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Blocking tumor-induced inflammation impacts cancer development

Date:
October 3, 2012
Source:
University of California, San Diego Health Sciences
Summary:
Researchers at the University of California, San Diego School of Medicine report the discovery of microbial–dependent mechanisms through which some cancers mount an inflammatory response that fuels their development and growth.

Mouse colorectal tumors display inflammatory infiltration by macrophages (green) and activated stromal cells (red). The question of why and how tumors recruit immune cells remains unknown.
Credit: UC San Diego School of Medicine

Researchers at the University of California, San Diego School of Medicine report the discovery of microbial–dependent mechanisms through which some cancers mount an inflammatory response that fuels their development and growth.

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The findings are published in the October 3, 2012 Advanced Online Edition of Nature.

The association between chronic inflammation and tumor development has long been known from the early work of German pathologist Rudolph Virchow. Harvard University pathologist Harold Dvorak later compared tumors with “wounds that never heal,” noting the similarities between normal inflammation processes that characterize wound- healing and tumorigenesis or tumor-formation.

Indeed, 15 to 20 percent of all cancers are preceded by chronic inflammation – a persistent immune response that can target both diseased and healthy tissues. Chronic hepatitis, for example, may result in hepatocellular carcinoma (liver cancer) and inflammatory bowel disease can eventually cause a form of colon cancer, known as colitis-associated cancer.

Still, most cancers are not preceded by chronic inflammation. On the other hand, they exploit ubiquitous, infiltrating immune cells to unduly provoke and hijack the host inflammatory reaction. Until now, the mechanism of so-called “tumor-elicited inflammation,” which is detected in most solid malignancies, was poorly explained.

“The tumor-associated inflammatory reaction is an emerging and vibrant field for biomedical studies. It may hold the keys for future preventive and therapeutic measures,” said first author Sergei Grivennikov, PhD, noting that studies of long-term users of non-steroidal anti-inflammatory drugs, such as aspirin, have revealed that general inhibition of inflammation reduces the risk of cancer death by up to 45 percent, depending on the type of cancer. “So inhibition of inflammation during cancer development may be beneficial.”

Studying early colonic tumors in humans and in animal models, the researchers, led by principal investigator Michael Karin, PhD, Distinguished Professor of Pharmacology and head of the Laboratory of Gene Regulation and Signal Transduction at UC San Diego, found that developing tumors disrupt tissue homeostasis (the normal, healthy functioning of tissues), in part because they lack a particular protective protein coating and a tight seal between their epithelial cells – a basic cell type that covers most internal surfaces and organs. Without that coating and the cellular seal, ordinarily benign, commensal bacteria present in the colon can enter the tumor to be recognized by immune cells as invaders, launching an inflammatory reaction.

In addition, said Grivennikov, who is a scientist in Karin’s lab, “cell-to-cell contacts are defective in tumors, further allowing entry of microbial products from the intestinal lumen into the tumor. These microbial products are recognized by tumor-associated macrophages and dendritic cells, which are normally isolated from commensal microflora by the intestinal barrier.”

In response, the immune cells produce signaling proteins called cytokines that further spur the inflammatory process. Chief among these is a cytokine called Interleukin-23, which regulates tumor-elicited inflammation and triggers the production of other inflammatory cytokines that promote tumor development and progression.

Grivennikov said that when researchers reduced the presence of commensal microflora through a combination of broad spectrum antibiotics, tumor-elicited inflammation and tumor growth were dampened.

“This is a very nice demonstration of how tumor-elicited inflammation in cancers that arise in the absence of underlying chronic inflammatory disease can be induced,” he said. “The next step is to look for the upregulation of Interleukin-23 and related cytokines in colon cancer patients, inhibit these cytokines and determine whether these impact cancer progression and response to therapy.”

