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Inhibiting collagen Ⅰ production and tumor cell colonization in the lung via miR-29a-3p loading of exosome-/liposome-based nanovesicles

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Acta Pharmaceutica Sinica B 2022年第2期12卷 939-951页

作者： Yan Yan Cancan Du Xixi Duan Xiaohan Yao Jiajia Wan Ziming Jiang Zhongyu Qin Wenqing Li Longze Pan Zhuoyu Gu Fazhan Wang Ming Wang Zhihai Qin Medical Research Center the First Affiliated Hospital of Zhengzhou UniversityZhengzhou UniversityZhengzhou 450052China Academy of Medical Sciences Zhengzhou UniversityZhengzhou 450052China Department of Urology the First Affiliated Hospital of Zhengzhou UniversityZhengzhou UniversityZhengzhou 450052China Changzhi Medical College Changzhi 046000China Institute of Biophysics Chinese Academy of SciencesBeijing 100101China

The lung is one of the most common sites for cancer metastasis.Collagens in the lung provide a permissive microenvironment that supports the colonization and outgrowth of disseminated tumor cells.Therefore,down-regulating the production of collagens may contribute to the inhibition of lung metastasis.It has been suggested that mi R-29 exhibits effective anti-fibrotic activity by negatively regulating the expression of collagens.Indeed,our clinical lung tumor data shows that mi R-29 a-3 p expression negatively correlates with collagen I expression in lung tumors and positively correlates with patients’outcomes.However,suitable carriers need to be selected to deliver this therapeutic mi RNA to the lungs.In this study,we found that the chemotherapy drug cisplatin facilitated mi R-29 a-3 p accumulation in the exosomes of lung tumor cells,and this type of exosomes exhibited a specific lung-targeting effect and promising collagen down-regulation.To scale up the preparation and simplify the delivery system,we designed a lung-targeting liposomal nanovesicle(by adjusting the molar ratio of DOTAP/cholesterol-mi RNAs to 4:1)to carry mi R-29 a-3 p and mimic the exosomes.This liposomal nanovesicle delivery system significantly down-regulated collagen I secretion by lung fibroblasts in vivo,thus alleviating the establishment of a pro-metastatic environment for circulating lung tumor cells.

关键词： Lung metastasis miR-29a-3p CollagenⅠ Liposomal nanovesicle Exosomes Fibroblasts pre-metastatic niche

Immunogenic hydrogel toolkit disturbing residual tumor “seeds” and pre-metastatic “soil” for inhibition of postoperative tumor recurrence and metastasis

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Acta Pharmaceutica Sinica B 2022年第8期12卷 3383-3397页

作者： Minglu Zhou Qingting Zuo Yuan Huang Lian Li Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry and Sichuan Province Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial TechnologyWest China School of PharmacySichuan UniversityChengdu 610041China

Tumor recurrence and metastasis is the leading cause of mortality for postoperative breast cancer patients. However, chemotherapy intervention after surgery is often unsatisfactory, because residual microtumors are difficult to target and require frequent administration. Here, an all-in-one and oncefor-all drug depot based on in situ-formed hydrogel was applied to fit the irregular surgical trauma, and enable direct contact with residual tumors and sustained drug release. Our immunological analysis after resection of orthotopic breast tumor revealed that postsurgical activation of CXCR4-CXCL12 signal exacerbated the immunosuppression and correlated with adaptive upregulation of PD-L1 in recurrent tumors. Thus, a multifunctional hydrogel toolkit was developed integrating strategies of CXCR4 inhibition,immunogenicity activation and PD-L1 blockade. Our results showed that the hydrogel toolkit not only exerted local effect on inhibiting residual tumor cell “seeds” but also resulted in abscopal effect on disturbing pre-metastatic “soil”. Furthermore, vaccine-like effect and durable antitumor memory were generated, which resisted a secondary tumor rechallenge in 100% cured mice. Strikingly, one single dose of such modality was able to eradicate recurrent tumors, completely prevent pulmonary metastasis and minimize off-target toxicity, thus providing an effective option for postoperative intervention.

