title: Notch signaling in CD66+ cells drives the progression of human cervical cancers.
abstract: Human epithelial tumor progression and metastasis involve cellular invasion, dissemination in the vasculature, and regrowth at metastatic sites. Notch signaling has been implicated in metastatic progression but its roles have yet to be fully understood. Here we report the important role of Notch signaling in maintaining cells expressing the carcinoembryonic antigen cell adhesion molecule CEACAM (CD66), a known mediator of metastasis. CD66 and Notch1 were studied in clinical specimens and explants of human cervical cancer, including specimens grown in a pathophysiologically relevant murine model. Gene expression profiling of CD66(+) cells from primary tumors showed enhanced features of Notch signaling, metastasis, and stemness. Significant differences were also seen in invasion, colony formation, and tumor forming efficiency between CD66(+) and CD66(-) cancer cells. Notably, CD66(+) cells showed a marked sensitivity to a Notch small molecule inhibitor. In support of studies in established cell lines, we documented the emergence of a tumorigenic CD66(+) cell subset within a metastatic lesion-derived cervical-cancer cell line. Similar to primary cancers, CD66 expression in the cell line was blocked by chemical and genetic inhibitors of ligand-dependent nuclear Notch signaling. Collectively, our work on the oncogenic properties of CD66(+) cells in epithelial cancers provides insights into the nature of tumor progression and offers a mechanistic rationale to inhibit the Notch signaling pathway as a generalized therapeutic strategy to treat metastatic cancers.
authors.affiliation: National Centre for Biological Sciences, Tata Institute of Fundamental Research, UAS-GKVK Campus and Department of Radiotherapy, Kidwai Memorial Institute of Oncology, Bangalore, India.
authors.forename: Jeevisha
authors.initials: J
authors.lastname: Bajaj
authors.forename: Tessy Thomas
authors.initials: TT
authors.lastname: Maliekal
authors.forename: Eric
authors.initials: E
authors.lastname: Vivien
authors.forename: Chitra
authors.initials: C
authors.lastname: Pattabiraman
authors.forename: Sweta
authors.initials: S
authors.lastname: Srivastava
authors.forename: H
authors.initials: H
authors.lastname: Krishnamurthy
authors.forename: V
authors.initials: V
authors.lastname: Giri
authors.forename: Deepa
authors.initials: D
authors.lastname: Subramanyam
authors.forename: Sudhir
authors.initials: S
authors.lastname: Krishna
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D002294:Carcinoma, Squamous Cell / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D015815:Cell Adhesion Molecules / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D018450:Disease Progression; D005260:Female; D005434:Flow Cytometry; D020869:Gene Expression Profiling; D006801:Humans; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D051880:Receptors, Notch / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D018874:Spheroids, Cellular; D014183:Transplantation, Heterologous; D002583:Uterine Cervical Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology
chemical_list: D015703:Antigens, CD; C069847:CD66 antigens; D015815:Cell Adhesion Molecules; D051880:Receptors, Notch