Blood vessel brakes boost tumors

Putting the brakes on blood vessel growth, or linkurl:angiogenesis,; surrounding a tumor can boost rather than stymie tumor growth, according to two papers out this week in Nature -- complicating a long-held belief in cancer biology. "Angiogenesis is very complex event and you really have to look at multiple aspects of it"

By | November 10, 2008

Putting the brakes on blood vessel growth, or linkurl:angiogenesis,; surrounding a tumor can boost rather than stymie tumor growth, according to two papers out this week in Nature -- complicating a long-held belief in cancer biology. "Angiogenesis is very complex event and you really have to look at multiple aspects of it" when applying the biology to treatments, linkurl:Andreas Friedl,; a cancer biologist at the University of Wisconsin who was not involved with either study, told The Scientist. "These papers show we need a much more nuanced understanding" of the protein, vascular endothelial growth factor (VEGF). Studies conducted in the lab of linkurl:Judah Folkman,; the late cancer biologist, that began in the linkurl:1970s; showed that inhibiting growth factors such as VEGF delay malignancy and cause tumors to shrink. The findings suggested that such factors help tumors flip on an angiogenic switch and that the resulting blood vessel growth is required for malignancy. Based on this hypothesis, researchers have developed cancer therapies, such as Avastin, that inhibit angiogenesis by blocking VEGF receptors. But those drugs have not worked as well as researchers had hoped, extending survival rates by an average of four months, according to linkurl:David Cheresh,; a molecular biologist at UCSD. That may be because the role of VEGF is more complicated than researchers once believed, said linkurl:Randall Johnson,; a cancer biologist also at UCSD. (Cheresh and Johnson each led one of the studies, and were co-authors on the other.) linkurl:Angiogenic inhibitors; reduce VEGF in all cell types, but VEGF produced by different tumor-associated cell types may be playing different roles. Johnson's study focused on the role of VEGF in myeloid cells, because earlier studies suggested linkurl:macrophages; played a vital role in cancer progression. He created transgenic mice in which VEGF was knocked out specifically in myeloid cells, and bred the knockouts with another transgenic strain predisposed to develop mammary cancer, commonly used for studying breast cancer. All of the resulting mice developed cancer, but at 20 weeks the mice whose myeloid cells lacked VEGF had larger tumors. The results stunned Johnson's group, he said, because they so sharply contradicted past findings that VEGF tumor cell knockouts slowed tumor growth. So they tested VEGF myeloid knockouts by injecting them with two cultured cancer cell lines, and discovered that the cancer invaded tissues faster than in normal mice. In a second surprise, chemotherapy drugs worked more effectively in the mice lacking VEGF, causing the tumors to shrink faster. "These are dramatic results," linkurl:Jeffrey Pollard,; a cancer geneticist at Albert Einstein Cancer Center who was not involved with the study, told The Scientist. "Prior to this, it had been taken as fact that [an angiogenic switch] was required for malignant transformation, when in fact, [this study shows] you don't need it." The second set of studies, led by Cheresh, sheds some light on why blocking VEGF activity leads to tumor growth by more deeply exploring the biology of tumor blood vessels. Blood vessels supporting tumors differ from normal ones, Cheresh explained. They tend to have "leaky walls," because they have only a fraction of the pericytes, or smooth muscle cells, surrounding the walls of normal vessels. linkurl:Previous studies;$=citationsensor showed blocking VEGF resulted in less leaky blood vessels. Cheresh's group hypothesized that high levels of VEGF in tumors might be working to suppress pericyte function by interfering with the receptor on pericytes known as the platelet-derived growth factor (PDGF) receptor. By stimulating smooth muscle cells with VEGF and PDGF and then examining receptor activity with immunostaining and immunoprecipitation, the researchers discovered that the receptors for VEGF and PDGF form a complex that essentially turns off the PDGF receptor. "Too much VEGF suppresses the pericyte and inhibits vessel maturation," Cheresh told The Scientist. By blocking VEGF, you allow the pericytes to regulate vascular growth and mature, Cheresh said. That regulatory step, however, doesn't happen in tumors because VEGF levels are constantly high. "We've effectively learned the molecular basis of how to tip the balance from dysfunctional [vasculature] to functional," Cheresh said. In tumors, VEGF and PDGF level become "unbalanced," he said, and "if you can bring them into sync, the result is blood vessels that are more mature." Cancer therapies that use VEGF inhibitors reduce the number of blood vessels, but they also produce vessels whose walls are less leaky, allowing the passage of nutrients, but also a clear path for chemotherapies to better access -- and kill -- the tumor. Not only do the findings open up new ways for researchers to look at how VEGF functions in tumors but they suggest that the relationship between PDGF and VEGF may be important in identifying linkurl:future; drug targets. "The problem with chemotherapy is that you can have a great drug, but if it doesn't make it to the tumor, it doesn't matter," said Cheresh. "By tuning the tumor vasculature to the tumor, one can get better drug delivery to the tumor." Editor's note (posted November 11): This article has been updated from its original version, which incorrectly quoted Jeffrey Pollard as stating angiogenesis was required for malignant transformation, when in fact it is the angiogenic switch that is usually associated with malignant transformation. The Scientist regrets the error.


Avatar of: anonymous poster

anonymous poster

Posts: 125

November 13, 2008

biomedical scientists must stop looking at the biological processes as simple "on or off" or "this or that" dichotomous processes, even for a single factor such as VEGF. It may be necessary for the convenience of easier comprehension, but nature doesn't simply work dichotomously, particularly at the molecular level.

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