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Research discovers how platelets initiate ovarian cancer metastasis
08-14-2020
by Mel J. Yeates  |  Email the author
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COLLEGE STATION, Tx. & HOUSTON—Recent collaboration between Dr. Abhishek Jain, assistant professor in the Department of Biomedical Engineering and the Department of Medical Physiology in the College of Medicine at Texas A&M University, and researchers from the Departments of Gynecologic Oncology and Cancer Biology at MD Anderson Cancer Center, has elucidated the interaction between ovarian cancer tumors, blood vessels and platelets. The research has been published in Blood Advances.
 
The researchers found that tumors break the blood vessel barriers in order to communicate with the blood cells, such as platelets. When tumors come into contact with platelets, they can then begin to metastasize.
 
It was known that platelets are one of the initiators of ovarian cancer metastasis, but researchers didn’t know how platelets were introduced to the tumor cells. Jain's team designed the OvCa-Chip in order to view the biological processes between tumors and platelets.
 
“Over the period of 5 days of platelet perfusion, we found consistent expression of P-selectin on the platelets, and they were activated within the microenvironment of the OvCa-Chip. Three days after platelet perfusion, we observed adhesion of platelets on the surface of cancer-influenced endothelial cells of the OvCa-Chip, but no platelets were observed in the Control-Chip, in which cancer cells were absent,” the study says. “We also saw platelets colonized into a tumor, thus confirming that, similar to the in vivo situation, platelets extravasated from the vascular lumen into the tumor compartment within our OvCa-Chips.
 
“Quantification of adherent platelets revealed that, from 72 hours onward, there was rapid acceleration in platelet adhesion. Correspondingly, the platelets attached to the endothelium eventually crossed the barriers and migrated into the tumor compartment during the same time frame. When the endothelium was completely removed, platelet extravasation was at its maximum when the tumor cells were present, but nearly absent when replaced with benign cells, suggesting that platelet extravasation is controlled by gain or loss of endothelium.”
 
“These data showed that our OvCa-Chip could model platelet extravasation dynamics and provide a tool to evaluate how ovarian cancer cells influence the vascular luminal microenvironment and trigger platelet extravasation and subsequent migration toward the lumina over time,” continues the article. “Because it is widely known that immune cell trafficking occurs in cancer and vascular barrier function is compromised, these observations in organ chips prompted us to hypothesize that platelet extravasation is triggered by ovarian cancer cells through systematic and dynamic disruption of the neighboring endothelium.” 
 
Researchers found that tumor cells systematically broke down the endothelial cells. Once this barrier was gone, blood cells and platelets entered the tumor microenvironment and could be recruited for metastasis.
 
“We also found an increased expression of endothelial Akt in the presence of ovarian cancer cells in our model, which has also been reported to be activated in some metastatic cancers and contributes to cancer growth and endothelial survival,” the study states. “To further establish the possibility of endothelial activation in ovarian cancer that may regulate platelet extravasation, we also quantitated the expressions of vascular endothelial Tie-2, Pyk-1, and Rac-1 genes, which are known to directly influence activation and transvascular migration of blood leukocytes and neutrophils. We found that their expression was significantly increased in the OvCa-Chip relative to that in the Control-Chip, indicating their involvement in the endothelial activation needed for platelet extravasation.”
 
“These results strongly confirm that the vascular barrier degradation that we observed within the OvCa-Chip is supported by the genetic activation of vascular endothelial signaling pathways (Src/ERK/FAK), attenuation of vascular integrity (VE-cadherin–β-catenin expression), and overexpression of prostimulatory signals for communication with blood cells (Pyk-1/Tie-2/Rac-1). Further, these data demonstrate our system’s ability to analyze several corresponding genetic signatures in a complex disease model consisting of multitissue interactions, which may be difficult to perform with in vivo models,” concludes the article.
Jain pointed out that harnessing this knowledge could change how clinicians approach ovarian cancer treatment, suggesting that anti-vascular drugs could be considered along with anticancer treatments. The organ-on-a-chip technology is capable of testing these novel drug treatments and combinations; it might also be able to aid in diagnostics.
 
“You have to understand that these are chips that are living. They contain living cells. The advantage is that these are all actually human samples,” Jain pointed out in an interview with the International Society on Thrombosis and Hemostasis. “So what we think the future for this technology is, is perhaps we can advance it in the direction of personalized medicine where we could actually take stem cells from patients and other patient-derived cells and make this entire chip from a single patient.”
 
Code: E08142001

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