Cancer and Inflammation

Inflammation is simply a physiologic response process generated by the body in response to injury, infection, or irritation. In acute stages, the inflammatory process is vital to the healing process; however, chronic inflammation can increase disease- associated morbidity. New insights into the chronic inflammatory process now provide evidence that this mechanism is a negative contributor to an ever-expanding list of chronic conditions, including Alzheimer's disease, cardiovascular diseases, diabetes, asthma, cancer, and even depression.

Epidemiological studies have shown that chronic inflammation predisposes individuals to various types of cancer and the host response to malignant disease shows several parallels with inflammation and wound healing. It is estimated that underlying infections and inflammatory responses and linked to 15-30% of all death from cancer worldwide. The functional relationship between inflammation and cancer is not new. In 1863, Virchow hypothesized that the origin of cancer was at sites of chronic inflammation, in part based on his hypothesis that some classes of irritants, together with the tissue injury and ensuing inflammation they cause, enhance cell proliferation (1). Today, the causal relationship between inflammation, innate immunity and cancer is more widely accepted.

In a sense, tumours act as wounds that fail to heal (2).The hallmarks of cancer-related inflammation include the presence of inflammatory cells and inflammatory mediators (for example, chemokines, cytokines and prostaglandins) in tumour tissues, tissue remodelling and angiogenesis (growth of new blood vessels) similar to that seen in chronic inflammatory responses, and tissue repair.

Presence of LYVE-1-positive macrophages during bladder cancer progression. Representative photomicrographs indicating LYVE-1-positive cells. Tumour associated macrophages (TAMS) are indicated by a red arrow.

Evidence currently available suggests that in established, progressively growing solid tumours, tumour associated macrophages (TAMs) are reprogrammed to induce immune suppression of host defenses in situ, through release of specific cytokines, prostanoids and other humoral mediators. This disordered response, results in the inhibition of effective anti-cancer cell-mediated immune mechanisms. Concurrently, TAMs produce tumour growth promoting factors. The summation of this complex interplay of biological factors results in progressive tumour growth and tumour cell dissemination.

An overview of inflammation and carcinogenesis

A key attribute of an effective Immune system is to be able to detect the presence of trouble - this could be dead or damaged cells, tumour cells or infection with viruses, bacteria or eukaryotic parasites. Some aspects of this have already been dealt with; acute inflammation is the major system for sensing trauma. However, the Immune system needs to be able to detect more subtle changes and also needs to encourage a two-way communication between the innate and adaptive immune responses.

In terms of protection against infection the ability of certain cells to detect the presence of prokaryotic molecules (like bacteria) is of primary importance. Though there is considerable sophistication and subtlety to the mechanisms which do this we can focus here on 3 cells types: mast, macrophages and dendritic cells.

Typical primary immune system response to an assault

Mast cells primarily detect danger via receptors for activated complement. They also use antibodies as sensing tools via Fc receptors for both IgE (high affinity) and IgG (low affinity).

Macrophages are exquisitely sensitive to the lipopolysaccharides (LPS) produced by certain bacteria. They respond by producing cytokines notably TNFalpha, but also IL1 and IL6. These mediators induce the Acute Phase Response, which is a rapid systemic response which massively increases the concentration of many key serum proteins to aid the host defence response. C reactive protein (CRP) and Mannose binding protein are natural activators of the Complement system.

The previous image shows a summary of the important cells and molecules in the human immune system - the top half of the picture represents detection of invaders, and the bottom half represents the defence which is triggered by that detection.

The immune system cell communication network

Several different cell types coordinate their efforts as part of the immune system, including B cells, T cells, macrophages, neutrophils, basophils and eosinophils. Each of these cell types has a distinct role in the immune system, and communicates with other immune cells using secreted factors called cytokines, including interleukins, TNF, and the interferons. Macrophages phagocytose foreign bodies and are antigen-presenting cells, using cytokines to stimulate specific antigen dependent responses by B and T cells and non-specific responses by other cell types. T cells secrete a variety of factors to coordinate and stimulate immune responses to specific antigen, such as the role of helper T cells in B cell activation in response to antigen. The proliferation and activation of eosinophils, neutrophils and basophils respond to cytokines as well. Cytokine communication is often local, within a tissue or between cells in close proximity. Each of the cytokines is secreted by one set of cells and provokes a response in another target set of cells, often including the cell that secretes the cytokine.
Some cytokines, like IL-1, interferons and TNF, stimulate a broad inflammatory response in response to infection or injury. Other cytokines have more specific functions such the following examples. IL-2 stimulates the proliferation and activation of B and T cells. IL-4 plays a role in the differentiation of Th2 cells, in allergic responses, and in the switching of antibody types. IL-5 stimulates the production and maturation of eosinophils during inflammation. IL-8 is a chemokine, a chemotactic factor that attracts neutrophils, basophils and T cells to sites of inflammation. IL-12 and IL-18 are involved in helper T cell differentiation. IL-10 apparently acts to repress secretion of proinflammatory cytokines. The complex interplay of these different cytokine functions with immune cells is essential for correct immune function.

