontal comparison with other cancers.This paper provides a comprehensive perspective of recent and foundational studies on the role of CAFs in RCC and other types of cancers and new insights for further study of CAFs in RCC.
基金National Natural Science Foundation of China,Grant/Award Numbers:81802352,82002541,81772555,81902428National Science Foundation for Distinguished Young Scholars of China,Grant/Award Number:81625016+4 种基金Shanghai Sailing Program,Grant/Award Number:20YF1409000Shanghai Rising-Star Program,Grant/Award Number:20QA1402100Shanghai Anticancer Association Young Eagle Program,Grant/Award Number:SACA-CY19A06Clinical and Scientific Innovation Project of Shanghai Hospital Development Center,Grant/Award Numbers:SHDC12018109,SHDC12019109Scientific Innovation Project of Shanghai Education Committee,Grant/Award Number:2019-01-07-00-07-E00057。
文摘As a critical component of the tumor microenvironment(TME),cancerassociated fibroblasts(CAFs)play important roles in cancer initiation and progression.Well-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.Activated 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 cascades.The 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 therapies.Here,we review recent advances in studies of signaling pathways in CAFs and briefly discuss some future perspectives on CAF research.
基金the National Research and Development Program of China(Nos.2018YFA0208900,2020YFA0211200,and 2020YFA0710700)the National Natural Science Foundation of China(Nos.82172757 and 31972927)+2 种基金the Scientific Research Foundation of Huazhong University of Science and Technology(No.3004170130)the Program for HUST Academic Frontier Youth Team(No.2018QYTD01)the HCP Program for HUST.
文摘Cancer-associated fibroblasts(CAFs)play an important role in facilitating the progression of triple-negative breast cancer(TNBC)by deteriorating the tumor mechanical microenvironment(TMME).Herein,we designed a CAFs-targeting nanomedicine by conjugating doxorubicin(DOX)-loaded hydroxyethyl starch-IR780 nanoparticles(NPs)with Cys-Arg-Glu-Lys-Ala(CREKA)peptide,which had a special affinity for fibronectin overexpressed on CAFs.After systemic administration,the NPs efficiently targeted CAFs and generated hyperthermia upon light irradiation,decreasing CAFs through the combination of chemo-and photothermal-therapies.Thus,a series of changes in TMME were achieved by reducing CAFs,which further disrupted the niche of cancer stem cells(CSCs)to affect their survival.As a result,the tumor growth was significantly inhibited in 4T1 tumors.The strategy of TMME modulation and CSCs elimination through targeting and depleting CAFs provides a novel therapeutic treatment for desmoplastic solid tumors.
基金National Natural Science Foundation of China,Grant/Award Numbers:82072623,82270573,82203618Zhejiang Province Natural Science Foundation,Grant/Award Number:LZ22H160002Zhejiang Province Medicine and Health Science and Technology Project,Grant/Award Numbers:2023KY722,2023KY785。
文摘Background The interplay between gut microbiota and tumor microenvironment(TME)in the pathogenesis of colorectal cancer(CRC)is not well explored.Here,we elucidated the functional role of Bifidobacterium adolescentis(B.a)on CRC and investigated its possible mechanism on the manipulation of cancer-associated fibroblasts(CAFs)in CRC.Methods Different CRC animal models and various cell line models were established to explore the function of B.a on CRC.The single-cell RNA sequencing(scRNA-seq)or flow cytometry was used to detect the cell subsets in the TME of CRC.Western blot,quantitative real-time polymerase chain reaction(qRT-PCR),or immunofluorescence staining were performed to examine the activation of Wnt signaling and growth arrest specific 1(GAS1)on CD143+CAFs.Chromatin immunoprecipitation quantitative real-time PCR(CHIP-qPCR)was performed to investigate the regulation of transcription factor 4(TCF4)on GAS1.Multi-immunofluorescence assay examined the expression level of CD143 and GAS1 on tissue microarray.Results We found that B.a abundance was significantly reduced in CRC patients from two independent cohorts and the bacteria database of GMrepo.Supplementation with B.a suppressed ApcMin/+spontaneous or AOM/DSS-induced tumorigenesis in mice.scRNA-seq revealed that B.a facilitated a subset of CD143+CAFs by inhibiting the infiltration of Th2 cells,while promoting the TNF-alpha+B cells in TME.CD143+CAFs highly expressed GAS1 and exhibited tumor suppressive effect.Mechanistically,GAS1 was activated by the Wnt/β-catenin signaling in CD143+CAFs.B.a abundance was correlated with the expression level of CD143 and GAS1.The level of CD143+CAFs predicted the better survival outcome in CRC patients.Conclusions These results highlighted that B.a induced a new subset of CD143+CAFs by Wnt signaling-regulated GAS1 to suppress tumorigenesis and provided a novel therapeutic target for probiotic-based modulation of TME in CRC.
