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Feeding the Flame: New Research Adds to Role of Inflammation in Cancer Development

Vicki Brower

When Rudolf Virchow observed in 1863 that tumors—whose English name comes from the Latin "tumere," to swell—harbor leukocytes, he saw a connection between inflammation and cancer. Since the early 20th century, scientists have come to understand that hepatitis B and C, Epstein-Barr virus, and infectious agents such as Helicobacter pylori initiate long-term local tissue inflammation that can result in cancer.

A protective mechanism by which an organism responds to infection, injury, or tissue damage, inflammation had been considered a secondary reaction to cancer. But a growing body of research that examines the tumor microenvironment is providing information on the molecular mechanisms behind inflammation's role in initiating and/or promoting a wide range of cancers, with new implications for prevention, monitoring, and treatment.

A recent study published in November in Science by JeanMarie Houghton, Ph.D., of the University of Massachusetts School of Medicine, and Timothy Wang, M.D., of Columbia University College of Physicians and Surgeons in New York, provided strong support for a connection between inflammation and cancer. Houghton and Wang found that in mice, Helicobacter felis, an H. pylori–like bacterium, caused gastric cancer to develop by recruiting stem cells from the bone marrow that migrated to the stomach.



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JeanMarie Houghton

 
"The bacteria cause chronic inflammation, resulting in the architectural distortion of cells. The correct signals necessary for appropriate cell differentiation and growth are lacking in this disordered, inflammatory environment, resulting in metaplasia and dysplasia," Houghton said. "Inflammation causes local tissue damage, which includes local stem cell damage, and ultimately the recruitment of new stem cells from the bone marrow."

In the inflammatory environment, which Houghton describes as "a bad neighborhood," cytokines are produced that cause abnormal gastric cell death and local stem cell death. This is crucial for the next step, the signaling to the bone marrow to move stem cells to the area of damage.

"Once the bone marrow–derived stem cells engraft, it appears that these cells are inherently mutagenic," Houghton said. Cancer develops as a result of the continued push for these cells to divide and repair the damaged mucosa in the environment of chronic inflammation, which sets the stage for more rounds of unscheduled cell death, proliferation, and genetic changes in surrounding cells.

Johns Hopkins professor Phil Beachy, Ph.D., published a study in November in Nature that showed that faulty stem cell repair in chronic irritation could lead to cancer by enabling local repair-oriented stem cells to proliferate, thereby accumulating mutations. This theory differs slightly from that of Houghton and Wang, who found that stem cells that became cancerous were recruited to areas of irritation and inflammation when local stem cells repairing damage became damaged themselves.

‘Wounds That Do Not Heal’

The recent upsurge of studies linking cancer and inflammation were inspired by an astute observation made two decades ago by Harold Dvorak, M.D., now chief of pathology at Beth Israel Deaconess Medical Center in Boston. In 1984, Dvorak observed that inflammation and cancer share some basic developmental mechanisms (angiogenesis) and cells (lymphocytes, macrophages, and mast cells), and that tumors act like "wounds that do not heal."

He noted that tumor stroma formation and wound healing use the same substance (vascular endothelial growth factor [VEGF]) to clot blood and to form new blood vessels. Tumors keep producing VEGF, whereas in wounds, its production is self-limiting. "A primary distinction between angiogenesis associated with wound healing and that of neoplasia lies in the ability to turn off pro-angiogenic signals in the former," observed University of California at San Francisco researcher Lisa Coussens, Ph.D.



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Lisa Coussens

 
Evidence of inflammation in and around tumors was long considered to be a sign of the body's successful attempt to mount an immune response, but that way of thinking is changing. "In the 1970s, we found that tumor-associated macrophages, which are a major component of the inflammatory leukocyte infiltrate of tumors, were actually promoting tumor growth in vivo and in vitro, producing co-factors ... [that] indirectly promote angiogenesis," said Alberto Mantovani, M.D., of the Mario Negri Institute for Pharmacological Research in Milan, Italy.

"We now know that leukocytes and cytokines found in tumors and their microenvironment are more likely to contribute to growth, progression, and immunosuppression than [to] mount an antitumor response," Mantovani said.

