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The Scripps Research Institute 的研究人員提出可能用來
A team of scientists at The Scripps Research Institute has identified a potential treatment strategy against metastatic cancer cells that has never been tried before.
Metastasis is a major problem with cancer because it allows tumor cells to spread to other parts of the body (See Supporting Material: Cancer and Metastasis). While solid tumors can be removed surgically or treated with chemotherapy or radiation, metastatic cells that have already entered the circulation are capable of opening a passageway through blood vessels in order to spread to various organs throughout the body.
Once tumor cells leave their primary tumor, they enter the blood stream and ultimately must find an exit strategy in order to set up new "satellite" lesions in one or more distant organs. The potential treatment strategy targets this final step of the metastatic cascade--the exit of the metastatic cells from the bloodstream.
"We know that the normal blood vessel wall is one final barrier that metastatic tumor cells must overcome, which allows them to find their way out of the bloodstream and into a metastatic site," says Immunology Professor David A. Cheresh, who led the research with postdoctoral fellow Sara Weis at The Scripps Research Institute. To exit the blood stream, says Cheresh, the tumor cells stimulate the local blood vessels to briefly open their cell-cell junctions so that they can implant themselves into a new organ site.
In the latest issue of the Journal of Cell Biology, Cheresh, Weis, and their colleagues report the dramatic effect of using a class of compounds known as Src kinase inhibitors to treat metastatic cancer in mice. Rather than conventional chemotherapies, which target the tumor cells, Cheresh and colleagues suggest a new approach that would increase the protective barrier strength of the host blood vessels and prevent tumor cells from exiting the bloodstream.
To support their approach, Cheresh, Weis, and their colleagues demonstrate that mice that are genetically deficient in the Src gene are resistant to tumor cell metastasis. Furthermore, blocking Src in normal mice dramatically protects the mice against metastatic tumors because it keeps the cancer cells "sandbagged" in the bloodstream where they are vulnerable to attack and clearance from the immune system.
"You can imagine that a prolonged treatment [with Src kinase inhibitors] may actually help people ward off some of the most deadly and metastatic cancers," says Cheresh. "Currently, anti-cancer drugs are typically aimed at the tumor cells themselves. The problem is that genetically unstable tumor cells are able to develop resistance to one or more drugs, ultimately overwhelming the host. We keep changing the combination, and the cells keep picking the lock. With this new approach, we are essentially bolting the door closed."
Sandbagging Cancer Cells
The possible new treatment strategy for cancer cell metastasis stems from several years of basic research conducted by Cheresh and his collaborators into an area of biology known as cell adhesion.
Cell adhesion is a topic of major importance because it is the basis for how groups of cells form and define functionally distinct tissues and organs in the body. Blood vessels are lined by what are known as endothelial cells, which adhere to one another and line the body's blood vessels like bricks lining a subterranean tunnel.
Cheresh and other basic science researchers over the past decades have identified a number of the adhesion molecules that hold these endothelial cells together. They have also identified the signaling mechanisms that defeat cell adhesion and induce endothelial cells to let go of one another during events like angiogenesis--the growth of new blood vessels that often accompanies tumor growth.
Some of the most metastatic tumor cells secrete a protein known as vascular endothelial growth factor (VEGF). VEGF stimulates a protein called Src kinase, which causes proteins known as cadherins to disengage from each other. Normally, cadherins are something like the mortar in between the endothelial cell bricks, and they maintain the integrity of blood vessel walls. When tumor cells release VEGF within blood vessels, Src kinases respond to this by causing the vascular cell cadherins to break apart and allow the tumor cell to get out of the circulation and into an environment where the tumor cell can survive and propagate.
Blocking the Exits
Targeting growth factors like VEGF or its downstream target Src is an emerging paradigm for fighting cancer. In fact, the U.S. Food and Drug Administration recently approved Avastin, a VEGF inhibitor, for fighting colorectal cancer.
However, VEGF is unique among growth factors in that it also causes vascular permeability where it is released. This is easily seen when looking at the blood supply to tumors under the microscope, says Cheresh. "Anywhere there is VEGF, there is a vascular permeability," he says. "Tumors have blood vessels that are very leaky."
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作者:admin@医学,生命科学 2010-11-02 22:44
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