Real-time microscopic imaging of tumour-stroma interactions during chemotherapy
Live imaging reveals how the tumour microenvironment contributes to the resistance to anticancer drugs
- Date : 24 Apr 2012
- Topic : Imaging
It should be possible to significantly improve the response of common cancers to existing "classical" chemotherapy drugs by introducing agents that alter the interaction of cancer cells with tumour micro-environment. It is well known that genetic mutations and epigenetic changes in cancer cells contribute to a tumour's capacity to resist treatment. But tumours 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 tumour micro-environment – influence drug resistance.
In research published online on 17 April in the journal Cancer Cell, Cold Spring Harbor Laboratory Assistant Professor Mikala Egeblad and her team report using "live" microscopy to observe how cancer cells in mouse tumours react to the widely used chemotherapeutic agent doxorubicin. They found that selective inhibition of two factors that regulate the tumour micro-environment - enzymes matrix metalloproteinases (MMPs) and a class of immune signalling molecules called chemokines - made breast tumours more responsive to the drug.
Response to cancer drugs can be boosted by altering tumour micro-environment
Egeblad's team used real-time microscopic imaging to scrutinize how cancer cells react to doxorubicin in the context of different tumour micro-environments. The resulting time-lapse movies revealed how drugs flowed through – and leaked out of – blood vessels feeding tumours; the manner and rate at which drugs killed cancer cells in tumours of different stages of advancement; and dynamics of the interactions between cells of the tumour and those of the surrounding stromal tissue, before, during and after drug administration.
According to the researchers, the micro-environment contributes critically to drug response, specifically via regulation of the permeability of blood vessels running through and around the tumour, 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 tumour stage. Observing tumours 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 tumour 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.
Existing chemical inhibitors of MMP enzymes have failed in clinical trials. According to study researchers, their data suggest that these or other drugs that affect vascular permeability could be used to achieve better responses to chemotherapies.
Another important discovery gleaned from the team's real-time imaging was that myeloid cells were consistently recruited to the tumour site during chemotherapy. Myeloid cells tend to be drawn to places where cells have died. The team found that this attraction, called chemotaxis, is the result of the activation of signalling by CCL2, a member of a class of immune cell recruiting molecules called chemokines.
By knocking out the gene encoding the receptors (CCR2) for this chemokine, the team was able to diminish myeloid cell recruitment to the tumour. Importantly, this also resulted in a significantly improved response to doxorubicin and to another commonly used chemotherapy drug, cisplatin. This observation is important because it points to a novel way of potentially boosting the cancer cell-killing effectiveness of chemotherapeutic drugs.
The Cold Spring Harbor Laboratory team now has the goal of finding additional ways to boost the response chemotherapy by determining how the myeloid cells that are recruited to tumours during chemotherapy contribute to the response of cancer cells to drug treatment.
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