title: Imaging tumor-stroma interactions during chemotherapy reveals contributions of the microenvironment to resistance.
abstract: Little is known about the dynamics of cancer cell death in response to therapy in the tumor microenvironment. Intravital microscopy of chemotherapy-treated mouse mammary carcinomas allowed us to follow drug distribution, cell death, and tumor-stroma interactions. We observed associations between vascular leakage and response to doxorubicin, including improved response in matrix metalloproteinase-9 null mice that had increased vascular leakage. Furthermore, we observed CCR2-dependent infiltration of myeloid cells after treatment and that Ccr2 null host mice responded better to treatment with doxorubicin or cisplatin. These data show that the microenvironment contributes critically to drug response via regulation of vascular permeability and innate immune cell infiltration. Thus, live imaging can be used to gain insights into drug responses in situ.
authors.affiliation: Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA.
authors.forename: Elizabeth S
authors.initials: ES
authors.lastname: Nakasone
authors.forename: Hanne A
authors.initials: HA
authors.lastname: Askautrud
authors.forename: Tim
authors.initials: T
authors.lastname: Kees
authors.forename: Jae-Hyun
authors.initials: JH
authors.lastname: Park
authors.forename: Vicki
authors.initials: V
authors.lastname: Plaks
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Ewald
authors.forename: Miriam
authors.initials: M
authors.lastname: Fein
authors.forename: Morten G
authors.initials: MG
authors.lastname: Rasch
authors.forename: Ying-Xim
authors.initials: YX
authors.lastname: Tan
authors.forename: Jing
authors.initials: J
authors.lastname: Qiu
authors.forename: Juwon
authors.initials: J
authors.lastname: Park
authors.forename: Pranay
authors.initials: P
authors.lastname: Sinha
authors.forename: Mina J
authors.initials: MJ
authors.lastname: Bissell
authors.forename: Eirik
authors.initials: E
authors.lastname: Frengen
authors.forename: Zena
authors.initials: Z
authors.lastname: Werb
authors.forename: Mikala
authors.initials: M
authors.lastname: Egeblad
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000493:pharmacokinetics / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000493:pharmacokinetics / Q000627:therapeutic use; D016923:Cell Death / Q000187:drug effects; D002945:Cisplatin / Q000493:pharmacokinetics / Q000627:therapeutic use; D004317:Doxorubicin / Q000493:pharmacokinetics / Q000627:therapeutic use; D019008:Drug Resistance, Neoplasm; D005260:Female; D008264:Macrophages / Q000187:drug effects / Q000473:pathology; D008325:Mammary Neoplasms, Experimental / Q000188:drug therapy* / Q000473:pathology; D020780:Matrix Metalloproteinase 9 / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D022423:Myeloid Cells / Q000187:drug effects / Q000473:pathology; D054390:Receptors, CCR2 / Q000235:genetics / Q000502:physiology; D014407:Tumor Cells, Cultured; D059016:Tumor Microenvironment / Q000187:drug effects*
chemical_list: D000903:Antibiotics, Antineoplastic; D000970:Antineoplastic Agents; D054390:Receptors, CCR2; D004317:Doxorubicin; D020780:Matrix Metalloproteinase 9; C501830:Mmp9 protein, mouse; D002945:Cisplatin