关键词： Hydrogel Postoperative treatment Tumor recurrence pre-metastatic niche CXCR4 inhibition Immunotherapy Local therapy Immunogenic cell death

The theory of tumor ecosystem

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Cancer Communications 2022年第7期42卷 587-608页

作者： Xueman Chen Erwei Song Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation Guangdong-Hong Kong Joint Laboratory for RNA MedicineSun Yat-sen Memorial HospitalSun Yat-sen UniversityGuangzhouGuangdong 510120P.R.China Breast Tumor Center Sun Yat-sen Memorial HospitalSun Yat-sen UniversityGuangzhouGuangdong 510120P.R.China

Cancer cells can be conceived as“living organisms”interacting with cellular or non-cellular components in the host internal environment,not only the local tumor microenvironment but also the distant organ niches,as well as the immune,nervous and endocrine systems,to construct a self-sustainable tumor ecosystem.With increasing evidence for the systemic tumor-host interplay,we predict that a new era of cancer therapy targeting the ecosystemic vulnerability of human malignancies has come.Revolving around the tumor ecosystem scoped as different hierarchies of primary,regional,distal and systemic onco-spheres,we comprehensively review the tumor-host interaction among cancer cells and their local microenvironment,distant organ niches,immune,nervous and endocrine systems,highlighting material and energy flow with tumor ecological homeostasis as an internal driving force.We also substantiate the knowledge of visualizing,modelling and subtyping this dynamically intertwined networkwith recent technological advances,and discuss ecologically rational strategies formore effective cancer therapies.

关键词： ecological therapy neuroendocrine system onco-sphere tumor-host interplay pre-metastatic niche tumor ecosystem tumor immunity tumor microenvironment

Emerging landscapes of nanosystems based on pre-metastatic microenvironment for cancer theranostics

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Chinese Chemical Letters 2022年第9期33卷 4157-4168页

作者： Yongchao Chu Tao Sun Chen Jiang Key Laboratory of Smart Drug Delivery(Ministry of Education) Minhang HospitalState Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain ScienceInstitutes of Brain ScienceDepartment of PharmaceuticsSchool of PharmacyResearch Center on Aging and MedicineFudan UniversityShanghai 201203China

The emergence of disseminated metastasis is the leading cause of mortality in patients with malignant tumor.The pre-metastatic microenvironment,including the primary tumor-derived components,pre-metastatic niche(PMN),circulating tumor cells(CTCs),micro-metastases,and tumor immune microenvironment(TIM),are the crucial factors to initiate metastasis and form macro-metastases.It may be a more promising strategy for directly targeting pre-metastatic microenvironment-interrelated factors and cells before they have the chance to form secondary tumors to prevent metastasis.During recent years,a variety of nanosystems,with specific microstructures and functional properties,have been devised to selectively target pre-metastatic cells components and interrelated molecular,and exhibited strong potential on anti-metastatic therapy by absorbing and neutralizing primary tumor-derived components,preventing establishment of the PMN,eliminating the CTCs,eradicating the micro-metastases and modulating the TIM.In this review,we comprehensively review the emerging nanosystems based on the pre-metastatic microenvironments.Hopefully,this review can cast new lights for early preventing and attenuating metastatic progression.

关键词： Circulating tumor cells pre-metastatic niche Cancer metastasis Tumor immune microenvironment Micro-metastasis

Senescent mesenchymal stem/stromal cells in pre-metastatic bone marrow of untreated advanced breast cancer patients

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Oncology Research 2023年第3期31卷 361-374页

作者： FRANCISCO RAÚL BORZONE MARÍA BELÉN GIORELLO LEANDRO MARCELO MARTINEZ MARÍA CECILIA SANMARTIN LEONARDO FELDMAN FEDERICO DIMASE EMILIO BATAGELJ GUSTAVO YANNARELLI NORMA ALEJANDRA CHASSEING Laboratorio de Inmunohematología Instituto de Biología y Medicina Experimental(IBYME)Consejo Nacional de Investigaciones Científicas y Técnicas(CONICET)Buenos AiresArgentina Division of Hematology and Medical Oncology Department of MedicineWeill Cornell Medical CollegeNew YorkUSA Laboratorio de Regulación Génica y Células Madre Instituto de Medicina TraslacionalTrasplante y Bioingeniería(IMeTTyB)Universidad Favaloro-CONICETBuenos AiresArgentina Facultad de Ciencias de la Salud Universidad Nacional del Centro de la Provincia de Buenos Aires(UNCPB)TandilBuenos AiresArgentina Servicio de Hematología Hospital Militar CentralBuenos AiresArgentina Servicio de Oncología Hospital Militar CentralBuenos AiresArgentina

