How tumor-causing cells are recruited in cancers linked to chronic inflammation
Chronic inflammation is directly associated with several types of cancer, yet the reasons as to why this happens at a cellular level remain unclear. Now, an international team of scientists led by researchers at The Wistar Institute has identified a multistep process showing not only how these cancers develop but also potentially discovering new therapeutic targets that could halt the formation and progression of tumor cells.
The findings were published online by the Journal of Experimental Medicine.
While inflammation is an important part of how we recover from disease and injury, chronic inflammation has been linked to a variety of cancers, such as basal cell carcinoma, lung, liver, colon cancer and others. Numerous studies have associated chronic inflammation with cancer, yet research has been largely unable to describe the roles of specific cells when this happens.
“While we know that cancer is initiated because of genetic alterations, we also know that cancer’s development relies heavily on environmental factors,” said Dmitry Gabrilovich, M.D., Ph.D., The Wistar Institute’s Christopher M. Davis Professor, Professor and Program Leader of the Translational Tumor Immunology Program, and Professor in the Tumor Microenvironment and Metastasis Program. “Inflammatory conditions are closely linked to cancer, yet it’s a very complex process, making it difficult to determine how certain components contribute to the development of cancer.”
Gabrilovich and his fellow investigators demonstrated that inflammatory conditions are associated with a specific phenotype of myeloid cells called immature granulocytic cells.
Using transgenic mice that expressed this phenotype, Gabrilovich’s lab created conditions in which the granulocytic cells would accumulate in the absence of typical methods of inflammation, such as tissue damage or infection. When the mice were exposed to a tumor-promoting substance called TPA, the researchers observed a dramatic increase in the formation of benign tumors, or papillomas, usually among the first signs of the formation of skin cancer.
Gabrilovich and his team found that the granulocytic cells arrive at the skin and stimulate the migration of lymphocytes, which in turn stimulate the abnormal growth of keratinocytes, the most common type of skin cell found in the epidermis. The granulocytic cells are able to “recruit” these lymphocytes by releasing a specific factor called chemokine CCL4. This factor then recruits CD4+ T cells that produce interleukin-17 (IL-17), a proinflammatory cytokine that has already been linked to chronic inflammation and inflammatory cancers.
Through a series of steps, this study implicates that granulocytic cells accumulate and serve as the first step of tumor formation, followed by the recruitment of CD4+ T cells that produce IL-17. The combination of these events ultimately results in the development of cancer. While this study focused on skin cancer, Gabrilovich said that the study could apply to any type of cancer linked to chronic inflammation. If proven for other conditions this mechanism could open an opportunity for potential therapeutic targeting in patients with chronic inflammation that predispose a patient to cancer.
An association between the development of cancer and inflammation has long-been appreciated. The inflammatory response orchestrates host defenses to microbial infection and mediates tissue repair and regeneration, which may occur due to infectious or non-infectious tissue damage. Epidemiological evidence points to a connection between inflammation and a predisposition for the development of cancer, i.e. long-term inflammation leads to the development of dysplasia. Epidemiologic studies estimate that nearly 15 percent of the worldwide cancer incidence is associated with microbial infection. Chronic infection in immunocompetent hosts such as human papilloma virus or hepatitis B and C virus infection leads to cervical and hepatocellular carcinoma, respectively. In other cases, microbes may cause cancer due to opportunistic infection such as in Kaposi’s sarcoma (a result of human herpes virus (HHV)-8 infection) or inappropriate immune responses to microbes in certain individuals, which may occur in gastric cancer secondary to Helicobacter pylori colonization or colon cancer because of long-standing inflammatory bowel disease precipitated by the intestinal microflora. In many other cases, conditions associated with chronic irritation and subsequent inflammation predispose to cancer, such as the long-term exposure to cigarette smoke, asbestos, and silica.
Observing signs of inflammation, such as leukocyte infiltration, at tumors infected with microbes or sites of chronic irritation is expected. However, as first observed by Virchow in the middle of the 19th century, many tumors for which infection or irritation are not necessarily a predisposing factor, such as mammory adenocarcinoma, show a “lymphoreticular infiltrate.” Many tumors of this type contain activated fibroblasts and macrophages, in addition to a gene expression profile with an inflammatory signature. Quantitative aspects of wound repair or inflammatory gene expression often correlate negatively with cancer stage and prognosis. Further evidence for the role of inflammation has come from the use of non-steroidal anti-inflammatory drugs (NSAIDs) in the prevention of spontaneous tumor formation in people with familial adenomatous polyposis (FAP). Thus, cancer and inflammation are related by epidemiology, histopathology, inflammatory profiles, and the efficacy of anti-inflammatory drugs in prophylaxis. These observations have provided impetus for investigation and hypothesis on the mechanisms and semantics of the relationship between cancer and inflammation.
There is evidence to suggest the inflammatory and immune systems may inhibit the development of cancer. This may occur by two cancer-associated recognition events. In tumor immunosurveillance, the host may have a dedicated mechanism to perceive and eliminate transformed cells. Adaptive immune recognition of tumor-associated and specific antigens also may be an important means by which the immune system controls the development of cancer. Such topics will not be covered here. However, it seems the net effect of the inflammatory system is to positively affect tumor development. The relationship between cancer and inflammation is not simple and cannot be reduced to one grand theory. Previous reviews have focused on various aspects of the relationship between cancer and inflammation, such as the role of various inflammatory cells, mediators, or signaling pathways in cancer. The focus of this essay will be to discuss the relationship between cancer and inflammation along the organizing principle that the inflammatory response maintains physiological processes such as tissue homeostasis and repair after injury and that in this role, inflammation may be an ancillary, or perhaps inseparable, aspect of tumor development.
“If we are able to target these granulocytic cells directly, we may be able to prevent the inflammatory effects of IL-17, which would provide a great benefit to individuals with a high risk of developing these types of cancer,” said Vinit Kumar, Ph.D., a member of the Gabrilovich laboratory and one of the co-authors of the study.
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This work was supported by the National Institutes of Health grant CA 100062. Other grants supporting this studying included Grants P50 CA168536 and R01CA157303.
This study was made possible through the efforts of an international team of scientists. In particular, Dr. Gabrilovich said study co-authors Vinit Kumar and Sridevi Mony were instrumental in the completion of this study. Other co-authors of this study who have been or currently are members of the Gabrilovich laboratory include Laxminarasimha Donthireddy, Thomas Condamine, Myrna L. Ortiz (currently at H. Lee Moffitt Cancer Center), Anna Martner (currently at the Sahlgrenska Cancer Center at the University of Gothenberg, Sweden), and Brianna Lenox (also currently at Sahlgrenska Cancer Center). Other co-authors of the study include Noreen Luetteke from Moffitt; John Seykora from the University of Pennsylvania; Stella C. Knight from Imperial College London, England; George Malietzis and Gui Han Lee from Imperial College and St. Mark’s Hospital, Harrow, England; Morgan Moorghen from St. Mark’s; and Esteban Celis from Georgia Regents University Cancer Center.
The Wistar Institute is an international leader in biomedical research with special expertise in cancer research and vaccine development. Founded in 1892 as the first independent nonprofit biomedical research institute in the country, Wistar has long held the prestigious Cancer Center designation from the National Cancer Institute. The Institute works actively to ensure that research advances move from the laboratory to the clinic as quickly as possible. The Wistar Institute: Today’s Discoveries - Tomorrow’s Cures. Wistar Science Saves Live.
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Ben Leach
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The Wistar Institute
Journal
Journal of Experimental Medicine