Imaging tumor-stroma interactions during chemotherapy reveals contributions of the microenvironment to resistance

Cancer Cell. 2012 Apr 17;21(4):488-503. doi: 10.1016/j.ccr.2012.02.017.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

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


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