The presence of inflammatory cells such as macrophages and mast cells in and around tumors now seems to be more than circumstantial and may be intrinsic to a tumor's ability to subvert immunity and to lead to angiogenesis, Coussens added. She has shown that mast cells contribute to angiogenesis in the early stage of cancer, but that anti-inflammatory cytokines can turn off this process. Inflammatory cells found in a disordered, inflammatory environment are packed with products of cyclooxygenase (COX) activity, proinflammatory cytokines, chemokines, reactive oxygen species, adhesion molecules, and proteases, which aid and abet tumor growth.

Perhaps the most well known in this cast of characters is COX-2, an enzyme involved in inflammation. Dozens of clinical trials have been testing nonsteroidal anti-inflammatory drugs (NSAIDs) and, more specifically, COX-2 inhibitors for the prevention of various types of cancer. But last fall, interim analyses of some of the trials that included the drugs Vioxx (rofecoxib) and Celebrex (celecoxib) found that the drugs may increase the risk of heart attack and stroke. More than 12 chemoprevention trials using COX-2 inhibitors have now been halted to allow for careful analysis for adverse cardiovascular outcomes. Although this is bad news for these drugs and the patients who take them, it can provide an opportunity to open up the field for researchers to take a closer look at other emerging inflammation factors, including cytokines, chemokines, tumor-associated macrophages, and transcription factors, as possible targets for cancer chemoprevention and treatment.

Cytokines and Chemokines

Cytokines (the chemical messengers of the immune system) and chemokines (a class of cytokines that can mobilize white blood cells) influence cell survival, growth, mutation, proliferation, angiogenesis, and movement of and communication between tumor and stromal cells in the tumor microenvironment, said Frances Balkwill, Ph.D., professor of cancer biology at Cancer Research U.K.'s Translational Research Laboratory in London. One's risk of cancer development and spread may be related to individual variations in pro-inflammatory cytokine genes. "Pro-inflammatory cytokine genes can act as cancer promoters," Balkwill said.

Her research focuses on the inflammatory cytokine tumor necrosis factor alpha (TNF-{alpha}). "In animal models of inflammatory and autoimmune diseases, cytokine-, chemokine-, and receptor-antagonists have been very effective, which led us to wonder if they would have similar effects in cancer."

In a number of animal models, TNF-{alpha} has a pro-cancer effect and appears to be involved in early transformation of epithelial cells, said Balkwill. There are a number of ongoing clinical trials using two TNF-{alpha} antagonists, Enbrel (etanercept) and Remicade (infliximab), which are approved for use in rheumatoid arthritis and Crohn's disease, in ovarian and renal cell cancer, either alone or in combination with chemotherapy.

Chemokines are a subset of cytokines produced by tumor-associated macrophages and other cells that drive directed migration of leukocytes in inflammation, determine macrophage and lymphocyte infiltration into human cancer, and contribute to T-cell polarization. While different cancers express many chemokines and receptors, CXCR4 is most common, found in 23 cancer types so far. Early work shows that chemokine-receptor antagonists inhibit macrophage infiltration, can induce tumor cell apoptosis and arrest growth, and prevent metastatic spread, Balkwill said.

Chemokines and other inflammatory cells are used to predict cancer behavior and prognosis, but some researchers believe that they could be useful in diagnosis and treatment as well. For example, it has been shown that women with breast cancer who have high levels of CXCR4 have poor overall survival and higher rates of metastasis. A recent study suggests why that is. Researchers at the University of Texas M. D. Anderson Cancer Center in Houston traced the movement of HER-2–positive breast cancer cells specifically to lungs, liver, and bone through CXCR4. They found that breast cancer cells that overexpress HER-2 proteins also overexpress CXCR4 and that cells breaking loose of the tumor possess excess CXCR4 receptors. When the researchers blocked CXCR4 expression in mouse tumors, the cancers became less invasive.

Colony-stimulating factor 1 (CSF-1), the main growth factor for macrophages, is also widely overexpressed in reproductive organ cancers and is associated with poor survival. "Not only is [CSF-1] a major component of the cytokine mixture in the tumor microenvironment, most importantly, it locally blocks dendritic cells from maturing into antigen-presenting cells, encourages the growth of tumor-associated macrophages, and accounts for the immunosuppressive nature of the tumor environment," said Jeffrey Pollard, M.D., director of the Center for the Study of Reproductive Biology and Women's Health of the Albert Einstein School of Medicine in New York.

