Michael J Mitchell and Michael R King 2013 New J. Phys. 15 015008
Video Transcript for “Fluid shear stress sensitizes cancer cells to receptor mediated apoptosis via trimeric death receptors.” Hello, my name is Mike Mitchell, and I am a PhD candidate in biomedical engineering at Cornell University. I work in the laboratory of Professor Michael King, and our paper is titled: “Fluid shear stress sensitizes cancer cells to receptor-mediated apoptosis via trimeric death receptors.”
The motivation behind our work is to explore the treatment of circulating tumor cells to prevent cancer metastasis. In basic terms, metastasis occurs when cancer cells detach from a primary tumor and enter the circulation. These circulating tumor cells, or CTCs, can utilize the circulation as a “highway”, and adhere within blood vessels to travel into distant tissues and form secondary tumors. For primary tumors, surgery or radiation therapy is generally successful at removing the tumor. Once metastasis occurs, it is very challenging to stop the spread of cancer because very small tumors, termed micrometastases, form in distant tissues that are too small to detect and treat. It is this metastatic spread that makes cancer so deadly.
Our lab is currently exploring the idea of whether CTCs can be treated in the bloodstream, to reduce the chances of cancer metastasis. One therapeutic we are currently investigating is TRAIL, which is unique in that it induces cell death in a variety of cancer cell types, but leaves nearly all of the body’s healthy cells unharmed. TRAIL binds to death receptors expressed on the cancer cell surface, which can trimerize in the presence of TRAIL and signal for programmed cell death, known as apoptosis.
One of the main differences between cancer cells in the tumor microenvironment and the vascular microenvironment is fluid shear stress exposure, with shear forces being much greater in the bloodstream than in tumor tissue. We were interested in addressing the question of whether exposure to fluid shear stress affects how cancer cells respond to therapeutics such as TRAIL.
The basis of our study was that we treated colon and prostate cancer cells with TRAIL, and then exposed the cells to fluid shear stress. What we found was that fluid shear stress actually enhances the apoptotic effects of TRAIL, when compared to cells that were exposed to static conditions. When we further increased the shear force that cancer cells are exposed to, or increased the amount of time that cancer cells are exposed to fluid shear forces, the sensitization to TRAIL further increased.
But what about other drugs? Is fluid shear stress sensitization a broad effect demonstrated by many kinds of drugs? To test this we also treated cells with doxorubicin, an FDA approved drug used in the treatment of cancer, which induces cancer cell death using a different mechanism from TRAIL. TRAIL binds to surface receptors to signal apoptosis, whereas doxorubicin enters the cell and intercalates with DNA, which can inhibit basic cellular processes and induce cell death.
We discovered that fluid shear stress had NO measurable effect on doxorubicin-induced apoptosis. Whether cells were exposed to static conditions or fluid shear stress, the percentage of cells undergoing apoptosis remained the same. This indicates that the sensitization to apoptosis is specific to TRAIL.
We also performed studies probing the molecular mechanism of this sensitization. When we inhibited the caspase pathway within cancer cells, which signals for TRAIL-induced apoptosis, the entire apoptotic response was abolished, indicating that the sensitization to TRAIL is caspase-dependent.
So where does the sensitization originate from? We looked for changes in the expression of death receptors on the surface of the cancer cells, but whether exposed shear stress or not, the number of death receptors on the cell surface remained unaltered. Future efforts will focus on examining fluid shear stress effects on the trimerization of death receptors, as well as the spatial distribution of death receptors on the cancer cell surface.
The main conclusion of this study is that fluid shear stress exposure can sensitize cancer cells to TRAIL. This could make TRAIL an ideal candidate for the treatment of cancers metastasizing through the bloodstream. These studies also reveal the possibility that death receptors on the CTC surface can sense fluid shear forces. We are currently investigating strategies to control how these receptors respond to fluid shear stresses, as a novel form of TRAIL therapy. That concludes our video, thanks for watching.