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J Bone Oncol ; 26: 100341, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33425672


BACKGROUND: Bone remodeling is disrupted in metastatic disease, which affects > 70% of metastatic castration-resistant prostate cancer (mCRPC) patients. As a result, abnormal levels of specific bone turnover biomarkers (BTMs) are released. In this prospective ancillary analysis of the Italian real-world study ABITUDE, four markers were measured during abiraterone acetate plus prednisone (AAP) treatment in chemotherapy-naïve mCRPC men failing androgen-deprivation therapy. METHODS: Patients were enrolled if a blood sample was obtained before the first administration of abiraterone (baseline); ad-hoc blood samples were withdrawn during routine tests after 3, 6, and 12 months. A centralized lab measured bone alkaline phosphatase (BALP, osteoblast activity marker), type-I collagen-C-telopeptide (CTX-1, bone resorption marker), parathyroid hormone (PTH) and vitamin D (vitD). At each time point, intra-patient variations vs baseline were compared by the signed-rank test (statistical significance: P-value < 0.05). RESULTS: Of 481 patients enrolled in ABITUDE, 186 (median age: 76 [range: 53-93] years) met the substudy criteria: 74.7% had bone metastases, 11.8% were on bone-targeted therapies (BTT) and 14.0% on vitD supplementation. BALP decreased significantly at month 6 (P = 0.0010) and 12 (P < 0.0001) and CTX-1 at month 6 (P = 0.0028); PTH increased at month 3 (P < 0.0001); no significant difference in vitD levels was observed. Similar findings were observed in BTT-untreated patients. The reduction in BALP and CTX-1 levels was more pronounced in patients with than without bone metastases; in the latter group, no significant variation in BALP and CTX-1 levels was observed. CONCLUSIONS: AAP seems to exert an effect on the microenvironment of metastatic but not of normal bone, which likely contributes to its antitumoral activity.

Nanomedicine ; 19: 95-105, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31028887


Functional RNAs, such as microRNAs, are emerging as innovative tools in the treatment of aggressive and incurable cancers. In this study, we explore the potential of silica dioxide nanoparticles (SiO2NPs) in the delivery of biologically active miRNAs. Focusing on the tumor-suppressor miR-34a, we evaluated miRNAs delivery by SiO2NPs into the mammary gland, using in vitro as well as in vivo model systems. We showed that silica nanoparticles can efficiently deliver miR-34a into normal and cancer epithelial cells grown in culture without major signs of toxicity. Delivered miRNA retained the ability to silence artificial as well endogenous targets and can reduce the growth of mammospheres in 3D culture. Finally, miR-34a delivery through intra-tumor administration of SiO2NPs leads to a reduced mammary tumor growth. In conclusion, our studies suggest that silica nanoparticles can mediate the delivery of miR-34a directly into mammary tumors while preserving its molecular and biological activity.

Células Epiteliais/metabolismo , Neoplasias Mamárias Animais/metabolismo , MicroRNAs/administração & dosagem , Nanopartículas/química , Animais , Proliferação de Células , Endocitose , Feminino , Camundongos Endogâmicos C57BL , Nanopartículas/ultraestrutura , Dióxido de Silício/química
Oncogene ; 38(3): 360-374, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30093634


The role of the tumour-suppressor miR-34 family in breast physiology and in mammary stem cells (MaSCs) is largely unknown. Here, we revealed that miR-34 family, and miR-34a in particular, is implicated in mammary epithelium homoeostasis. Expression of miR-34a occurs upon luminal commitment and differentiation and serves to inhibit the expansion of the pool of MaSCs and early progenitor cells, likely in a p53-independent fashion. Mutant mice (miR34-KO) and loss-of-function approaches revealed two separate functions of miR-34a, controlling both proliferation and fate commitment in mammary progenitors by modulating several pathways involved in epithelial cell plasticity and luminal-to-basal conversion. In particular, miR-34a acts as endogenous inhibitor of the Wnt/beta-catenin signalling pathway, targeting up to nine upstream regulators at the same time, thus modulating the expansion of the MaSCs/early progenitor pool. These multiple roles of miR-34a are maintained in a model of human breast cancer, in which chronic expression of miR-34a in triple-negative mesenchymal-like cells (enriched in cancer stem cells-CSCs) could promote a luminal-like differentiation programme, restrict the CSC pool, and inhibit tumour propagation. Hence, activation of miR-34a-dependent programmes could provide a therapeutic opportunity for the subset of breast cancers, which are rich in CSCs and respond poorly to conventional therapies.

Neoplasias da Mama/patologia , Glândulas Mamárias Animais/citologia , MicroRNAs/fisiologia , RNA Neoplásico/fisiologia , Animais , Neoplasias da Mama/metabolismo , Diferenciação Celular , Linhagem Celular Tumoral , Proliferação de Células/fisiologia , Autorrenovação Celular/fisiologia , Células Epiteliais/metabolismo , Feminino , Humanos , Glândulas Mamárias Animais/anormalidades , Glândulas Mamárias Animais/metabolismo , Células-Tronco Mesenquimais/metabolismo , Camundongos , Camundongos Knockout , MicroRNAs/genética , Células-Tronco Neoplásicas/metabolismo , Esferoides Celulares , Neoplasias de Mama Triplo Negativas/metabolismo , Neoplasias de Mama Triplo Negativas/patologia , Via de Sinalização Wnt