Role of inflammation in the evolution of cancer

To understand the role of inflammation in the evolution of cancer, it is important to understand what inflammation is and how it contributes to physiological and pathological processes such as wound healing and infection (Fig. 1). In response to tissue injury, a multifactorial network of chemical signals initiate and maintain a host response designed to 'heal' the afflicted tissue. This involves activation and directed migration of leukocytes (neutrophils, monocytes and eosinophils) from the venous system to sites of damage, and tissue mast cells also have a significant role.

When tissue homeostasis is perturbed, sentinel macrophages and mast cells immediately release soluble mediators, such as cytokines, chemokines matrix remodelling proteases and reactive oxygen species (ROS), and bioactive mediators such as histamine, that induce mobilization and infiltration of additional keucocytes into damaged tissue (a process that is known as inflammation). Macrophages and mast cells can also activate vascular and fibroblast responses in order to orchestrate the elimination of invading organisms and initiate local tissue repair.

Acute activation of innate immunity sets the stage for activation of the more sophisticated adaptive immune system. Induction of efficient primary adaptive immune responses requires direct interactions with mature antigen-presenting cells and pro-inflammatory milieu.

Together, acute activation of these distinct immune-response pathways efficiently removes or eliminates invading pathogens, damaged cells and extracellular matrix (ECM). In addition, once assaulting agents are eliminated, immune cells are crucially involved in normalizing cell-proliferation and cell death pathways to enable re-epitheliarization and new extracellular matrix synthesis. Once wound healing is complete, inflammation resolves and tissue homeostasis returns.

In (a) a normal skin tissue have a highly organized and segregated architecture. Epithelial cells sit atop a basement membrane separated from the vascularized stromal (dermis) compartment. Upon wounding or tissue assault, platelets are activated and release vasoactive mediators that regulate vascular permeability, influx of serum fibrinogen, and formation of the fibrin clot. They also release proteolytic enzymes necessary for remodelling of extracellular matrix. In combination, granulocytes, monocytes and fibroblasts are recruited, the venous network restored, and re-epithelialization across the wound occurs. Epithelial and stromal cell types engage in a reciprocal signalling dialogue to facilitate healing. Once the wound is healed, the reciprocal signalling subsides.
In (b) an invasive carcinomas is less organized. Neoplasia-associated angiogenesis and lymphangiogenesis produces a chaotic vascular organization of blood vessels and lymphatics where neoplastic cells interact with other cell types (mesenchymal, haematopoietic and lymphoid) and a remodelled extracellular matrix. Neoplastic cells produce an array of cytokines and chemokines that are mitogenic and/or chemoattractants for granulocytes, mast cells, monocytes/macrophages, fibroblasts and endothelial cells. In addition, activated fibroblasts and infiltrating inflammatory cells secrete proteolytic enzymes, cytokines and chemokines, which are mitogenic for neoplastic cells, as well as endothelial cells involved in neoangiogenesis and lymphangiogenesis. These factors potentiate tumour growth, stimulate angiogenesis, induce fibroblast migration and maturation, and enable metastatic spread via engagement with either the venous or lymphatic networks.

In the late 1990s, Frances Balkwill of the institute of Cancer at Queen Mary, University of London, had been doing research on a cytokine known as tumour necrosis factor (TNF), which was named for its ability to kill cancer cells when administered directly into a tumour at high levels. But when TNF lingers as a chronic, low level presence in the tumour, it acts very differently. Balkwill's lab turned off the TNF gene in mice so that the rodents could not produce the protein: to their surprise, the mice did not contract tumours. All the people who were working on TNF as an anticancer agent were horrified. This cytokine they thought was a treatment for cancer was actually working as an endogenous tumour promoter.

