Vascular permeability and immune cell infiltration are key determinants of drug efficacy.
Major finding: Vascular permeability and immune cell infiltration are key determinants of drug efficacy.
Approach: Fluorescent reporter mice enabled live imaging of drug distribution and stromal cell tracking.
Impact: Inhibitors of matrix metalloproteinases or chemokine signaling may improve drug responses.
Most of what is known about tumor responses to cytotoxic chemotherapies is based on cell culture or tumor xenografts that do not accurately recapitulate the microenvironment of human cancers. To visualize tumor progression and drug response in the context of the tumor microenvironment and track stromal cells, Nakasone and colleagues crossbred the mammary tumor virus (MMTV) promoter-driven polyoma middle T oncogene (PyMT) mouse model to various fluorescent reporter lines and imaged live mice using spinning disk confocal microscopy. Treatment with doxorubicin reduced tumor volume in MMTV–PyMT mice with multiple tumors but induced more necrotic cell death in intermediate-stage tumors compared with early- or late-stage tumors. However, cancer cells from all tumor stages were similarly sensitive to doxorubicin in vitro, indicating that extrinsic drug resistance mechanisms operate in vivo. Real-time imaging following treatment with doxorubicin revealed that myeloid cells (labeled by colony-stimulating factor 1 receptor–enhanced GFP) were recruited to tumors and that intratumoral doxorubicin concentrations were associated with vascular permeability (as measured by leakage of fluorescently labeled dextran into the extravascular space). Notably, mammary tumors transplanted into mice deficient for matrix metalloproteinase 9, a host inhibitor of vascular permeability, or chemokine (C-C motif) receptor 2, which mediates recruitment of myeloid cells to tumors, showed increased sensitivity to doxorubicin. These findings indicate that vascular permeability and chemokine signaling regulated by components of the tumor microenvironment mediate extrinsic drug resistance and that combining matrix metalloproteinase or chemokine signaling inhibitors with traditional chemotherapy may improve clinical outcomes.
Nakasone ES, Askautrud HA, Kees T, Park JH, Plaks V, Ewald AJ, et al. Imaging tumor-stroma interactions during chemotherapy reveals contributions of the microenvironment to resistance. Cancer Cell 2012;21:488–503.
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