Breast cancer is the predominant form of carcinoma among women worldwide,with 70%of advanced patients developing bone metastases,with a high mortality rate.In this sense,the bone marrow(BM)mesenchymal stem/stromal cells(MSCs)are critical for BM/bone homeostasis,and failures in their functionality,transform the BM into a premetastatic niche(PMN).We previously found that BM-MSCs from advanced breast cancer patients(BCPs,infiltrative ductal carcinoma,stage III-B)have an abnormal profile.This work aims to study some of the metabolic and molecular mechanisms underlying MSCs shift from a normal to an abnormal profile in this group of patients.A comparative analysis was undertaken,which included self-renewal capacity,morphology,proliferation capacity,cell cycle,reactive oxygen species(ROS)levels,and senescence-associatedβ‑galactosidase(SA‑β‑gal)staining of BMderived MSCs isolated from 14 BCPs and 9 healthy volunteers(HVs).Additionally,the expression and activity of the telomerase subunit TERT,as well as telomere length,were measured.Expression levels of pluripotency,osteogenic,and osteoclastogenic genes(OCT-4,SOX-2,M-CAM,RUNX-2,BMP-2,CCL-2,M-CSF,and IL-6)were also determined.The results showed that MSCs from BCPs had reduced,self-renewal and proliferation capacity.These cells also exhibited inhibited cell cycle progression and phenotypic changes,such as an enlarged and flattened appearance.Additionally,there was an increase in ROS and senescence levels and a decrease in the functional capacity of TERT to preserve telomere length.We also found an increase in pro-inflammatory/pro-osteoclastogenic gene expression and a decrease in pluripotency gene expression.We conclude that these changes could be responsible for the abnormal functional profile that MSCs show in this group of patients.

关键词： Mesenchymal stem/stromal cells Senescence Breast cancer Bone marrow pre-metastatic niche Bone metastasis

Tumor-derived exosomes:Nanovesicles made by cancer cells to promote cancer metastasis

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Acta Pharmaceutica Sinica B 2021年第8期11卷 2136-2149页

作者： Hongwei Chen Venkata Chengalvala Hongxiang Hu Duxin Sun Department of Pharmaceutical Sciences College of PharmacyUniversity of MichiganAnn ArborMI 48109USA College of Literature Scienceand the ArtsUniversity of MichiganAnn ArborMI 48109USA

Nanomedicine usually refers to nanoparticles that deliver the functional drugs and siRNAs to treat cancer.Recent research has suggested that cancer cells can also make nanoparticles that also deliver functional molecules in promoting cancer metastasis,which is the leading cause of various cancer mortalities.This nanoparticle is called tumor-derived vesicles,or better-known as tumor-derived exosomes(TEXs).TEXs are nanoscale membrane vesicles(30 e140 nm)that are released continuously by various types of cancer cells and contain tumor-derived functional biomolecules,including lipids,proteins,and genetic molecules.These endogenous TEXs can interact with host immune cells and epithelial cells locally and systemically.More importantly,they can reprogram the recipient cells in favor of promoting metastasis through facilitating tumor cell local invasion,intravasation,immune evasion,extravasation,and survival and growth in distant organs.Growing evidence suggests that TEXs play a key role in cancer metastasis.Here,we will review the most recent findings of how cancer cells harness TEXs to promote cancer metastasis through modulating vascular permeability,suppressing systemic immune surveillance,and creating metastatic niches.We will also summarize recent research in targeting TEXs to treat cancer metastasis.

