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CD73 Regulates Stemness and Epithelial-Mesenchymal Transition in Ovarian Cancer-Initiating Cells
- Source :
- Stem Cell Reports, Stem Cell Reports, Vol 10, Iss 4, Pp 1412-1425 (2018)
- Publication Year :
- 2018
- Publisher :
- Elsevier BV, 2018.
-
Abstract
- Summary Cancer-initiating cells (CICs) have been implicated in tumor development and aggressiveness. In ovarian carcinoma (OC), CICs drive tumor formation, dissemination, and recurrence, as well as drug resistance, thus accounting for the high death-to-incidence ratio of this neoplasm. However, the molecular mechanisms that underlie such a pathogenic role of ovarian CICs (OCICs) remain elusive. Here, we have capitalized on primary cells either from OC or from its tissues of origin to obtain the transcriptomic profile associated with OCICs. Among the genes differentially expressed in OCICs, we focused on CD73, which encodes the membrane-associated 5′-ectonucleotidase. The genetic inactivation of CD73 in OC cells revealed that this molecule is causally involved in sphere formation and tumor initiation, thus emerging as a driver of OCIC function. Furthermore, functional inhibition of CD73 via either a chemical compound or a neutralizing antibody reduced sphere formation and tumorigenesis, highlighting the druggability of CD73 in the context of OCIC-directed therapies. The biological function of CD73 in OCICs required its enzymatic activity and involved adenosine signaling. Mechanistically, CD73 promotes the expression of stemness and epithelial-mesenchymal transition-associated genes, implying a regulation of OCIC function at the transcriptional level. CD73, therefore, is involved in OCIC biology and may represent a therapeutic target for innovative treatments aimed at OC eradication.<br />Graphical Abstract<br />Highlights • CD73 is enriched in ovarian cancer-initiating cells (OCICs) • CD73 orchestrates OCIC stemness and EMT • OC initiation and growth require CD73 activity • OCIC-associated CD73 is a therapeutic target useful for OC eradication<br />Cavallaro et al. characterized the transcriptome of OCIC-enriched primary cultures and found CD73 as an upregulated gene. CD73 was then shown to regulate the expression of stemness and EMT-associated genes. The expression and function of CD73 in OCICs is required for tumor initiation, and CD73-targeted drugs decrease the rate of tumor take and inhibit cancer growth.
- Subjects :
- cancer stem cells
0301 basic medicine
MED/40 - GINECOLOGIA E OSTETRICIA
Tumor initiation
medicine.disease_cause
Biochemistry
Epithelium
Transcriptome
0302 clinical medicine
Ovarian carcinoma
lcsh:QH301-705.5
5'-Nucleotidase
Ovarian Neoplasms
lcsh:R5-920
MED/04 - PATOLOGIA GENERALE
EMT
Gene Expression Regulation, Neoplastic
ovarian cancer
adenosine
030220 oncology & carcinogenesis
Neoplastic Stem Cells
Female
lcsh:Medicine (General)
cancer-initiating cells
cancer stem cell
Epithelial-Mesenchymal Transition
cancer-initiating cell
Context (language use)
Biology
GPI-Linked Proteins
Article
03 medical and health sciences
CD73
Cancer stem cell
Cell Line, Tumor
Spheroids, Cellular
Genetics
medicine
Humans
Epithelial–mesenchymal transition
Fallopian Tubes
Cell Proliferation
Cell Biology
medicine.disease
030104 developmental biology
lcsh:Biology (General)
Cancer research
Ovarian cancer
Carcinogenesis
Developmental Biology
Subjects
Details
- ISSN :
- 22136711
- Volume :
- 10
- Database :
- OpenAIRE
- Journal :
- Stem Cell Reports
- Accession number :
- edsair.doi.dedup.....21bd5ff737d479b1d7075759096ac2d2