Funding for this research came, in part, from the Crohn’s and Colitis Foundation of America, National Institutes of Health/National Institute of Diabetes and Digestive and Kidney Diseases grant K99-DK088589; UCSD DDRDC Pilot Grant DK080506; the Croucher Foundation and China Postdoctoral Science Foundation; the Strategic Young Researcher Overseas Visits Program for Accelerating Brain Circulation; SPAR Austria; National Institutes of Health grants R01CA082223, A1043477 and DK035108 and the American Association for Cancer Research.

Co-authors include Kepeng Wang, UCSD Laboratory of Gene Regulation and Signal Transduction, Department of Pharmacology and Pathology and the Biomedical Research Institute, Shenzhen-PKU-HKUST Medical Center, China; Daniel Mucida, La Jolla Institute for Allergy and Immunology and the Laboratory of Mucosal Immunology, The Rockefeller University, New York; C. Andrew Stewart, Cancer and Inflammation Program, Laboratory of Experimental Immunology, Center for Cancer Research, National Cancer Institute, National Institutes of Health; Bernd Schnabl, UCSD Department of Medicine, School of Medicine; Dominik Jauch and Guann-Yi Yu, UCSD Laboratory of Gene Regulation and Signal Transduction, Department of Pharmacology and Pathology; Koji Taniguchi, UCSD Laboratory of Gene Regulation and Signal Transduction, Department of Pharmacology and Pathology and Department of Microbiology and Immunology, Keio University School of Medicine, Tokyo; Christoph H. Österreicher, UCSD Department of Medicine, School of Medicine and Institute of Pharmacology, Center for Physiology and Pharmacology Medical University of Vienna, Austria; Kenneth E. Hung, Department of Medicine, Tufts Medical Center, Boston; Christian Datz, Department of Internal Medicine, Oberndorf Hospital, Paracelsus Medical University Salzburg, Austria; Ying Feng and Eric R. Fearon, Departments of Internal Medicine, Human Genetics and Pathology, University of Michigan Medical School; Mohamed Oukka, Seattle Children’s Research Institute, Washington; Lino Tessarollo, Mouse Cancer Genetics Program, National Cancer Institute, National Institutes of Health; Vincenzo Coppola, Department of MVIMG, Ohio State University-CCC, Wexner Medical Center; Felix Yarovinsky, Department of Immunology, University of Texas Southwestern Medical Center; Hilde Cheroutre, La Jolla Institute for Allergy and Immunology; Lars Eckmann, UCSD Department of Medicine, School of Medicine; and Giorgio Trinchieri, Cancer and Inflammation Program, Laboratory of Experimental Immunology, Center for Cancer Research, National Cancer Institute, National Institutes of Health.


Story Source:

The above story is based on materials provided by University of California, San Diego Health Sciences. Note: Materials may be edited for content and length.


Journal Reference:

  1. Sergei I. Grivennikov, Kepeng Wang, Daniel Mucida, C. Andrew Stewart, Bernd Schnabl, Dominik Jauch, Koji Taniguchi, Guann-Yi Yu, Christoph H. Österreicher, Kenneth E. Hung, Christian Datz, Ying Feng, Eric R. Fearon, Mohamed Oukka, Lino Tessarollo, Vincenzo Coppola, Felix Yarovinsky, Hilde Cheroutre, Lars Eckmann, Giorgio Trinchieri, Michael Karin. Adenoma-linked barrier defects and microbial products drive IL-23/IL-17-mediated tumour growth. Nature, 2012; DOI: 10.1038/nature11465

Cite This Page:

University of California, San Diego Health Sciences. "Blocking tumor-induced inflammation impacts cancer development." ScienceDaily. ScienceDaily, 3 October 2012. <www.sciencedaily.com/releases/2012/10/121003131959.htm>.
University of California, San Diego Health Sciences. (2012, October 3). Blocking tumor-induced inflammation impacts cancer development. ScienceDaily. Retrieved October 30, 2014 from www.sciencedaily.com/releases/2012/10/121003131959.htm
University of California, San Diego Health Sciences. "Blocking tumor-induced inflammation impacts cancer development." ScienceDaily. www.sciencedaily.com/releases/2012/10/121003131959.htm (accessed October 30, 2014).

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