关键词： Tumor-derived exosomes Metastasis Vasculature leaky Immunosuppression pre-metastatic niche Therapeutic implications Exosome targeting Nanocarrier

Exosomal CD44 Cooperates with Integrin α6β4 to Support Organotropic Metastasis via Regulating Tumor Cell Motility and Target Host Cell Activation

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Engineering 2021年第10期7卷 1413-1423页

作者： Wei Mu Yajie Xu Pengfei Gu Wenbo Wang Jingquan Li Yang Ge Hui Wang Center for Single-Cell Omics School of Public Health Shanghai Jiao Tong University School of Medicine CAS Key Laboratory of Nutrition Metabolism and Food Safety Shanghai Institute of Nutrition and Health Chinese Academy of Sciences National Research Center for Translational Medicine Shanghai Jiao Tong University School of Medicine

Rapid metastasis to vital organs such as the lung,liver,and brain is responsible for the vast majority of pancreatic cancer deaths.Liver metastasis of pancreatic cancer accounts for the high mortality rate in patients.Exosomes derived from pancreatic cancer cells tend to be enriched in proteins that are anchored to the cell membrane,supporting the reprogramming of the tumor microenvironment and the progression of distant metastatic lesions.For the first time,our study has demonstrated that cluster of differentiation 44(CD44),a transmembrane glycoprotein delivered by exosomes,is involved in the metastatic process of pancreatic cancer.Moreover,CD44 was found to interact with integrin α6β4 to form a complex,thereby remodeling intracellular skeleton proteins,and to promote tumor cell motility through the activation of the Src and Ras signaling cascades.Notably,we also demonstrated that the CD44-α6β4 complex can be delivered to the target region via the paracrine effects of exosomes.The selective uptake of CD44-competent tumor exosomes by liver cells activated fibrotic pathways and generated a pre-metastatic niche by stimulating the cytokines,proinflammatory factors,and growth factors that ultimately support tumor metastasis.Our results suggest the potential application of exosomal CD44 as a biomarker for the clinical diagnosis of and therapy for pancreatic cancer.

关键词： Pancreatic cancer Organotropic metastasis Exosomes pre-metastatic niche CD44

Exosomal CD44 Cooperates with Integrin a6b4 to Support Organotropic Metastasis via Regulating Tumor Cell Motility and Target Host Cell Activation

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Engineering 2021年第10期7卷 1413-1423页

作者： Wei Mu Yajie Xu Pengfei Gu Wenbo Wang Jingquan Li Yang Ge Hui Wang Center for Single-Cell Omics School of Public HealthShanghai Jiao Tong University School of MedicineShanghai 200025China CAS Key Laboratory of Nutrition Metabolism and Food SafetyShanghai Institute of Nutrition and HealthChinese Academy of SciencesShanghai 200031China National Research Center for Translational Medicine Shanghai Jiao Tong University School of MedicineShanghai 200031China

Rapid metastasis to vital organs such as the lung,liver,and brain is responsible for the vast majority of pancreatic cancer deaths.Liver metastasis of pancreatic cancer accounts for the high mortality rate in patients.Exosomes derived from pancreatic cancer cells tend to be enriched in proteins that are anchored to the cell membrane,supporting the reprogramming of the tumor microenvironment and the progression of distant metastatic lesions.For the first time,our study has demonstrated that cluster of differentiation 44(CD44),a transmembrane glycoprotein delivered by exosomes,is involved in the metastatic process of pancreatic cancer.Moreover,CD44 was found to interact with integrin a6b4 to form a complex,thereby remodeling intracellular skeleton proteins,and to promote tumor cell motility through the activation of the Src and Ras signaling cascades.Notably,we also demonstrated that the CD44–a6b4 complex can be delivered to the target region via the paracrine effects of exosomes.The selective uptake of CD44-competent tumor exosomes by liver cells activated fibrotic pathways and generated a pre-metastatic niche by stimulating the cytokines,proinflammatory factors,and growth factors that ultimately support tumor metastasis.Our results suggest the potential application of exosomal CD44 as a biomarker for the clinical diagnosis of and therapy for pancreatic cancer.

关键词： Pancreatic cancer Organotropic metastasis Exosomes pre-metastatic niche CD44