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: Elizabeth S Nakasone, Hanne A Askautrud, Tim Kees, Jae-Hyun Park, Vicki Plaks, Andrew J Ewald, Miriam Fein, Morten G Rasch, Ying-Xim Tan, Jing Qiu, Juwon Park, Pranay Sinha, Mina J Bissell, Eirik Frengen, Zena Werb, Mikala Egeblad
• Journal: Cancer cell (Cancer Cell) Vol. 21 Issue 4 Pg. 488-503 (Apr 17 2012) ISSN: 1878-3686 [Electronic] United States
• PMID: 22516258 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2012 Elsevier Inc. All rights reserved.

Chemical References

• Antibiotics, Antineoplastic
• Antineoplastic Agents
• Receptors, CCR2
• Doxorubicin
• Matrix Metalloproteinase 9
• Mmp9 protein, mouse
• Cisplatin

Topics

• Animals
• Antibiotics, Antineoplastic (pharmacokinetics, therapeutic use)
• Antineoplastic Agents (pharmacokinetics, therapeutic use)
• Cell Death (drug effects)
• Cisplatin (pharmacokinetics, therapeutic use)
• Doxorubicin (pharmacokinetics, therapeutic use)
• Drug Resistance, Neoplasm
• Female
• Macrophages (drug effects, pathology)
• Mammary Neoplasms, Experimental (drug therapy, pathology)
• Matrix Metalloproteinase 9 (genetics)
• Mice
• Mice, Inbred C57BL
• Myeloid Cells (drug effects, pathology)
• Receptors, CCR2 (genetics, physiology)
• Tumor Cells, Cultured
• Tumor Microenvironment (drug effects)