Current Drug Targets

ISSN: 1389-4501

Current Drug Targets
Volume 9, Number 5, May 2008

Contents

Inflammatory Bowel Disease and Inflammation-Associated Colon Cancer: Partners in Crime
Guest Editor: Silvio Danese


Editorial Pp. 360


The Role of Genetics in Inflammatory Bowel Disease Pp. 361-368
L. Henckaerts, C. Figueroa, S. Vermeire and M. Sans
[Abstract]


Signaling Molecules: The Pathogenic Role of the IL-6/STAT-3 Trans Signaling Pathway in Intestinal Inflammation and in Colonic Cancer Pp. 369-374
R. Atreya and M.F. Neurath
[Abstract]


Cytokines: From Gut Inflammation to Colorectal Cancer Pp. 375-380
M.C. Fantini and F. Pallone
[Abstract]


Mucosal T Cell Proliferation and Apoptosis in Inflammatory Bowel Disease Pp. 381-387
A. Sturm, H.S.P. de Souza and C. Fiocchi
[Abstract]


Immune-non Immune Networks in Intestinal Inflammation Pp. 388-394
M. Hausmann and G. Rogler
[Abstract]


The Pathogenic Role of Intestinal Flora in IBD and Colon Cancer Pp. 395-403
M. Rescigno
[Abstract]


Tolerance in Intestinal Inflammation and Cancer Pp. 404-412
M. Vulcano, S. Danese and A. Sica
[Abstract]


New Insights into Inflammatory Bowel Disease Pathophysiology: Paving the Way for Novel Therapeutic Targets Pp. 413-418
T. Stefanelli, A. Malesci, A. Repici, S. Vetrano and S. Danese
[Abstract]


General Articles


Microbial Gut Overgrowth Guarantees Increased Spontaneous Mutation Leading to Polyclonality and Antibiotic Resistance in the Critically Ill Pp. 419-421
H.K.F. van Saene, N. Taylor, V. Damjanovic and R.E. Sarginson
[Abstract]


Hypoxia Inducible Factor-1α, Endothelial Progenitor Cells, Monocytes, Cardiovascular Risk, Wound Healing, Cobalt and Hydralazine: A Unifying Hypothesis Pp. 422-435
M.R. Hoenig, C. Bianchi and F.W. Sellke
[Abstract]




Abstracts

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Editorial

Chronic inflammation makes individuals susceptible to cancer. This is true in many forms of inflammatory diseases, including Inflammatory bowel disease (IBD).

The link between inflammation and the promotion of cancer was first observed in the nineteenth century, but only in recent years it has became a generally accepted phenomenon. Epidemiological studies have clearly shown that chronic inflammation predisposes individuals to certain cancers, and conversely that non-steroidal anti-inflammatory agents protects against some tumors. Most Epidemiological studies have shown that chronic inflammation predisposes individuals to certain cancers, and conversely that non-steroidal anti-inflammatory agents protect against several tumours. Most precancerous and cancerous tissues show signs of inflammation; this involves the movement of innate immune cells into the tissue, the presence of specific inflammatory signalling molecules (cytokines and chemokines), changes in tissue structure (remodelling), and the formation of new blood vessels (angiogenesis).

Further studies found that cancer-associated inflammation actually promotes tumour growth and progression. For instance, innate immune cells called tumour-associated macrophages work their way into precancerous tissue, and can release factors that promote tumour growth and metastasis. Accordingly, in many human tumours, the infiltration of large numbers of these macrophages is associated with poor prognosis. Moreover, increased expression of genes associated with macrophage infiltration (such as CD68) forms part of the molecular signatures that herald poor prognosis in certain cancers.

All the above described processes occur also in IBD, where it has been longly recognized a heightened risk of developing colonic cancer in both ulcerative colitis (UC) and colonic Crohn’s disease (CD). For long time the association between colonic cancer and IBD has been only epidemiological. However, very recently, many of the molecular mechanisms linking the two processes have started to be clarified.

