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

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 

作者机构：Laboratorio de InmunohematologíaInstituto de Biología y Medicina Experimental(IBYME)Consejo Nacional de Investigaciones Científicas y Técnicas(CONICET)Buenos AiresArgentina Division of Hematology and Medical OncologyDepartment of MedicineWeill Cornell Medical CollegeNew YorkUSA Laboratorio de Regulación Génica y Células MadreInstituto de Medicina TraslacionalTrasplante y Bioingeniería(IMeTTyB)Universidad Favaloro-CONICETBuenos AiresArgentina Facultad de Ciencias de la SaludUniversidad Nacional del Centro de la Provincia de Buenos Aires(UNCPB)TandilBuenos AiresArgentina Servicio de HematologíaHospital Militar CentralBuenos AiresArgentina Servicio de OncologíaHospital Militar CentralBuenos AiresArgentina 

出 版 物：《Oncology Research》 (肿瘤学研究（英文）)

年 卷 期：2023年第31卷第3期

页      面：361-374页

核心收录：

学科分类：1002[医学-临床医学] 100214[医学-肿瘤学] 10[医学] 

基　　金：Supported by the FONCYT,Argentina(PICT 2016-#1093) CONICET,Argentina(PIP2014-2016,#300) Fundación Florencio Fiorini(Subsidio 2021-2022),Argentina. 

主　　题：Mesenchymal stem/stromal cells Senescence Breast cancer Bone marrow Pre-metastatic niche Bone metastasis 

摘      要：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.