Scripps scientists identify white blood cells responsible for growth, metastasis of tumors

Recent discovery has shown that a particular kind of white blood cells known as neutrophils, bone marrow-derived cells that generally serve as "first responders" at sites of severe inflammation, play a direct role in the growth and spread of tumors

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LA JOLLA, Calif.—It is well known that the human body, particularly the immune system, can occasionally turn against itself. Allergies, for instance, are the result of the immune system overreacting to and targeting supposed pathogens. Autoimmune diseases are a more common example, in which the body mistakenly targets parts of its own systems as being infected and attacks the cells.
But scientists at the Scripps Research Institute have found that this double-edged nature of the immune system also plays a particular role in cancer and the metastasis of tumors.
A recent discovery has shown that a particular group of white blood cells known as neutrophils, bone marrow-derived cells that generally serve as "first responders" at sites of severe inflammation, play a direct role in the growth and spread of tumors. Scripps Research Professor James Quigley, Staff Scientist Elena Deryugina and their colleagues had established in previous work that neutrophils promote angiogenesis, or the growth of new blood vessels, in healthy tissue. Their most recent research has shown that these white blood cells also play a critical role in the development of blood vessels in tumors, as noted in the article published in the September 2011 print issue of the American Journal of Pathology. 
"During tumor development, neutrophils appear to be one of the first inflammatory cell types on the scene," Deryugina, who led the study, said in a press release.
Neutrophils' capabilities in the formation of new blood vessels stem from an enzyme known as matrix metalloproteinase type 9, or MMP-9, which is synthesized by several different types of white blood cells and is linked to tumor development. The version synthesized by neutrophils, however, is particularly potent and is not bound up with the natural inhibitory regulating agents that other cells produce in conjunction with the enzyme.
To determine the full extent of neutrophils' role in and affect on tumor growth, the Scripps team experimented with increasing and decreasing the number of neutrophils that were allowed to flow into two kinds of early-stage tumors that had been transplanted into chicken embryos and mice. They tested several kinds of MMP-9, both with and without dampening agents, and the results established that the version produced by neutrophils was responsible for enhancing angiogenesis in the tumors. In addition, the newly formed blood vessels also functioned as "escape routes" for the tumor cells to spread. After cutting off the flow of neutrophils, the researchers were also able to "rescue" angiogenesis by raising the amount of neutrophils they allowed back to tumors. Angiogenesis is one of the key factors in the growth and spread of tumors, as cancerous cells are unable to reproduce without the influx nutrients carried through blood vessels. 
"By dampening neutrophil influx into tumors, we dampen angiogenesis, but we also dampen metastasis," Quigley said in a press release. "And when we rescue angiogenesis, we also rescue the high metastatic rate of the tumors."
Quigley and Deryugina found that they could significantly reduce the number of neutrophils that would gather by neutralizing IL-8 (interleukin 8), a chemical attractant that draws the white blood cells to inflammation sites and which Quigley notes is highly specific to neutrophils. When the researchers blocked IL-8, angiogenesis and the penetration of blood vessels by tumor cells dropped, emphasizing neutrophils' role in the development and spread of two different forms of cancer. Additionally, only the uninhibited form of the enzyme synthesized by neutrophils was capable of reversing the dampening effect caused by cutting off the flow of neutrophils to the tumors. When the enzyme was combined with its natural inhibitory agents, similar rescue of angiogenesis did not occur.
Given how large of a role they play in the growth of tumors, neutrophils present an attractive target as a potential avenue of therapy, since blocking them can drastically decrease metastasis. Quigley notes that they can also be targeted by anti-inflammatory drugs currently on the market, since those drugs are intended to prevent the influx of inflammatory cells like neutrophils in the first place. For tumors that cause particularly strong inflammatory responses, though, the researchers note that the best treatment might be the use of drugs that specifically target neutrophils, either by inhibiting the enzyme they deliver or preventing their response in the first place. One method, as their research showed, would involve blocking IL-8. Quigley says that they are moving forward by focusing on other cytokines that might attract neutrophils.
"By blocking IL-8 in tumor-bearing animals, we were only able to reduce neutrophil influx 50 or 60 percent, so that meant there's still another 40 or 50 percent neutrophils coming in," Quigley notes. "It's not clear how they're getting in by an IL-8-independent method, and the possibility is that there are other cytokines that are neutrophil-specific."
"We're starting to look at all the inflammatory or bone-marrow derived cells that are coming into tumors as the tumor develops in coordination with its generation of new blood vessels," he adds.
The study was funded by the National Institutes of Health, Scripps Translational Science Institute, the Max Kade Foundation and the National Cancer Institute. The other authors of the paper, "Neutrophil MMP-9 in Tumor Progression," include Bernhard Schweighofer, Tatyana A. Kupriyanova, Ewa Zajac and Veronica C. Ardi, of Scripps Research, as well as Erin M. Bekes, previously a UCSD graduate student conducting her thesis at Scripps Research and now a postdoctoral fellow at the NYU School of Medicine.

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