The ready availability of knockout mice, in which the effects of selectively switching off genes could be tested, helped to highlight the cancer-inflammation link. Coussens and her UCSF colleagues Douglas Hanahan and Zena Werb reported in 1999 that mice engineered with activated cancer genes but without mast cells developed premalignant tissue that did not progress to full malignancy. In 2001, Jeffrey W. Pollard and his co-workers at the Albert Einstein College of Medicine described mice that were genetically engineered to be susceptible to breast cancer tumours but that produced precancerous tussue that did not turn malignant unless it enlisted the assistance of macrophages.

Tumour cells produce various cytokines and chemokines that attract leukocytes. The inflammatory component of a developing neoplasm may include a diverse leukocyte population - for example, neutrophils, dendritic cells, macrophages, eosinophils and mast cells, as well as lymphocytes - all of which are capable of producing an assorted array of cytokines, cytotoxic mediators including reactive oxygen species, serine and cysteine proteases, MMPs and membrane-perforating agents, and soluble mediators of cell killing, such as TNF-, interleukins and interferons (7) (8).

The balance of cytokines in any given tumour is critical for regulating the type and extent of inflammatory infiltrate that forms. Tumours that produce little or no cytokines or an overabundance of anti-inflammatory cytokines induce limited inflammatory and vascular responses, resulting in constrained tumour growth. In contrast, production of an abundance of pro-inflammatory cytokines can lead to a level of inflammation that potentiates angiogenesis, thus favouring neoplastic growth. Alternatively, high levels of monocytes and/or neutrophil infiltration, in response to an altered balance of pro- versus anti-inflammatory cytokines, can be associated with cytotoxicity, angiostasis and tumour regression. In tumours, interleukin-10 is generally a product of tumour cells and tumour-associated macrophages.

Diet and the impact on inflammation and cancer

Writing note: include here some introduction text. I have to bridge to omega 3 and other immunomodulators. The key point is to demonstrate the immunotherapeutic  factors of these foods/supplements. If I have enough time I should add the work performed by  Dr Nobuto Yamamoto and how to turn TAMS into cancer cell enemies (if I finally get an interview with him or his son). Could beta glucan do the same? An hypothesis to explore. I should also write about cytokines, stress and immunity. I probably should include more explanation about the other facet of this topic, the eicosanoids especially because of their importance in the context of omega 3.

Omega 3 as a modulator of inflammation

Among the fatty acids, it is the omega-3 polyunsaturated fatty acids (PUFA) which possess the most potent immunomodulatory activities, and among the omega-3 PUFA, those from fish oil—eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA)—are more biologically potent than -linolenic acid (ALA).

Some of the effects of omega-3 PUFA are brought by modulating of the amount and types of eicosanoids made, and other effects are elicited by eicosanoid-independent mechanisms, including actions upon intracellular signaling pathways, transcription factor activity and gene expression. Animal experiments and clinical intervention studies indicate that omega-3 fatty acids have anti-inflammatory properties and, therefore, might be useful in the management of inflammatory and autoimmune diseases.

Coronary heart disease, major depression, aging and cancer are characterized by an increased level of interleukin 1 (IL-1), a proinflammatory cytokine. Similarly, arthritis, Crohn’s disease, ulcerative colitis and lupus erythematosis are autoimmune diseases characterized by a high level of IL-1 and the proinflammatory leukotriene LTB4 produced by omega-6 fatty acids. There have been a number of clinical trials assessing the benefits of dietary supplementation with fish oils in several inflammatory and autoimmune diseases in humans, including rheumatoid arthritis, Crohn’s disease, ulcerative colitis, psoriasis, lupus erythematosus, multiple sclerosis and migraine headaches. Many of the placebo-controlled trials of fish oil in chronic inflammatory diseases reveal significant benefit, including decreased disease activity and a lowered use of anti-inflammatory drugs.

The brain as an immune system modulator

New field of research, known as psychoneuroimmunology, is exploring how the immune system and the brain may interact to influence health. For years stress has been suspected of increasing susceptibility to various infectious diseases or cancer. Now evidence is mounting that the immune system and the nervous system may be inextricably interconnected.

Research has shown that a wide range of stresses, from losing a spouse to facing a tough examination, can deplete immune resources, causing levels of B and T cells to drop, natural killer cells to become less responsive, and fewer IgA antibodies to be secreted in the saliva.