In this special issue of Current Drug Target, key opinion leaders in the field of IBD and inflammation-associated colon cancer will summarize the advances in the knowledge of the pathogenesis of both forms of IBD. In the last decade, a tremendous progression in the genetic field of CD and UC has been made. This has helped to clarify some key and unexpected pathogenic events. For instance, it is now firmly established that in CD the innate immunity may play an underrated role in its pathogenesis. In addition, many of the cytokine networks and signaling molecules that mediate intestinal inflammation have been identified. This progress with the help of the biotechnology has lead to design entirely new therapeutic approaches, with the establishment of the so called biological therapies. Some of these biological therapies are now commonly used in the routine IBD clinic, and are considerably changing the natural history of both forms of IBD. Beside creating new and more specific and selective therapies, the understanding of the mechanisms that underlie intestinal inflammation and the use in the laboratory of animal models reproducing inflammation-associated colon cancer has helped in shedding light also on the steps that go from inflammation to cancer, and in identifying new therapeutic targets to avoid the progression from gut inflammation to cancer, that act as partners in crime in the intestinal scene.

Abbreviations: CD, Crohn's disease; UC, ulcerative colitis; IBD, inflammatory bowel disease.


Silvio Danese
Division of Gastroenterology
Istituto Clinico Humanitas-IRCCS in
Gastroenterology
Viale Manzoni
Rozzano, Milan
Italy
Tel: 011-39-3392318230
E-mail: sdanese@hotmail.com


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The Role of Genetics in Inflammatory Bowel Disease
L. Henckaerts, C. Figueroa, S. Vermeire and M. Sans

The volume of research undertaken on the genetic susceptibility of inflammatory bowel disease (IBD) has been tremendous. Genome-wide linkage studies pointed towards more than 10 chromosomal regions and fine-mapping of these regions led to the identification of a number of genes, including CARD15 (NOD2), DLG5, OCTN1 and 2, TLR4 and CARD4 (NOD1). With the recent completion of the human genome project, whole genome association studies (WGAS) have now become possible and have identified additional genes (IL23R, IRGM, PTGER4, ATG16L1) for Crohn’s disease and ulcerative colitis, that have subsequently been replicated. At present, the CARD15 gene is still the most understood susceptibility gene, explaining around 20% of the genetic predisposition to Crohn’s disease. Prediction of disease phenotype and response to the main therapies has for many years been a dream for physicians treating IBD patients. Only now, we start to accumulate some evidence proving that genetic factors indeed influence both the clinical course of IBD patients and their likelihood of responding to certain therapies. In the coming years, we expect an exponential increase in the efforts devoted to research in this area. The optimal prediction of both disease behaviour and response to therapy might result from complex combinations of clinical, biochemical, serological and genetic factors.


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Signaling Molecules: The Pathogenic Role of the IL-6/STAT-3 Trans Signaling Pathway in Intestinal Inflammation and in Colonic Cancer
R. Atreya and M.F. Neurath

Although the precise etiology of inflammatory bowel diseases (IBD) still remains unclear, considerable progress has been made in the identification of novel signal transduction pathways that elucidate the immunopathogenesis involved in the perpetuation of the inflammatory process. As both ulcerative colitis and Crohn’s disease are associated with an increased risk for developing colorectal cancer (CRC) and precancerous dysplastic epithelial changes, further studies have concentrated on finding a common signaling pathway that could serve as a mechanistic link between inflammation and associated colonic cancer in IBD.

This review presents the current data concerning the pathogenic role of the IL-6/STAT-3 trans signaling pathway in IBD and colorectal cancer. Furthermore it evaluates the possible therapeutic potential of targeting this pathway for the therapy of IBD and CRC


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Cytokines: From Gut Inflammation to Colorectal Cancer
M.C. Fantini and F. Pallone

Colorectal cancer represents a life-threatening complication of inflammatory bowel diseases. Statistics indicate that the risk to develop colorectal cancer is higher in patients affected by ulcerative colitis and to a lesser extent by Crohn´s disease and that such a risk is directly proportional to the number of years of active disease. These observations suggest that chronic inflammation may substantially contribute to cancer development. However the molecular mechanisms underlying this process have been only recently started to be clarified. Indeed from the initial concept that the release of free radicals during inflammation might induce the accumulation of genetic mutations thus leading to the onset of dysplastic cells, it is now becoming clear that the large amount of cytokines and growth factors released during inflammation by immune and non immune cells may influence the carcinogenesis process.

