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Targeting Cancer-associated fibroblasts with hydroxyethyl starch nanomedicine boosts cancer therapy

Nano Research 2023年第5期16卷 7323-7336页

作者： Chong Wang Huimin Wang Hai Yang Chen Xu Qiang Wang Zheng Li Zhijie Zhang Jiankun Guan Ximiao Yu Xiaoquan Yang Xiangliang Yang Zifu Li National Engineering Research Center for Nanomedicine College of Life Science and TechnologyHuazhong University of Science and TechnologyWuhan 430074China GBA Research Innovation Institute for Nanotechnology Guangzhou 510530China Key Laboratory of Biomedical Photonics(HUST) Ministry of EducationHuazhong University of Science and TechnologyWuhan 430074China Key Laboratory of Molecular Biophysics of Ministry of Education College of Life Science and TechnologyHuazhong University of Science and TechnologyWuhan 430074China Hubei Key Laboratory of Bioinorganic Chemistry and Materia Medical Huazhong University of Science and TechnologyWuhan 430074China Hubei Engineering Research Center for Biomaterials and Medical Protective Materials Huazhong University of Science and TechnologyWuhan 430074China Hubei Bioinformatics and Molecular Imaging Key Laboratory College of Life Science and TechnologyHuazhong University of Science and TechnologyWuhan 430074China

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.

关键词： hydroxyethyl starch Cancer-associated fibroblasts tumor mechanical microenvironment cancer stem cells combination therapy

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Natural products remodel Cancer-associated fibroblasts in desmoplastic tumors

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Acta Pharmaceutica Sinica B 2020年第11期10卷 2140-2155页

作者： Rujing Chen Leaf Huang Kaili Hu Murad Research Center for Modernized Chinese Medicine Institute of Interdisciplinary Integrative Medicine ResearchShanghai University of Traditional Chinese MedicineShanghai 201203China Division of Pharmacoengineering and Molecular Pharmaceutics Center for Nanotechnology in Drug DeliveryEshelman School of PharmacyUniversity of North Carolina at Chapel HillChapel HillNC 27599USA

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.

关键词： Natural products Desmoplastic tumors Cancer-associated fibroblasts Tumor microenvironment Extracellular matrix Traditional Chinese medicine cancer treatment

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Impact of STAT-signaling pathway on Cancer-associated fibroblasts in colorectal cancer and its role in immunosuppression

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World Journal of Gastrointestinal Oncology 2024年第5期16卷 1705-1724页

作者： Damián Sánchez-Ramírez Mónica G Mendoza-Rodríguez Omar R Alemán Fernando A Candanedo-González Miriam Rodríguez-Sosa Juan JoséMontesinos-Montesinos Mauricio Salcedo Ismael Brito-Toledo Felipe Vaca-Paniagua Luis I Terrazas Unidad de Investigacion en Biomedicina Facultad de Estudios Superiores IztacalaUniversidad Nacional Autonoma de MexicoTlalnepantla 54090Estado de MexicoMexico Department of Biology Facultad de QuimicaUniversidad Nacional Autonoma de MexicoCiudad UniversitariaMexico City 04510Mexico Department of Pathology National Medical Center Century XXIInstituto Mexicano del Seguro SocialMexico City 06720Mexico Laboratorio de Células Troncales Mesenquimales Unidad de Investigación Médica en Enfermedades OncológicasHospital de Oncología Centro Medico Nacional Siglo XXIInstituto Mexicano del Seguro SocialMexico City 06720Mexico Unidad de Investigacion en Biomedicina y Oncologia Genomica Instituto Mexciano del Seguro SocialMexico City 07300Mexico Servicio de Colon y Recto Hospital de Oncología Centro Medico Nacional Siglo XXIInstituto Mexicano del Seguro SocialMexico City 06720Mexico Laboratorio Nacional en Salud Facultad de Estudios Superiores IztacalaUniversidad Nacional Autónoma de MéxicoTlalnepantla 54090Estado de MexicoMexico

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.

关键词： Cancer-associated fibroblasts Signal transducer and activator of transcription signaling Colorectal cancer Immunity Immunosuppression

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CRABP2 regulates infiltration of Cancer-associated fibroblasts and immune response in melanoma

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Oncology Research 2024年第2期32卷 261-272页

作者： SHUANGSHUANG ZENG XI CHEN QIAOLI YI ABHIMANYU THAKUR HUI YANG YUANLIANG YAN SHAO LIU Department of Pharmacy Xiangya HospitalCentral South UniversityChangsha410008China National Clinical Research Center for Geriatric Disorders Xiangya HospitalCentral South UniversityChangsha410008China Pritzker School of Molecular Engineering Ben May Department for Cancer ResearchUniversity of ChicagoChicagoILUSA Department of Pathology The Second Affiliated Hospital of Shandong First Medical UniversityTaian271000China

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.

