It should be possible to significantly improve the response of common cancers to existing "classical" chemotherapy drugs, say scientists at Cold Spring Harbor Laboratory (CSHL), by introducing agents that alter the interaction of cancer cells with their immediate surroundings, called the tumor microenvironment.
In research published online today in the journal Cancer Cell, CSHL Assistant Professor Mikala Egeblad and her team report using "live" microscopy to observe how cancer cells in mouse tumors react to the widely used chemotherapeutic agent doxorubicin. They found that selective inhibition of two factors that regulate the tumor microenvironment -- enzymes called matrix metalloproteinases (MMPs) and a class of immune signaling molecules called chemokines -- made breast tumors in mice more responsive to the drug.
It is well known that genetic mutations and epigenetic changes in cancer cells contribute to a tumor's capacity to resist treatment. But tumors contain many other cells besides cancer cells and surprisingly little is known about how factors secreted from these non-cancerous cells -- "stromal" cells, which constitute the tumor microenvironment - influence drug resistance. Such cells include white blood cells, some of which are inflammatory.
Egeblad's team used real-time microscopic imaging to scrutinize how cancer cells react to doxorubicin in the context of different tumor microenvironments. The resulting time-lapse movies revealed how drugs flowed through - and leaked out of - blood vessels feeding tumors; the manner and rate at which drugs killed cancer cells in tumors of different stages of advancement; and dynamics of the interactions between cells of the tumor and those of the surrounding stromal tissue, before, during and after drug administration.
"We were able to see clearly that the microenvironment contributes critically to drug response," Egeblad says, "specifically via regulation of the permeability, or 'leakiness,' of blood vessels running through and around the tumor, and also by impacting the local recruitment of inflammatory cells."
When viewed at the microscopic level, resistance to doxorubicin was found to be associated with tumor stage. Observing tumors continuously following drug administration led to the discovery that this response correlated with the ability of blood vessels to transport doxorubicin to the cancer cells, which was comparatively greatest not early or late, but at intermediate stages of tumor development.
Mice engineered to lack the gene that encodes the MMP9 enzyme, which helps regulate the permeability of blood vessels, "had significantly leakier blood vessels, and this corresponded strikingly with a better response to doxorubicin," according to Egeblad.