title: Notch1 regulates angio-supportive bone marrow-derived cells in mice: relevance to chemoresistance.
abstract: Host responses to chemotherapy can induce resistance mechanisms that facilitate tumor regrowth. To determine the contribution of bone marrow-derived cells (BMDCs), we exposed tumor-bearing mice to chemotherapeutic agents and evaluated the influx and contribution of a genetically traceable subpopulation of BMDCs (vascular endothelial-cadherin-Cre-enhanced yellow fluorescent protein [VE-Cad-Cre-EYFP]). Treatment of tumor-bearing mice with different chemotherapeutics resulted in a three- to 10-fold increase in the influx of VE-Cad-Cre-EYFP. This enhanced influx was accompanied by a significant increase in angiogenesis. Expression profile analysis revealed a progressive change in the EYFP population with loss of endothelial markers and an increase in mononuclear markers. In the tumor, 2 specific populations of VE-Cad-Cre-EYFP BMDCs were identified: Gr1⁺/CD11b⁺ and Tie2high/platelet endothelial cell adhesion moleculelow cells, both located in perivascular areas. A common signature of the EYFP population that exits the bone marrow is an increase in Notch. Inducible inactivation of Notch in the EYFP⁺ BMDCs impaired homing of these BMDCs to the tumor. Importantly, Notch deletion reduced therapy-enhanced angiogenesis, and was associated with an increased antitumor effect of the chemotherapy. These findings revealed the functional significance of a specific population of supportive BMDCs in response to chemotherapeutics and uncovered a new potential strategy to enhance anticancer therapy.
authors.affiliation: Department of Medical Oncology, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Jeanine M L
authors.initials: JM
authors.lastname: Roodhart
authors.forename: Huanhuan
authors.initials: H
authors.lastname: He
authors.forename: Laura G M
authors.initials: LG
authors.lastname: Daenen
authors.forename: Arnaud
authors.initials: A
authors.lastname: Monvoisin
authors.forename: Chad L
authors.initials: CL
authors.lastname: Barber
authors.forename: Miranda
authors.initials: M
authors.lastname: van Amersfoort
authors.forename: Jennifer J
authors.initials: JJ
authors.lastname: Hofmann
authors.forename: Freddy
authors.initials: F
authors.lastname: Radtke
authors.forename: Timothy F
authors.initials: TF
authors.lastname: Lane
authors.forename: Emile E
authors.initials: EE
authors.lastname: Voest
authors.forename: M Luisa
authors.initials: ML
authors.lastname: Iruela-Arispe
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D000970:Antineoplastic Agents / Q000494:pharmacology; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D001854:Bone Marrow Cells / Q000166:cytology / Q000502:physiology*; D015820:Cadherins / Q000378:metabolism; D018827:Carcinoma, Lewis Lung / Q000188:drug therapy* / Q000235:genetics; D002945:Cisplatin / Q000494:pharmacology*; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000235:genetics; D019008:Drug Resistance, Neoplasm / Q000502:physiology; D015674:Mammary Neoplasms, Animal / Q000188:drug therapy / Q000235:genetics; D051379:Mice; D057507:Mice, 129 Strain; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D008822:Mice, Transgenic; D017239:Paclitaxel / Q000494:pharmacology*; D051881:Receptor, Notch1 / Q000235:genetics / Q000502:physiology*; D023041:Xenograft Model Antitumor Assays; D000099152:Cadherin 5
chemical_list: D015703:Antigens, CD; D000970:Antineoplastic Agents; D000972:Antineoplastic Agents, Phytogenic; D015820:Cadherins; D002945:Cisplatin; D017239:Paclitaxel; D051881:Receptor, Notch1; D000099152:Cadherin 5; C497762:Notch1 protein, mouse