Modifying blood vessel permeability and blocking myeloid cell recruitment boosts doxorubicin efficacy.
Through direct observation of how cancer cells respond to chemotherapy in their native microenvironment, scientists have identified factors that impact on the effectiveness of doxorubicin therapy and demonstrated that modifying tumor stromal interactions could improve the effectiveness of existing drugs. The Cold Spring Harbor Laboratory-led team used spinning disk confocal microscopy to evaluate acute cellular responses to doxorubicin treatment in a mouse model of breast cancer known as the mammary tumor virus (MMTV) promoter-driven polyoma middle T oncogene (PyMT) model. These animals display progressive stages of tumorigenesis that are similar to human luminal type B breast cancer. Of particular use is the fact that an individual mouse will display different stages of tumor at the same time, allowing the researcher to compare doxorubicin response in differently-sized and developmental-staged tumors in a single animal.
The resulting visualization results data demonstrated a clear association between vascular leakage and response to doxorubicin. In fact, the researchers found that the greatest response to therapy occurred at an intermediate stage of tumor development (rather than at early or late stage), when the tumor-feeding blood vessels were at their most leaky. The imaging studies also showed that CCL2-responsive CCR2+ myeloid cells were consistently recruited to the tumor site during chemotherapy, and that recruitment of CCR2+ monocytes correlated with tumor relapse.
Importantly, tumors in mice engineered to lack matrix metalloproteinase-9 (MMP9), which as a result demonstrated leakier blood vessels, exhibited improved response to doxorubicin therapy. This finding was particularly encouraging as MMP inhibitors have to date failed in clinical trials, the authors note. Similarly, knocking out CCR2, which is the receptor on myeloid cells that responds to the CCL2 signal and triggers chemotaxis to tumor sites, led to reduced myeloid cell recruitment and improved response to doxorubicin or cisplatin therapy.
Reporting their findings in Cancer Cell, Mikala Egeblad, Ph.D., et al say their data demonstrates how live imaging can be used to gain insights into drug responses in vivo, and confirm that the microenvironment play a key role in treatment effectiveness. Moreover, they conclude, “our results suggest that existing drugs that inhibit MMPs or chemokine signaling may be effective when combined with traditional chemotherapies.” The researchers’ findings are described in a paper titled “Imaging Tumor-Stroma Interactions during Chemotherapy Reveals Contributions of the Microenvironment to Resistance.”