Targeting the tumor microenvironment has shown promising results in both preclinical and clinical studies as a therapeutic strategy for various types of cancer. Disrupting the stromal-cancer cell interactions can inhibit tumor growth, reduce metastatic spread, and improve patient outcomes.
As tumor microenvironment plays a pivotal role in tumor development, our work sheds light on how MSCs and cancer cells respond to various types of chemotherapeutics in 2D and 3D, as well as in co-cultures. Combating drug resistance is one of the greatest challenges in cancer treatment and despite the fact that tumor microenvironment may be an integral part of therapy failure, we still do not fully understand the role of MSCs in it. We have selected nine chemotherapeutic agents with different mechanisms of action, tested them on MSCs and cancer cells, and showed for the first time that MSCs are also susceptible to certain drugs, no matter whether their proliferation rate is significantly lower compared to cancer cells. Strikingly, no signs of apoptosis were observed in MSCs, suggesting alternative mechanisms of cell death.
We also created a novel and reproducible 3D spheroid model to study the interactions of MSCs and cancer cells in a 3D environment. Using this model, we demonstrated that close physical proximity of MSCs is required to support cancer cell survival during chemotherapeutic treatment, as no increased cancer cell drug tolerance was found in 2D co-cultures.
The TME is a complex system that plays a major role in tumor development and treatment response. Understanding its true role could change the game, opening new avenues for designing smart drugs to target MSCs alone or in combination with cancer cells to enhance therapeutic efficacy. From a practical point of view, our results can be used as a template for in vitro ascertainment of patient-derived tumors, using not only the cancer cells but also tumor associated-MSCs to construct spheroids that more accurately model drug response.
It is impossible to predict what TME research holds for the future, but it will certainly be exciting and important. We hope that the observations we have made and the models we have developed can contribute to new discoveries in the field.
