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Scientists at The Scripps Research Institute have shown that aparticular white blood cell plays a direct role in the developmentand spread of cancerous tumors. Their work sheds new light on thedevelopment of the disease and points toward novel strategies fortreating early-stage cancers . The study was published in September 2011 print issue of theAmerican Journal of Pathology. Scripps Research Professor James Quigley, Staff Scientist ElenaDeryugina, and colleagues had previously demonstrated that whiteblood cells known as neutrophils - bone marrow-derived cells thatfunction as "first responders" at sites of acute inflammation -promote the growth of new blood vessels in normal, healthy tissue. The team has now tied these cells to the induction and growth ofnew blood vessels in malignant tumors and to the spread of tumorcells through those newly formed vessels. The scientists have alsouncovered some of the mechanisms underpinning this process - whichcould be interrupted by properly targeted drugs. Potent and Uninhibited The Scripps Research team has been particularly interested inneutrophils, in part because several studies have demonstrated alink between elevated neutrophil levels and high rates of tumorinvasion among cancer patients. Mounting evidence has alsoindicated that neutrophils play a particularly important roleduring the early stages of tumor development. "During tumor development, neutrophils appear to be one of thefirst inflammatory cell types on the scene," said Deryugina, whospearheaded the new study. The researchers have been especially interested in the bloodvessel-forming or "angiogenic," powers of neutrophils, which stemfrom a special enzyme they produce known as MMP-9 (matrixmetalloproteinase type 9). The enzyme is, in fact, synthesized by anumber of different types of white blood cells and has long beenlinked to tumor development. But the particular form synthesized byneutrophils is especially potent, in part because it does not comebound up with the natural inhibitory regulating agents that othercells supply. Whereas other types of white blood cells only manufacture theenzyme later and invariably deliver it in combination with one ofits natural inhibitors, neutrophils come loaded withpre-synthesized MMP-9 in a form that is unencumbered. Making the Case In a series of cleverly designed experiments, Quigley, Deryugina,and colleagues established a link between neutrophils, their MMP-9,and the growth and spread of tumors. The scientists alternately raised and lowered the quantity ofneutrophils allowed to flow into two different kinds of early-stagetumors, which had been transplanted into chicken embryos and mice.They also introduced several different versions of the enzyme,sometimes combining it with dampening agents, sometimes not. By observing the subsequent decrease and increase in the formationof new blood vessels, the Scripps Research team was able toestablish that the unique form of the enzyme delivered byneutrophils was directly responsible for heightening the growth ofnew blood vessels in the tumors. Just as importantly, they wereable to determine that the newly formed blood vessels served as"escape routes" or conduits for the spread of tumor cells beyondtheir initial location. First, the scientists established that the most aggressive tumors -that is, the ones that were able to most quickly penetrate thesurrounding blood vessels and spread to different areas - dependedon their ability to attract large numbers of neutrophils. The researchers then proceeded to spur the growth of new bloodvessels in even relatively nonaggressive tumors by supplyingadditional quantities of neutrophil-derived enzyme. They alsoblocked the formation of new vessels with the anti-inflammatorydrug ibuprofen and then restored, or "rescued," angiogenesis bypumping in additional enzyme. Quigley and Deryugina also drastically reduced the influx ofneutrophils by neutralizing IL-8 (interleukin 8), the chemicalattractant that draws neutrophils to sites of inflammation. Bloodvessel formation declined correspondingly, as did the penetrationof vessels by tumor cells, clearly linking neutrophils to thedevelopment and spread of two different, but highly aggressive,forms of cancer. To further strengthen that link, the researchersagain reversed the decline with an infusion of neutrophil-derivedenzyme. "By dampening neutrophil influx into tumors, we dampenangiogenesis, but we also dampen metastasis," Quigley said. "Andwhen we rescue angiogenesis, we also rescue the high metastaticrate of the tumors." Significantly, only the unregulated, uninhibited version of theenzyme provided by neutrophils reversed the dampening effect causedby reducing inflammation or cutting off the flow of neutrophils. Nosuch rescue occurred when the enzyme was combined with its naturalinhibiting agents - the same molecules that accompany the enzymewhen it is delivered by other kinds of white blood cells. Intriguing Possibilities The scientists note that the study suggests tumors that engender astrong inflammatory response may be particularly amenable toearly-stage treatment by drugs that specifically targetneutrophils, whether that means inhibiting the enzyme they deliveror simply preventing them from showing up in the first place. "It might be best to combat tumor angiogenesis earlier rather thanlater," Quigley said, adding that "more specifically directedanti-neutrophil agents might be better suited than a generalanti-inflammatory." The Quigley lab continues to investigate. In addition to Quigley and Deryugina, authors of this paper,"Neutrophil MMP-9 in Tumor Progression" ( doi:10.1016/j.ajpath.2011.05.031 ), include Bernhard Schweighofer, Tatyana A. Kupriyanova, EwaZajac, Veronica C. Ardi, all of Scripps Research; and Erin M.Bekes, formerly a UCSD graduate student doing her thesis at ScrippsResearch and now a postdoctoral fellow at the NYU School ofMedicine. See science/article/pii/S000294401100530X Support for this study came from the National Institutes of Health,Scripps Translational Science Institute, the Max Kade Foundation,and the National Cancer Institute. Additional References Citations. The e-commerce company in China offers quality products such as China Welding Wire Mesh , China Screen Metal Mesh, and more. For more , please visit Welding Wire Mesh today!
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