IL-6 and IL-23, cytokines which play key roles in the induction and maintenance of gut inflammation during IBDs, have been recently shown to influence the development and growth of colitis associated colorectal cancer. Moreover, the activation of the nuclear factor k B (NFkB), a transcription factor activated by several cytokines released during inflammation and responsible for many of their proinflammatory effects, have been shown to promote the growth of the colon tumors in experimental models.


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Mucosal T Cell Proliferation and Apoptosis in Inflammatory Bowel Disease
A. Sturm, H.S.P. de Souza and C. Fiocchi

Both forms of inflammatory bowel disease (IBD), Crohn's disease (CD) and ulcerative colitis (UC), represent prototypical conditions whose most salient features are the presence of chronic inflammation involving various parts of the intestinal tract and an increased risk of cancer, which is a complication directly related to the duration and activity of gut inflammation. Several factors have been implicated in the unrelenting mucosal inflammation of IBD, prominent among them being the presence of a persistently elevated number of activated T cells in the mucosa of CD and UC patients. These T cells display various defects of proliferation and apoptosis, and these abnormalities are credited with directly contributing to the pathogenesis of IBD and possibly the progression to colon cancer. This notion is supported by the observation that T cells are also prominently found infiltrating most tumors and are functionally impaired compared to T cells in the circulation. This establishes a parallel that may constitute a link between chronic intestinal inflammation and the development of malignancies in the inflamed intestine. This article will review some of the basic features of human intestinal mucosal T cells, examine the mechanisms underlying the processes of cell cycling and cell death, describe the defective proliferative and apoptotic function detected in CD and UC, and discuss the implications of modulating T cell apoptosis in IBD for therapeutic purposes and eventually decreasing the risk of cancer development.


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Immune-non Immune Networks in Intestinal Inflammation
M. Hausmann and G. Rogler

The intestinal mucosa forms a primary barrier providing both barrier function and immediate effective recognition of bacterial products invading the mucosa. This is of great importance for the prevention of permanent and chronic inflammation as a reaction to the commensal intestinal flora and the multitude of antigens present in the intestinal lumen. It is obvious that a tight network of specialized cell types and intense cell-cell communication is required to maintain this function and coordinate immunological reactions. Yet most publications are focused on unidirectional cause and effectchains.

Since a real integrated view on the network of cellular functions is not available or at least incomplete bidirectional immune cell interactions with epithelial cells, fibroblasts/myofibroblasts, adipocytes endothelial cells and the nervous system are reviewed in this article. Networking is certainly mediated by different effector pathways but limited resources are available to assemble a model of interactions in intestinal inflammatory diseases. However, recent development of know ledge regarding unidirectional and bidirectional effect-chains is exciting. Apart from the classical discrimination of immune cells (such as neutrophils, macrophages, and cytotoxic T cells) and non immune cells (epithelial cells, fibroblasts, adipocytes and endothelial cells) it became stunningly evident that not only the classical immune cells have the ability to track down pathogens as most of the mentioned cell types express pathogen recognition receptors (toll-like receptors, Nod2) and defense mechanisms (such as secretion of defensin).


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The Pathogenic Role of Intestinal Flora in IBD and Colon Cancer
M. Rescigno

The intestine is populated by a large variety of microorganisms that colonize the host soon after birth. The gut microflora contributes to several intestinal functions, including the development of the mucosal immune system, the absorption of complex macromolecules, the synthesis of aminoacids and vitamins and the protection against pathogenic microorganisms. Its composition varies along the different segments of the gut, with a gradient from the stomach to the colon where it is more abundant. Given the vital relationship between the microflora and the intestinal function, it is important that the microflora is kept continuously under control so to preserve gut homeostasis. When this is not achieved or perturbed, several immune disorders can arise, like allergies or inflammation. Protracted immune deregulations can also lead to severe disorders including diabetes, cancer and inflammatory bowel disease (IBD). It is therefore crucial that the immune system learns both to tolerate and to control the growth of beneficial microorganisms so to preserve the intestinal homeostasis. The mechanisms that are in place to achieve this control are not yet understood but recent work has started to unravel the complex relationship between several players including the microflora, intestinal barriers and immune cells. In this review we will analyze how the microflora interacts with the host and how deregulation of this interaction can lead to inflammatory disorders and eventually also to cancer.