关键词： CRABP2 Melanoma PD-1 Cancer-associated fibroblasts Immune infiltration

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Cancer-associated fibroblasts in breast cancer:Challenges and opportunities

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cancer Communications 2022年第5期42卷 401-434页

作者： Dengdi Hu Zhaoqing Li Bin Zheng Xixi Lin Yuehong Pan Peirong Gong Wenying Zhuo Yujie Hu Cong Chen Lini Chen Jichun Zhou Linbo Wang Affiliated Cixi Hospital Wenzhou Medical UniversityNingboZhejiang 315300P.R.China Affiliated Sir Run Run Shaw Hospital Zhejiang University School of Medicine(Key Laboratory of Cancer Prevention and InterventionMinistry of Education)HangzhouZhejiang 310016P.R.China Biomedical Research Center and Key Laboratory of Biotherapy of Zhejiang Province HangzhouZhejiang 310016P.R.China

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.

关键词： Cancer-associated fibroblasts breast cancer therapeutic target tumor microenvironment biomarker tumor heterogeneity

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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 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.

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

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Priming the tumor microenvironment by a Cancer-associated fibroblasts targeted liposome for improving deep tumor penetration of targeted nanovesicles and combined therapy

Priming the tumor microenvironment by a cancer-associated fi...

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2015年中国药学大会暨第十五届中国药师周

作者： Binlong Chen Wenbing Dai Bing He Hua Zhang Xueqing Wang Qiang Zhang Beijing Key Laboratory of Molecular Pharmaceutics and New Drug Delivery Systems School of Pharmaceutical Sciences Peking University State Key Laboratory of Natural and Biomimetic Drugs

Inefficient tumor penetration and drug resistance both related to tumor microenvironment are major barriers for traditional tumor-targeted chemotherapeutic drug delivery systems. Cancer-associated fibroblasts（CAFs） play a vitally important role during tumor initiation, angiogenesis, progression and metastasis. Navitoclax（Nav） can specifically induce apoptosis in CAFs, which are abundant in the stroma of solid tumor and the main source of collagen. Both CAFs and collagen can raise the interstitial fluid pressure（IFP） in tumor, which presents a transport barrier that restricts nanoparticle penetration into the deep of tumor, thereby limiting the efficacy of nano-drug delivery vehicles for cancer therapy. We have developed a novel tumor stroma-targeted nanovehicle, Nav-loaded nanoliposomes modified with peptide FH（FH-SSL-Nav）, which specifically binds to tenascin C, a protein mainly expressed by CAFs, to target and specifically eradicate CAFs, which have extensive cross-talk with cancer cells and play a pivotal role on maintaining tumor microenvironment beneficial to tumor growth and resistance to cancer therapies. Several experiments were performed to evaluate CAFs selective apoptosis, targeting and eradicating. Compared with SSL-Nav, FH-SSL-Nav achieved higher cellular uptake by flow cytometry and confocal microscopy, and exhibited stronger cytotoxicity in vitro. The in vivo tumor stroma targeting effect was further confirmed by near infrared imaging. Based on its primary effect of eradicating CAFs, FH-SSL-Nav exhibited excellent tumor microenvironment modulation including downregulation ECM deposition, decreasing interstitial fluid pressure（IFP） and facilitating blood perfusion. As a result, with physical barrier destroyed, more nanovesicles penetrated deep into tumor. In antitumor studies, it was proved again that FH-SSL-Nav greatly improved the tumor suppression of liposomal DOX with low toxicity. Thus, this study may provide a novel strategy for combined therapeutic regimens based on tumor microenvironment pri

关键词： Cancer-associated fibroblasts Tumor microenvironment Navitoclax, Liposomal doxorubicin Combination therapy Tumor penetration

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Research progress on the role of Cancer-associated fibroblasts in tumorigenesis and development

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Tumor Microenvironment Research 2020年第1期2卷 29-33页

作者： Xiao-Hui Liu Xiong-Zhi Wu Tianjin Medical University cancer Institute and Hospital National Clinical Center for CancerKey Laboratory of Cancer Prevention and TherapyTianjin 300060China

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.

