Fluid shear stress sensitizes cancer cells to receptor-mediated apoptosis via trimeric death receptors
This is a modal window.
The media could not be loaded, either because the server or network failed or because the format is not supported.
Formal Metadata
Title |
| |
Title of Series | ||
Number of Parts | 63 | |
Author | ||
License | CC Attribution 3.0 Unported: You are free to use, adapt and copy, distribute and transmit the work or content in adapted or unchanged form for any legal purpose as long as the work is attributed to the author in the manner specified by the author or licensor. | |
Identifiers | 10.5446/39022 (DOI) | |
Publisher | ||
Release Date | ||
Language |
Content Metadata
Subject Area | ||
Genre | ||
Abstract |
|
00:00
Electric power distributionParticle physicsPlain bearingVideoComputer animation
00:08
PaperEngineMeeting/Interview
00:28
Acoustic membraneMusical developmentEnergiesparmodusSpread spectrumTissue paperZirkulatorRoll formingRadiation therapyHot workingBlood vessel
01:21
Meeting/Interview
01:31
Domäne <Kristallographie>NeutronenaktivierungTypesettingField-effect transistorSignal (electrical engineering)BookbindingSunriseComputer animation
01:55
Matrix (printing)Roots-type superchargerZwischengitteratomPlain bearingTissue paperForceComputer animation
02:09
Basis (linear algebra)Computer animation
02:19
Plasma (physics)Acoustic membraneRestkernVolumetric flow rateOptometryPhotographic plateBasis (linear algebra)Computer animation
02:28
Effects unitComputer animationEngineering drawing
02:39
Dose (biochemistry)ForceComputer animationDiagram
02:52
Effects unitMeeting/Interview
03:00
NeutronenaktivierungMechanicDiagramProgram flowchart
03:12
NeutronenaktivierungAcoustic membraneMechanismus <Maschinendynamik>Domäne <Kristallographie>FadingPolradStock (firearms)Bookbinding
03:25
MeasurementMechanicEffects unitPottery
03:47
Domäne <Kristallographie>NeutronenaktivierungAcoustic membraneMechanicComputer animation
04:00
HailControl systemComputer animationEngineering drawing
04:08
MountainComputer animation
04:24
Effects unitElectric power distributionEffects unitSource (album)Computer animation
04:35
Roll formingMeeting/Interview
05:09
WatchVideoComputer animation
Transcript: English(auto-generated)
00:09
My name is Mike Mitchell and I am a PhD candidate at Cornell University in Biomedical Engineering. I work in the laboratory of Professor Michael King and the title of our paper is, Fluid
00:20
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
00:43
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
01:02
the tumor. However, once metastasis occurs, it is very challenging to stop the spread of cancer because very small tumors, termed micrometastasis, form in distant tissues and are too small to detect and treat. It is this metastatic spread that makes cancer so deadly.
01:21
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
01:42
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
02:06
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
02:24
and then exposed the cancer 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 are exposed to static conditions. When we further increase the shear force that cancer cells were exposed to, or increase
02:44
the amount of time that cancer cells were exposed to fluid shear forces, the sensitization of TRAIL was further increased. But what about other drugs? Is fluid shear stress sensitization a broad effect demonstrated by many kinds of drugs?
03:00
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
03:24
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.
03:42
This indicates that the sensitization to apoptosis is specific to TRAIL treatment. 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
04:05
to TRAIL is caspase-dependent. So where does this sensitization originate from? We looked for changes in the expression of death receptors on the surface of cancer cells, but whether exposed to shear stress or not, the number of death receptors on
04:21
the cell surface remain 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 our study is that fluid shear stress exposure can sensitize cancer
04:42
cells to TRAIL treatment. This can make TRAIL an ideal candidate for the treatment of cancers metastasizing via the bloodstream. These shear stress studies also reveal the possibility that death receptors on the CTC surface can sense fluid shear stress.
05:00
We are currently investigating strategies to control how these receptors respond to fluid shear stress as a novel form of TRAIL therapy. This concludes our video. Thanks for watching.