Biological links between the immune system and the central nervous system exist at several levels. One well-known pathway involves the adrenal glands, which, in response to stress messages from the brain, release corticosteroid hormones into the blood. In addition to helping a person respond to emergencies by mobilizing the body's energy reserves, these "stress hormones" decrease antibodies and reduce lymphocytes in both number and strength.

More recently, it has become apparent that hormones and neuropeptides (hormone-like chemicals released by nerve cells), which convey messages to other cells of the nervous system and organs throughout the body, also "speak" to cells of the immune system. Macrophages and T cells carry receptors for certain neuropeptides; natural killer cells, too, respond to them. Even more surprising, some macrophages and activated lymphocytes actually manufacture typical neuropeptides. At the same time, some lymphokines, secreted by activated lymphocytes such as interferon and the interleukins, can transmit information to the nervous system. Hormones produced by the thymus, too, act on cells in the brain.

In addition, the brain may directly influence the immune system by sending messages down nerve cells. Networks of nerve fibers have been found that connect to the thymus gland, spleen, lymph nodes, and bone marrow. Moreover, experiments show that immune function can be altered by actions that destroy specific brain areas.

Audio Visual Documentation

These two following videos, even tinted with some pharmaceutical references are very interesting presentation illustrating the relationship between the immune system and cancer.

Lisa Coussens is Professor of Pathology at the University of California, San Francisco (UCSF) and Co-Director of the Mouse Pathology Core Facility at the UCSF Helen Diller Family Comprehensive Cancer Center. Her training included seven years at Genentech Inc in the 1980s, where she participated in the cloning and characterization of receptor tyrosine kinases; PhD training in biological chemistry at the University of California, Los Angeles, USA; and postdoctoral work in Douglas Hanahan's laboratory at UCSF.

Her research focuses on the role of inflammatory cells and leukocyte proteases as critical regulators of skin, lung and breast cancer development. By studying mouse models of cancer development, the Coussens lab is identifying crucial molecules that are involved in regulating tumour-associated inflammation, matrix remodelling and angiogenesis. Identification of these important regulatory molecules reveals drug targets that can be used to design novel therapeutic strategies for arresting cancer development in humans.

Lisa Coussens is recipient of numerous awards, including the V Foundation Scholar award (2000), the Malinckrodt Award for Medical Research (2000), the AACR Gertrude B Elion Cancer Research Award (2002), and the Era of Hope Scholar Award (2006).

Dr. Michael Karin is currently a Professor of Pharmacology at the School of Medicine at the University of California, San Diego. He received his Ph.D. in Molecular Biology from UCLA in 1979. He is a leading world authority on signal transduction pathways that regulate gene expression in response to extracellular stimuli. Key achievements include definition of cis elements that mediate gene induction by hormones, cytokines and stress, identification and characterization of the transcription factors that recognize these elements and the protein kinase cascades that regulate their activities. He has published over 200 scientific articles and is an inventor on over 14 different patents or pending patent applications. Recently Dr. Karin was ranked first worldwide by the Institute of Scientific Information (ISI) in a recent listing of most-cited molecular biology and genetic research papers published in prestigious journals.

References

(1) Balkwill F.& Mantovani A. Inflammation and cancer: back to Virchow? Lancet 357, 539-545 (2001)

(2) Dvorak, H. F. Tumors: wounds that do not heal. Similarities between tumor stroma generation and wound healing. N. Engl. J. Med. 315, 1650-1659 (1986). 

(3) Karin E. de Visser et al. Paradoxical roles of the immune system during cancer development. Nature Cancer review vol 6 January 2006 24-37

(4) Alberto Mantovani. Cancer-related inflammation. Nature Vol 454 July 2008 436-444

(5) Lisa Coussens & Zena Werb. Inflammation and cancer. Nature vol. 420 December 2002 860-273

(6) Seth Rakoff-Nahoum. Why Cancer and Inflammation? Yale journal of biology and medicine 79 (2006) 123-130

(7) Kuper H. et al. Infections as a major preventable cause of human cancer. j. Intern. Med. 248, 171-183 (2000)

(8) Wahl L. et al. Tumor associated macrophages as targets for cancer therapy. J. Natl Cancer Inst. 90, 1583-1584 (1998)