关键词： Cancer-associated fibroblasts Tumor microenvironment Tumor angiogenesis Invasion Metastasis

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Biomimetic nanoparticles drive the mechanism understanding of shear-wave elasticity stiffness in triple negative breast cancers to predict clinical treatment

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Bioactive Materials 2023年第4期22卷 567-587页

作者： Dongdong Zheng Jin Zhou Lang Qian XueJiao Liu Cai Chang Shuang Tang Hongbo Zhang Shichong Zhou Department of Ultrasound Fudan University Shanghai Cancer CenterShanghai200032PR China Pharmaceutical Sciences Laboratory Åbo Akademi UniversityFI-00520TurkuFinland cancer Institute Fudan University Shanghai Cancer CenterShanghai200032PR China Institutes of Biomedical Sciences and Department of Chemistry Fudan UniversityShanghai200032PR China Department of Nuclear Medicine Fudan University Shanghai Cancer CenterShanghai200032PR China Turku Bioscience Center University of Turku andÅbo Akademi UniversityFI-00520TurkuFinland The First Affiliated Hospital of Wenzhou Medical University Wenzhou325000PR China

In clinical practice,we noticed that triple negative breast cancer(TNBC)patients had higher shear-wave elasticity(SWE)stiffness than non-TNBC patients and a higherα-SMA expression was found in TNBC tissues than the non-TNBC tissues.Moreover,SWE stiffness also shows a clear correlation to neoadjuvant response efficiency.To elaborate this phenomenon,TNBC cell membrane-modified polylactide acid-glycolic acid(PLGA)nanoparticle was fabricated to specifically deliver artesunate to regulate SWE stiffness through inhibiting CAFs functional status.As tested in MDA-MB-231 and E0771 orthotopic tumor models,CAFs functional status inhibited by 231M-ARS@PLGA nanoparticles(231M-AP NPs)had reduced the SWE stiffness as well as attenuated hypoxia of tumor as tumor soil loosening agent which amplified the antitumor effects of paclitaxel and PD1 inhibitor.Single-cell sequencing indicated that the two main CAFs(extracellular matrix and wound healing CAFs)that produces extracellular matrix could influence the tumor SWE stiffness as well as the antitumor effect of drugs.Further,biomimetic nanoparticles inhibited CAFs function could attenuate tumor hypoxia by increasing proportion of inflammatory blood vessels and oxygen transport capacity.Therefore,our finding is fundamental for understanding the role of CAFs on affecting SWE stiffness and drugs antitumor effects,which can be further implied in the potential clinical theranostic predicting in neoadjuvant therapy efficacy through non-invasive analyzing of SWE imaging.

关键词： Cancer-associated fibroblasts Biomimetic nanoparticles Shear-wave elasticity imaging Theranostic prediction

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Recent advances in cancer-associated fibroblast:Biomarkers,signaling pathways,and therapeutic opportunities

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Chinese Medical Journal 2024年第6期137卷 638-650页

作者： Donger Zhou Lei Zheng Department of Hepatobiliary-Pancreatic Surgery The Second Affiliated HospitalZhejiang University School of MedicineHangzhouZhejiang 310009China Sidney Kimmel Comprehensive cancer Center The Skip Viragh Pancreatic Cancer Center for Clinical Research and Careand The Bloomberg-Kimmel Institute for Immunotherapy at Johns Hopkins University School of MedicineBaltimoreMD 21287USA

Anti-cancer therapies usually focus on tumor cells,but non-tumor stromal components in the tumor microenvironment also play vital roles in tumor initiation and progression,which may be the prognostic factors and potential therapeutic targets.Cancer-associated fibroblasts(CAFs)are the essential component in the tumor environment,exhibiting high heterogeneity in their cell origin and phenotype with diverse functions that influence tumor angiogenesis,immune systems,and metabolism.Single-cell RNA sequencing and genetically engineered mouse models have increased our understanding of CAF diversity,and many subtypes have been defined.However,the precise functions of these subtypes need to be studied and validated.Studies of signaling pathways and epigenetic changes in CAFs facilitate understanding of the phenotypes of CAFs and the crosstalk between tumor cells and CAFs to provide potential therapeutic targets.Some clinical trials,including phase III trials targeting CAFs,have been performed recently.However,few of these trials have generated promising results,which indicates that the complexity of CAFs in the tumor microenvironment remains largely unknown,and in-depth investigations of CAFs should be performed.This review summarizes the research on CAFs,focusing on the heterogeneity of their phenotypes and functions,specific signaling pathways,and the therapeutic strategies involving CAFs.Additionally,we briefly discuss the current technologies commonly used in CAF studies and describe the challenges and future perspectives of CAF research.

关键词： Cancer-associated fibroblasts Tumor microenvironment Anti-cancer therapy Targeted therapy

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