Nucleolin overexpression in breast cancer cell sub-populations with different stem-like phenotype enables targeted intracellular delivery of synergistic drug combination.
Breast cancer stem cells (CSC) are thought responsible for tumor growth and relapse, metastization and active evasion to standard chemotherapy. The recognition that CSC may originate from non-stem cancer cells (non-SCC) through plastic epithelial-to-mesenchymal transition turned these into relevant cell targets. Of crucial importance for successful therapeutic intervention is the identification of surface receptors overexpressed in both CSC and non-SCC. Cell surface nucleolin has been described as overexpressed in cancer cells as well as a tumor angiogenic marker. Herein we have addressed the questions on whether nucleolin was a common receptor among breast CSC and non-SCC and whether it could be exploited for targeting purposes. Liposomes functionalized with the nucleolin-binding F3 peptide, targeted simultaneously, nucleolin-overexpressing putative breast CSC and non-SCC, which was paralleled by OCT4 and NANOG mRNA levels in cells from triple negative breast cancer (TNBC) origin. In murine embryonic stem cells, both nucleolin mRNA levels and F3 peptide-targeted liposomes cellular association were dependent on the stemness status. An in vivo tumorigenic assay suggested that surface nucleolin overexpression per se, could be associated with the identification of highly tumorigenic TNBC cells. This proposed link between nucleolin expression and the stem-like phenotype in TNBC, enabled 100% cell death mediated by F3 peptide-targeted synergistic drug combination, suggesting the potential to abrogate the plasticity and adaptability associated with CSC and non-SCC. Ultimately, nucleolin-specific therapeutic tools capable of simultaneous debulk multiple cellular compartments of the tumor microenvironment may pave the way towards a specific treatment for TNBC patient care.
CNC - Center for Neurosciences and Cell Biology, University of Coimbra, Faculty of Medicine (Polo I), Rua Larga, Coimbra 3004-504, Portugal; FFUC - Faculty of Pharmacy, University of Coimbra, Pólo das Ciências da Saúde, Azinhaga de Santa Comba, Coimbra 3000-548, Portugal.
Nuno A
NA
Fonseca
PhD Program in Experimental Biology and Biomedicine (PDBEB), Center for Neuroscience and Cell Biology, University of Coimbra, Faculty of Medicine (Polo I), Rua Larga, Coimbra 3004-504, Portugal; Biology of Reproduction and Stem Cell Group, Center for Neuroscience and Cell Biology, University of Coimbra, Faculty of Medicine (Polo I), Rua Larga, Coimbra 3004-504, Portugal.
Ana S
AS
Rodrigues
Immunology Institute, Faculty of Medicine (Polo I), University of Coimbra, Rua Larga, Coimbra 3004-504, Portugal; Immunology and Oncology Laboratory, Center for Neuroscience and Cell Biology, University of Coimbra, Faculty of Medicine (Polo I), Rua Larga, Coimbra 3004-504, Portugal.
Paulo
P
Rodrigues-Santos
Immunology Institute, Faculty of Medicine (Polo I), University of Coimbra, Rua Larga, Coimbra 3004-504, Portugal.
Vera
V
Alves
CNC - Center for Neurosciences and Cell Biology, University of Coimbra, Faculty of Medicine (Polo I), Rua Larga, Coimbra 3004-504, Portugal; PhD Program in Experimental Biology and Biomedicine (PDBEB), Center for Neuroscience and Cell Biology, University of Coimbra, Faculty of Medicine (Polo I), Rua Larga, Coimbra 3004-504, Portugal; IIIUC - Institute for Interdisciplinary Research, University of Coimbra, Casa Costa Alemão (Polo II), Rua Dom Francisco de Lemos, Coimbra 3030-789, Portugal.
