Catálogo de publicaciones - libros

The link with chronic inflammation and cancer has been recognized for certain cancers for several decades. However, only recently has the biology of chronic inflammation begun to be understood, to the point that it may play a major role in tumour development. The biology of chronic inflammation has many similarities with that of wound healing. In particular, local cell mediated immunity is attenuated and angiogenesis is increased along with other growth factors. When present long term, this provides the ideal environment for mutated cells to be nurtured and escape immune surveillance. It is of note that this process still appears to take two or three decades, as witnessed by the close association between chronic ulcerative colitis and colon cancer as well as chronic hepatitis and hepatocellular carcinoma. Closer study of the inflammatory pathways show the close interaction with apoptosis and antiapoptotic pathways, as well as the main tumour suppressor genes, such as p53, as well as a number of growth factors, such as the insulin-like growth factor. A full study of these processes reveals that there are key molecules in these pathways which may provide therapeutic as well as anti-inflammatory targets.

The pathogenesis of cancer represents a complex and multifactorial process requiring a number of acquired and genetic defects. It is becoming increasingly apparent that many cancers originate from a chronic inflammatory process. The topic of this review is the inflammatory response and development of gastrointestinal (GI) and pancreatic cancers. Here, we describe the development of various gastric colorectal and pancreatic cancers through an inflammatory process. The tumor microenvironment which predisposes to tissue destruction, subsequent attempts at healing and accumulation of cellular damage with loss of cell cycle control mechanisms is discussed. Components of the tumor microenvironment that are important in the final common pathway leading to cancer include the tumor stroma, tumor-associated macrophages, cytokines and chemokines and reactive oxygen and nitrogen species. Common signaling pathways that link inflammation with cancer are described and include the COX-2, NF-κB and phosphatidyl inositol 3-kinase (PI3K) pathways. Finally, therapies that can be directed to the inflammatory process as either treatment or prevention of these cancers will be discussed including novel inhibitors of signaling pathways which are currently in development.

Inflammation and cancer have been viewed as closely linked for many years. This link is not merely a loose association but causative. In colorectal cancer (CRC), chronic inflammation as observed in inflammatory bowel (IBD) disease is a key predisposing factor and IBD-associated CRC comprises five percent of all CRCs. Although the molecular mechanisms linking IBD with CRC are not well understood, recent results obtained in preclinical models point to the transcription factor NF-κB as a central player. On the one hand, NF-κB regulates the expression of various cytokines and modulates the inflammatory processes in IBD. On the other, NF-κB stimulates the proliferation of tumor cells and enhances their survival through the regulation of anti-apoptotic genes. Furthermore, it has been clearly established that most carcinogens and tumor promoters activate NF-κB, while chemopreventive agents generally suppress this transcription factor. Actually, several lines of evidence suggest that activation of NF-κB may cause cancer. These include the finding that NF-κB genes can be oncogenes, and that this transcription factor controls apoptosis, cell-cycle progression and proliferation, and possibly also cell differentiation.

Nuclear factor κB (NF-κB) is regarded as a key regulator of inflammation; hence, several inflammatory diseases result from deregulation of NF-κB signaling. There is, however, also increasing evidence for a preponderant role of NF-κB in tumor development and progression. Constitutive activation of NF-κB activity by signaling defects, mutations or chromosomal rearrangements can be found in a wide variety of cancers. Additionally, a causal link between inflammation and cancer has been noted, which makes NF-κB an interesting target for development of both anti-inflammatory and anti-cancer therapeutics. Here, we review current knowledge of NF-κB signal transduction, focusing on the regulation of its transcriptional activity by post-translational modification of the NF-κB subunits.

