Sandbagging Cancer In The Bloodstream

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."

Once in the circulation, tumor cells can travel to distant parts of the body. Often tumor cells that are in the bloodstream get lodged in small blood vessels. Up until now it has not been clear how the tumor cells actually get out of these vessels and form new tumors in distant organs, says Cheresh, but part of the answer may lie in the fact that these cells release VEGF when they are in the bloodstream, and the VEGF allows them to enter into the tissue.

Cheresh, Weis, and their colleagues thought that if they could prevent this by blocking VEGF or Src kinase--in essence, sandbagging the tumor cells in the bloodstream--this might have a positive therapeutic effect on patients with metastatic cancer, because the human immune system handles tumor cells very well if they are in the circulation.

"Tumor cells don't last in the circulation," explains Cheresh. "If you can increase the dwell time that tumor cells spend in circulation by reducing their capacity to get out, you effectively give the immune system a greater chance of winning the battle."

Cheresh, Weis, and their colleagues decided to test whether blocking VEGF-induced vascular permeability with something known as a Src kinase inhibitor might turn off metastatic tumor cells' exit strategy from the bloodstream. They examined the question by turning to a special type of mouse that Cheresh and his colleagues have used in their laboratory. These mice, born without the ability to make Src kinase protein, show no vascular leak response.

In laboratory studies, these animals showed a high degree of resistance to tumor metastasis. Separate experiments showed that normal mice treated with Src kinase inhibitors also acquired a high degree of resistance to the metastasis of tumor cells.

This suggests a possible new avenue to explore therapeutically in humans. Src kinase inhibitors might reduce the metastatic ability of cancer cells and improve the prognosis of patients treated with them.

Significantly, this approach reduces cancer cell metastasis by targeting a host protein (Src kinase), which means that it may be broadly applicable in many different types of cancer. Indeed, Cheresh and Weis tested Src kinase inhibitors against several types of metastatic cancer cell lines and found that it did work against most of them.

Of course, such a treatment strategy would have to be explored in the context of clinical trials before doctors knew for sure if it would work in humans, and these may take several years.

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The article "Endothelial barrier disruption by VEGF-mediated Src activity potentiates tumor cell extravasation and metastasis" is authored by Sara Weis, Jianhua Cui, Leo Barnes, and David Cheresh and appears in the October 25, 2004 issue of the Journal of Cell Biology. See: http://www.jcb.org.

The research was supported by the National Institutes of Health.

Background: Cancer and Metastasis

Cancer is a complicated disease--or, really, group of diseases--caused by subtle mutations within normal cells in different parts of the body. After certain mutations occur, a normal cell becomes cancerous, growing resistant to normal programmed cell death, dividing out of control, and forming a solid tumor.

Common to tumor cells are mutations that lead them to metastasize. The word "metastasis" comes from the Latin construction meaning to change position, and metastasis depends on the cancerous cells acquiring two separate abilities--increased motility and invasiveness.

Metastasis is a dangerous phenomenon in which cancer cells separate from a tumor mass, move through the bloodstream, anchor down in a distant tissue or organ, and begin a new cancer that might compromise the function of that organ. While surgeons can remove cancerous tissue, such procedures are greatly complicated if a tumor establishes new tumors in other organs. Although science and medicine have made tremendous strides in early detection and successful treatment, breast cancer and melanoma still claim tens of thousands of lives a year--usually due to the fact that these cancers tend to spread to other parts of the body even though the primary tumor was already removed.

The U.S. Centers for Disease Control and Prevention (CDC) reports that by the end of 2004, 215,990 U.S. women will have been diagnosed with new cases of invasive breast cancer and that an estimated 40,580 American women will die of the disease this year. Similarly, malignant melanoma, the deadliest type of skin cancer, claims many lives. According to the CDC, some 59,350 patients in the United States will be diagnosed with new cases of malignant melanoma in 2004 and 9,800 Americans will die of skin cancer.