Ana C
AC
Gregório
CNC - Center for Neurosciences and Cell Biology, University of Coimbra, Faculty of Medicine (Polo I), Rua Larga, Coimbra 3004-504, Portugal; PhD Program in Experimental Biology and Biomedicine (PDBEB), Center for Neuroscience and Cell Biology, University of Coimbra, Faculty of Medicine (Polo I), Rua Larga, Coimbra 3004-504, Portugal; IIIUC - Institute for Interdisciplinary Research, University of Coimbra, Casa Costa Alemão (Polo II), Rua Dom Francisco de Lemos, Coimbra 3030-789, Portugal.
Ângela
Â
Valério-Fernandes
CNC - Center for Neurosciences and Cell Biology, University of Coimbra, Faculty of Medicine (Polo I), Rua Larga, Coimbra 3004-504, Portugal; FFUC - Faculty of Pharmacy, University of Coimbra, Pólo das Ciências da Saúde, Azinhaga de Santa Comba, Coimbra 3000-548, Portugal; PhD Program in Experimental Biology and Biomedicine (PDBEB), Center for Neuroscience and Cell Biology, University of Coimbra, Faculty of Medicine (Polo I), Rua Larga, Coimbra 3004-504, Portugal.
Lígia C
LC
Gomes-da-Silva
Immunology Institute, Faculty of Medicine (Polo I), University of Coimbra, Rua Larga, Coimbra 3004-504, Portugal.
Manuel Santos
MS
Rosa
CNC - Center for Neurosciences and Cell Biology, University of Coimbra, Faculty of Medicine (Polo I), Rua Larga, Coimbra 3004-504, Portugal; TREAT U, S.A., Parque Industrial de Taveiro, Lote 44, Coimbra 3045-508, Portugal.
Vera
V
Moura
Biology of Reproduction and Stem Cell Group, Center for Neuroscience and Cell Biology, University of Coimbra, Faculty of Medicine (Polo I), Rua Larga, Coimbra 3004-504, Portugal; Department of Life Sciences, Faculty of Sciences and Technology, University of Coimbra, Calçada Martim de Freitas, Coimbra 3000-456, Portugal.
João
J
Ramalho-Santos
CNC - Center for Neurosciences and Cell Biology, University of Coimbra, Faculty of Medicine (Polo I), Rua Larga, Coimbra 3004-504, Portugal; FFUC - Faculty of Pharmacy, University of Coimbra, Pólo das Ciências da Saúde, Azinhaga de Santa Comba, Coimbra 3000-548, Portugal.
Sérgio
S
Simões
CNC - Center for Neurosciences and Cell Biology, University of Coimbra, Faculty of Medicine (Polo I), Rua Larga, Coimbra 3004-504, Portugal; FFUC - Faculty of Pharmacy, University of Coimbra, Pólo das Ciências da Saúde, Azinhaga de Santa Comba, Coimbra 3000-548, Portugal. Electronic address: jmoreira@ff.uc.pt.
João Nuno
JN
Moreira
D000595:Amino Acid Sequence; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage* / Q000494:pharmacology; D001940:Breast / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D002518:Ceramides / Q000008:administration & dosage* / Q000494:pharmacology; D004317:Doxorubicin / Q000008:administration & dosage* / Q000494:pharmacology; D016503:Drug Delivery Systems; D004357:Drug Synergism; D005260:Female; D006801:Humans; D008081:Liposomes / Q000737:chemistry / Q000378:metabolism; D051379:Mice; D008969:Molecular Sequence Data; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D010455:Peptides / Q000737:chemistry / Q000378:metabolism; D010750:Phosphoproteins / Q000235:genetics* / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D064726:Triple Negative Breast Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D015854:Up-Regulation; D000097796:Nucleolin
D000903:Antibiotics, Antineoplastic; D002518:Ceramides; D004317:Doxorubicin; D008081:Liposomes; D010455:Peptides; D010750:Phosphoproteins; D016601:RNA-Binding Proteins; D000097796:Nucleolin; C101954:N-caproylsphingosine
Cancer stem cells; Non-stem cancer cells; Nucleolin; Targeting; Triple negative breast cancer