Mouse studies show that CSF-1 is important in normal mammary duct development as well as in mammary tumor progression to metastasis. More than 70% of human breast tumors express CSF-1, so Pollard and his team set out to determine the relationship between CSF-1 and breast cancer progression. They found in their mouse study that the absence of the CSF-1 gene delayed cancer development to invasive, metastatic cancer but did not affect incidence or growth of primary tumors. A later study confirmed that overexpression of CSF-1 and its receptor are key to breast cancer initiation. "In addition to therapies directed at reducing inflammation or inhibiting the function of inflammatory cytokines, inhibiting [CSF-1 receptor expression] or CSF-1 synthesis with antisense could be a useful strategy in breast cancer and other epithelial cancers," Pollard said.

NF-{kappa}B

Nuclear factor {kappa}B (NF-{kappa}B) is a key transcription factor in infection and inflammation, and a handful of recent studies suggest that it is the missing link between chronic inflammation and cancer progression in animal models of colorectal and liver cancer. "What we thought we in immunology and inflammation ‘owned’—NF-{kappa}B—also turns out to be a part of cancer biology," said Michael Karin, Ph.D., of the University of California in San Diego. "We now believe that other types of cancer also may be related to the inflammatory process through NF-{kappa}B," Karin said.



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Michael Karin

 
Karin recently showed in research published in Cell that NF-{kappa}B plays a dual role in both initiation and promotion in a mouse model of colitis-associated cancer. It prevents inflammation-driven apoptosis of defective epithelial cells, and it increases epithelial cell proliferation by up-regulating macrophage-produced cytokines. In one mouse strain, Karin knocked out the NF-{kappa}B precursor gene, IKK-B, in macrophage precursor cells, and in the second mouse strain, he knocked out the gene in epithelial cells that line the intestines. In both cases, NF-{kappa}B could not be produced; in the macrophage model, tumor incidence was reduced by half, and tumors that did appear were smaller than in control mice. Mice lacking NF-{kappa}B in their intestinal epithelial cells had an 80% lower incidence of tumors due to apoptosis.

In another study published last year, Yinon Ben-Neriyah, M.D., Ph.D. and Eli Pikarsky, M.D., Ph.D., of Hebrew University in Jerusalem, showed that knockout mice that develop inflammation-related liver cancer do so not through genetic mutations but instead as a result of invading inflammatory cells and surrounding stromal endothelial cells, which produce TNF-{alpha} and then NF-{kappa}B. Although NF-{kappa}B was not necessary to encourage inflammation or hepatocyte proliferation and irregularity, cancer size and incidence was reduced when NF-{kappa}B was inactivated in dysplastic hepatocytes. "This showed that NF-{kappa}B contributes to tumorigenesis via the suppression of apoptosis," Ben-Neriyah said. Apoptosis in dysplastic hepatocytes can be induced by neutralizing TNF-{alpha} antibodies.

When cancer is already established, NF-{kappa}B is then unnecessary, but in the premalignant inflammatory environment, it provides a necessary survival signal, Ben-Neriyah said. "While not all cancers originate in inflammation, all cancer shows serious inflammatory activity after carcinogenesis," he added. Like oxygen that feeds a flame, inflammation is vital for cancer promotion; if no signals for promotion exist, the cancer cell dies. While a number of drug companies are working on NF-{kappa}B inhibitors, Karin said that there are still a lot of questions to be answered. "What mediates the crosstalk between epithelial cells and inflammatory cells? We know that necrosis activates inflammatory cells, but what are the relevant signaling pathways?" he said.

Necrosis, or unscheduled cell death found in chronic inflammatory and tumor environments, is an important driver of cancer as well, according to Michael Lotze, M.D., director of translational research at the University of Pittsburgh Molecular Medicine Institute. Like the presence of tumor-associated macrophages, necrosis is a marker of poor prognosis in many cancers, in contrast to apoptosis. Inflammatory cells and necrotic cells release a factor, HMGB1, which in turn fuels inflammation. HMGB1 is another potential target in cancer, as it can be easily detected and neutralized with a monoclonal antibody, Lotze said.

As researchers continue to uncover the secrets of the cancer–inflammation connection, they are using that information to devise new strategies for cancer prevention and treatment with targets that include cytokines and chemokines.

"The processes of cancer and chronic inflammation have parallels," Balkwill said. "In devising anticancer therapies, one must consider the context in which tumor cells thrive as well as the cells themselves."


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