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Tolerance in Intestinal Inflammation and Cancer
M. Vulcano, S. Danese and A. Sica

In the human body, mucosal surfaces of the intestinal tract are the largest and one of the most complex parts of the immune system. These surfaces are covered by a layer of epithelial cells which allows efficient absorption of nutrients but also serves to separate the intestine from an environment loaded with potential harmful agents. Discrimination between beneficial commensal bacteria, harmless antigens and pathogenic microorganisms is a central issue in the role that gut immune cells play in maintaining the balance between immune response and tolerance. However, the basis of this discrimination in the mucosal immune system, where this occurs and how it can affect both local and systemic responses is not yet well understood. Nevertheless, antigen uptake and presentation seems to be a crucial factor in this issue. In this review, we will discuss the key role of immune intestinal cells in the development of mucosal immunity, tolerance and disease.


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New Insights into Inflammatory Bowel Disease Pathophysiology: Paving the Way for Novel Therapeutic Targets
T. Stefanelli, A. Malesci, A. Repici, S. Vetrano and S. Danese

The etiopathogenesis of Crohn's disease (CD) and ulcerative Colitis (UC), the two major forms of inflammatory bowel disease (IBD), is still unknown. Although the exact cause and mechanisms of both IBD have yet to be completely understood, it is widely accepted that both CD and UC result from an inappropriate immune response that occurs in genetically susceptible individuals as the result of a complex interaction among environmental factors, microbial factors, and the intestinal immune system. In the last few years a tremendous advance in knowledge of the mechanisms underling intestinal inflammation in IBD has been achieved, leading to new therapeutic targets and novel drugs. These new therapeutic weapons have been specifically designed to selective shut down intestinal inflammation at different levels. Aim of this review is to summarize the recent advances in IBD pathophysiology and the new therapeutic targets and drugs that are changing the IBD clinical management.


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Microbial Gut Overgrowth Guarantees Increased Spontaneous Mutation Leading to Polyclonality and Antibiotic Resistance in the Critically Ill
H.K.F. van Saene, N. Taylor, V. Damjanovic and R.E. Sarginson

Polyclonality is defined as the occurrence of different genotypes of a bacterial species. We are of the opinion that these different clones originate within the patient. When infections and outbreaks occur, the terms of polyclonal infections and polyclonal outbreaks have been used, respectively. The origin of polyclonality has never been reported, although some authors suggest the acquisition of different clones from different animate and inanimate sources.

We think that the gut of the critically ill patient with microbial overgrowth is the ideal site for the de-novo development of new clones, following increased spontaneous mutation.


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Hypoxia Inducible Factor-1α, Endothelial Progenitor Cells, Monocytes, Cardiovascular Risk, Wound Healing, Cobalt and Hydralazine: A Unifying Hypothesis
M.R. Hoenig, C. Bianchi and F.W. Sellke

Bone marrow-derived mononuclear cells differentiate into endothelial cells in adult animals, including humans. These cells, endothelial progenitor cells (EPCs), play central roles in neovascularization in a variety of physiological and pathological processes. EPCs numbers are clinically relevant; in patients with vascular disease, EPC numbers are predictive of hard clinical endpoints and correlate with vascular health in patients without manifest atherosclerosis. EPCs express CXCR4 which allows homing to sites of neovascularization. The homing signal released by the target tissues is SDF-1 which is the ligand for CXCR4. With release of SDF-1 and reversal of the marrow/periphery gradient, EPCs are mobilized to the periphery where they are recruited to SDF-1 expressing tissues. The SDF-1/CXCR4 axis is the final common pathway for EPC mobilization by hypoxia, angiogenic peptides and G-CSF. Expression of SDF-1 in target tissues and CXCR4 in EPCs as well as angiogenic cytokines such as VEGF are regulated by hypoxia inducible factor-1α (HIF-1α ). This paper discusses evidence suggesting that depressed HIF-1α-mediated gene programming is the most fundamental of all cardiovascular risk factors and discusses the manipulation of this system with existing drugs such as Cobalt or Hydralazine. By stabilizing HIF-1α protein, these compounds will enhance EPC mobilization and function, thereby improving cardiovascular health overall. This paper discusses why previous studies with EPC transplantation or mobilization with G-CSF have had negative results and proposes the use of Cobalt and Hydralazine to enhance EPC function to overcome the dysfunctional EPC phenotype that is seen in patients with vascular disease or cardiovascular risk factors.