Interactions between tumor infiltrating leukocytes and tumor cells have been of great interest because of the possibility that immune cells either interfere with tumor progression or actively promote tumor growth. The tumor microenvironment is shaped by cells entering it, and their functions reflect the local conditions. Successive changes occurring at the tumor site during tumor progression resemble chronic inflammation. This chronic inflammatory reaction seems to be largely orchestrated by the tumor, and it seems to promote tumor survival. Molecular and cellular mechanisms linking the inflammatory reaction and cancer are emerging, and this review summarizes the current understanding of interactions between inflammatory and cancer cells in the tumor microenvironment.

Interactions of cancer cells with components of their microenvironment are crucial determinants in the decision making process which determines whether the cancer cells will progress towards a highly malignant phenotype or whether they will stay dormant or disappear altogether. The tumor microenvironment is composed of a plethora of soluble and cellular components. Many of these components deliver signals to tumor cells and thus modulate their phenotype thereby driving tumor progression. This chapter focuses on the interaction of tumor cells with endothelial cells through endothelial selectins and their fucosylated ligands expressed by the tumor cells. Comparisons are drawn between the utilization of this interaction axis by inflammatory leukocytes and by tumor cells.

The membrane-bound death ligands CD95L/FasL and TRAIL, which activate the corresponding death receptors CD95/Fas, TRAILR1 and TRAILR2, induce apoptosis in many tumour cells, but can also elicit an inflammatory response. This chapter focuses on the relevance of CD95L/FasL and TRAIL for the tumour surveillance function of natural killer cells and cytotoxic T-cells and discuss current concepts of utilizing these ligands in tumour therapy.

The role of infectious agents in the development of cancer is well-established. For example, numerous RNA and DNA viruses express dedicated oncoproteins that are able to transform cells in vitro and induce rapid tumor formation in experimental animals. Curiously, these acutely-transforming viruses are seldom associated with naturally occurring neoplasms of humans or animals. Conversely, the microbial pathogens that are linked to cancers in natural hosts rarely encode acutely transforming proteins. Moreover, they tend to down-regulate most of their genes except for genes affecting cell survival, often via the NF-κB pathway. This allows the pre-neoplastic cell to avoid triggering cytotoxic immunity and the ensuing acute inflammation. These host responses not only kill tumor cells directly, but also strongly suppress the development of new blood vessels (neovascularization), which is absolutely essential for neoplastic growth. Chronic inflammation, on the other hand, promotes neoplastic cell growth and may even be conducive to neovascularization. Thus, cancer-associated microbial pathogens must follow the “less is more” principle. According to this principle, only minor perturbations in cell proliferation and death are tolerated by the host, but in the long run, they are all that is necessary for tumorigenesis.

The cachexia syndrome, characterized by a marked weight loss, anorexia, asthenia and anaemia, is invariably associated with the growth of a tumour and leads to a malnutrition status caused by the induction of anorexia or decreased food intake. In addition, the competition for nutrients between the tumour and the host results in a state of accelerated catabolism, which promotes severe metabolic disturbances in the patient. The search for the cachectic factor(s) started a long time ago, and many scientific and economic efforts have been devoted to its discovery, but we are still a long way from a complete answer. The present review aims to evaluate the different molecular mechanisms and catabolic mediators (both humoural and tumoural) that are involved in cancer cachexia and to discuss their potential as targets for future clinical investigations.

After more than three decades of its declaration, the war against cancer still appears far from being won. Although there have been decisive victories in a few battles, such as the one against testicular cancer, the overall result is sobering. Hopes for an imminent cure had been raised among the public by the promises of molecular biology, combinatorial chemistry and high-throughput screening. These promises have manifested themselves in the widely proclaimed strategy of rationally targeted anticancer drug discovery, which may be summarized as the ‘one-gene-one target-one drug’ approach. Over the years, however, it has gradually become clear that, in most cases, treatment of cancer with a single drug may at best delay progression of the disease but is unlikely to lead to a cure. Thus, it appears that rationally targeted monotherapy will have to be replaced by rationally targeted combination therapy. Inhibitors of NF-κB look likely to become an important weapon in the anticancer combination therapy arsenal.