基金National Natural Science Foundation of China,Grant/Award Numbers:81602471,81672729,81972453,81972597Natural Science Foundation of Zhejiang Province,Grant/Award Numbers:LY19H160055,LY19H160059,LR22H160011+2 种基金Natural Science Foundation of Ningbo,Grant/Award Number:2019A610315Cixi Agricultural and Social Development Science and Technology Project,Grant/Award Number:CN2020006Zheng Shu Medical Elite Scholarship Fund。
文摘The tumor microenvironment is proposed to contribute substantially to the progression of cancers,including breast cancer.Cancer-associated fibroblasts(CAFs)are the most abundant components of the tumor microenvironment.Studies have revealed that CAFs in breast cancer originate from several types of cells and promote breast cancer malignancy by secreting factors,generating exosomes,releasing nutrients,reshaping the extracellular matrix,and suppressing the function of immune cells.CAFs are also becoming therapeutic targets for breast cancer due to their specific distribution in tumors and their unique biomarkers.Agents interrupting the effect of CAFs on surrounding cells have been developed and applied in clinical trials.Here,we reviewed studies examining the heterogeneity of CAFs in breast cancer and expression patterns of CAF markers in different subtypes of breast cancer.We hope that summarizing CAFrelated studies from a historical perspective will help to accelerate the development of CAF-targeted therapeutic strategies for breast cancer.
基金supported by National Institutes of Health(Grant No.CA198999,USA)the State Key Laboratory of Molecular Engineering of Polymers,Fudan University(China)+3 种基金the National Natural Science Foundation of China(Grant Nos.81202924 and81773909)Shanghai Rising-Star Program of China(Grant No.13QA1403400)Shanghai talent development funds(Grant No.201665,China)Shanghai municipal commission of health and family planning(Grant No.2017YQ060,China)
文摘Desmoplastic tumors have an abundance of stromal cells and the extracellular matrix which usually result in therapeutic resistance.Current treatment prescriptions for desmoplastic tumors are usually not sufficient to eliminate the malignancy.Recently,through modulating cancer-associated fibroblasts(CAFs)which are the most abundant cell type among all stromal cells,natural products have improved chemotherapies and the delivery of nanomedicines to the tumor cells,showing promising ability to improve treatment effects on desmoplastic tumors.In this review,we discussed the latest advances in inhibiting desmoplastic tumors by modeling CAFs using natural products,highlighting the potential therapeutic abilities of natural products in targeting CAFs for cancer treatment.
基金supported by the National Natural Science Foundation of China (Nos. 81000892, 81071801, and 30801341)the Research Fund for the Doctoral Program of Higher Education of China (No. 200803351107)
文摘Objective： Cancer-associated fibroblasts （CAFs） are one of the hallmarks of the cancer microenvironment. Recent evidence has indicated that CAFs are more competent in enhancing cancer cell growth and migration than normal fibroblasts. However, the unique protein expression of CAFs has not been fully elucidated. This study aims to investigate the characterizations of colon CAFs by comparing the differential protein expression between CAFs and normal fibroblasts. Methods： Primary fibroblasts were isolated from surgical specimen of human colon cancer and matched normal colonic tissue. Purity of the cell population was verified through immunostain analysis. Total cell lysates and conditioned media from each group of cells were extracted, and protein expression analysis was con- ducted using the surface-enhanced laser desorption/ionization time-of-flight mass spectrometry （SELDI-TOF-MS） ProteinChip platform. Results： Most primary cells showed typical fibroblast-like features after two weeks. Increased proportion of a-smooth muscle actin-positive myofibroblasts was detected within the CAFs in four of the six pairs of primary cells. Fibroblast activation protein was weakly expressed in most cells without differences. Using SELDI-TOF-MS ProteinChip platform, four protein peaks mass over charge ratio （m/z） 1142, 3011, 4035, and 4945 were detected in the total cell lysates, and two protein peaks m/z 1368 and 1389 were detected in the conditioned media. The potential candidate proteins found in the Swiss-Prot database include morphogenetic neuropeptides, FMRFamide-related peptides, insulin-like growth factor II, thymosin 13-4-like protein 3, and tight junction-associated protein 1. Conclusions： Using the SELDI-ProteinChip platform, differential protein expressions were identified in colon CAFs compared with normal colonic stromal fibroblasts. The complex proteomic alternations in colon CAFs may play important roles related to the colon cancer microenvironment.
