title: A novel population of local pericyte precursor cells in tumor stroma that require Notch signaling for differentiation.
abstract: Pericytes are perivascular support cells, the origin of which in tumor tissue is not clear. Recently, we identified a Tie1(+) precursor cell that differentiates into vascular smooth muscle, in a Notch-dependent manner. To understand the involvement of Notch in the ontogeny of tumor pericytes we used a novel flow immunophenotyping strategy to define CD146(+)/CD45(-)/CD31(-/lo) pericytes in the tumor stroma. This strategy combined with ex vivo co-culture experiments identified a novel pericyte progenitor cell population defined as Sca1(hi)/CD146(-)/CD45(-)/CD31(-). The differentiation of these progenitor cells was stimulated by co-culture with endothelial cells. Overexpression of the Notch ligand Jagged1 in endothelial cells further stimulated the differentiation of Sca1(hi)/CD146(-)/CD45(-)/CD31(-) cells into pericytes, while inhibition of Notch signaling with a γ-secretase inhibitor reduced this differentiation. However, Notch inhibition specifically in Tie1-expressing cells did not change the abundance of pericytes in tumors, suggesting that the pericyte precursor is distinct from the vascular smooth muscle cell precursor. Transplant experiments showed that the bone marrow contributes minimally to tumor pericytes. Immunophenotyping revealed that Sca1(hi)/CD146(-)/CD45(-)/CD31(-) cells have greater potential to differentiate into pericytes and have increased expression of classic mesenchymal stem cell markers (CD13, CD44, Nt5e and Thy-1) compared to Sca1(-/lo)/CD146(-)/CD45(-)/CD31(-) cells. Our results suggest that a local Sca1(hi)/CD146(-)/CD45(-)/CD31(-) pericyte progenitor resides in the tumor microenvironment and requires Notch signaling for differentiation into mature pericytes.
authors.affiliation: Genome Sciences Centre, British Columbia Cancer Agency, Vancouver, British Columbia, Canada.
authors.forename: Alexandre
authors.initials: A
authors.lastname: Patenaude
authors.affiliation: Terry Fox Laboratory, British Columbia Cancer Agency, Vancouver, British Columbia, Canada.
authors.forename: Stefan
authors.initials: S
authors.lastname: Woerher
authors.affiliation: Genome Sciences Centre, British Columbia Cancer Agency, Vancouver, British Columbia, Canada.
authors.forename: Patricia
authors.initials: P
authors.lastname: Umlandt
authors.affiliation: Genome Sciences Centre, British Columbia Cancer Agency, Vancouver, British Columbia, Canada.
authors.forename: Fred
authors.initials: F
authors.lastname: Wong
authors.affiliation: Genome Sciences Centre, British Columbia Cancer Agency, Vancouver, British Columbia, Canada.
authors.forename: Rawa
authors.initials: R
authors.lastname: Ibrahim
authors.affiliation: Integrated Oncology Program, British Columbia Cancer Agency, Vancouver, British Columbia, Canada.
authors.forename: Alastair
authors.initials: A
authors.lastname: Kyle
authors.affiliation: Genome Sciences Centre, British Columbia Cancer Agency, Vancouver, British Columbia, Canada.
authors.forename: Sandy
authors.initials: S
authors.lastname: Unger
authors.affiliation: Genome Sciences Centre, British Columbia Cancer Agency, Vancouver, British Columbia, Canada.
authors.forename: Megan
authors.initials: M
authors.lastname: Fuller
authors.affiliation: Genome Sciences Centre, British Columbia Cancer Agency, Vancouver, British Columbia, Canada.
authors.forename: Jeremy
authors.initials: J
authors.lastname: Parker
authors.affiliation: Integrated Oncology Program, British Columbia Cancer Agency, Vancouver, British Columbia, Canada.
authors.forename: Andrew
authors.initials: A
authors.lastname: Minchinton
authors.affiliation: Terry Fox Laboratory, British Columbia Cancer Agency, Vancouver, British Columbia, Canada; Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Connie J
authors.initials: CJ
authors.lastname: Eaves
authors.affiliation: Genome Sciences Centre, British Columbia Cancer Agency, Vancouver, British Columbia, Canada; Department of Pathology and Laboratory Medicine, British Columbia Cancer Agency, Vancouver, British Columbia, Canada; Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada. Electronic address: akarsan@bcgsc.ca.
authors.forename: Aly
authors.initials: A
authors.lastname: Karsan
mesh_terms: D000818:Animals; D000067696:Ataxin-1 / Q000378:metabolism; D016026:Bone Marrow Transplantation; D051929:CD146 Antigen / Q000378:metabolism; D018827:Carcinoma, Lewis Lung; D002454:Cell Differentiation; D018920:Coculture Techniques; D005434:Flow Cytometry; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D017493:Leukocyte Common Antigens / Q000378:metabolism; D008546:Melanoma, Experimental; D059630:Mesenchymal Stem Cells / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000378:metabolism*; D020286:Pericytes / Q000166:cytology*; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000378:metabolism; D042810:Receptor, TIE-1 / Q000378:metabolism; D051880:Receptors, Notch / Q000378:metabolism*; D015398:Signal Transduction; D013234:Stem Cells / Q000166:cytology
chemical_list: C000593749:ATXN1 protein, human; D000067696:Ataxin-1; C000593750:Atxn1 protein, mouse; D051929:CD146 Antigen; C497902:MCAM protein, human; C497903:Mcam protein, mouse; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D051880:Receptors, Notch; D042810:Receptor, TIE-1; D017493:Leukocyte Common Antigens; C516769:PTPRC protein, human; C516770:Ptprc protein, mouse