Anti-Inflammatory & Anti-Allergy Agents in Medicinal Chemistry (Formerly Current Medicinal Chemistry - Anti-Inflammatory and Anti-Allergy Agents) - Volume 10, Issue 4, 2011

Role of Inflammation in the Evolution of Cancer Disease In the course of its evolution cancer induces in the host changes of the immune system and energy metabolism which deeply affect its clinical conditions so much so that in some cases they are responsible for the death [1]. Several symptoms are associated to these events and involve various organs and systems: anorexia, nausea, weight loss (with reduction of lean mass and adipose tissue), enhanced increase of energy metabolism (with changes of the glucidic, lipidic and protein metabolism), immunodepression, anemia, fatigue. It is difficult to establish the exact moment when such changes actually start, but it could be hypothesized that they are the consequence of the interactions between the tumor and the host [2]. The hypothesis that the presence of the tumor and its continuous growth are responsible for the increased energy expenditure and for the progressive weight loss has been considered the most reliable so far. The presence in the host of continuously growing neoplastic tissue justifies by itself the increased energy needs; moreover, it is accompanied by the energy expenditure associated with chronic activation of the immune system, trying to counteract the tumour, which is energetically very costly [3]. However, the energy metabolism in cancer patients is affected by the onset, during the disease evolution, of symptoms such as anorexia, nausea and vomiting, which prevent a normal nutrition and thus a regular supply of glucose, lipids, proteins and vitamins [4]. The same molecules (cytokines) which regulate both the tumor development and the immune system functions are responsible for these symptoms [5, 6].....

In the course of its evolution the neoplastic disease is characterized by changes of the immune system and energy metabolism which deeply affect patient clinical conditions so much so that in some cases they are responsible for patient's death. Several symptoms are associated to these events and involve various organs and systems: anorexia, nausea, weight loss (with reduction of lean mass and adipose tissue), enhanced increase of energy metabolism with changes of the glucidic, lipidic and protein metabolism, fatigue, immunodepression, anemia. It is difficult to establish the precise moment when such changes actually start, but it could be hypothesized that they are the consequence of the interactions between the tumor and the host. The hypothesis that the presence of the tumor and its continuous growth are responsible for the increased energy expenditure and for the progressive weight loss, has been considered the most reliable so far. The presence in the host of continuously growing neoplastic tissue justifies by itself the increased patient energy needs; it is however accompanied by energy expenditure associated with chronic activation of the immune system, trying to counteract the tumour. The metabolic scenario is thus of two systems that require a continuous supply of energy substrates, particularly glucose. Glucose oxidation is the main energy source produced as ATP. A further glucose amount is also involved for the synthesis, through the phosphate pentose pathway, of compounds with high reducing power essential for the neutralisation of reactive oxygen species (ROS) produced during the various steps of the energy metabolism. The energy metabolism in cancer patients is affected by the onset, during the disease evolution, of symptoms such as anorexia, nausea and vomiting, which prevent a normal nutrition and thus a regular supply of glucose, lipids, proteins and vitamins. Antiblastic treatments and the same molecules (cytokines) which regulate the devolpment of the tumor and the immune system functions are responsible for these symptoms. Thus the finding that patients with solid tumors in advanced stages show a severe disruption of immunologic functions characterized by cell mediated immunity deficit and elevated serum levels of macrophage cytokines and acute phase proteins is of particular interest. High serum concentrations of cytokines and inflammatory proteins are associated with high levels of ROS and low levels of antioxidant enzymes. Tumor growth and immune system activation thus determine an overall metabolic picture characterized by: -increased glucose, lipid and protein requirements;-difficulty to introduce these substances with food because of anorexia, nausea and vomiting;-resorting to glucogenesis with depletion of protein and lipid stores and thus loss of weight;-difficult use of new formed glucose because of hypoinsulinemia and/or peripheral resistance to insulin;- oxidative damage induced by ROS on DNA, membrane lipoprotein, and enzymes and coenzymes which play a major role in the regulation of the main cell catabolic pathways. These mechanisms are involved in the development of the main symptoms of advanced cancer patients, i.e. weight loss, anemia and fatigue. According to this rationale a therapeutic approach aimed to target the inflammatory and metabolic pathways altered in the advanced neoplastic disease should be developed to impact patient symptoms and quality of life.

Although a great body of evidence is available on the immunosuppressive strategies employed by tumors in order to grow, cancer patients are not considered immunosuppressed individuals. Chemotherapy used in different cancer treatments frequently leads to leucopenia and affects immune responses. Tumors of the immune system can also cause immune alterations, due to their very nature. However, in the absence of preventive routine exams, patients can bear tumors for rather long periods of time without any specific indication, not being particularly prone to contracting infectious diseases compared to cancer free individuals. In this review, we analyze the existing data on the effects of tumors on the immune system of cancer patients. An interesting pattern emerges, suggesting that immunosuppression exerted by tumors is mainly local, rather than systemic. However, some alterations in DCs of cancer patients have been recently described, indicating the interactions between tumor and immune cells may be more complex than previously imagined. This has important implications of the design of anti-tumor therapies as well as in patient quality of life.

The main aim of the present review is to summarize and evaluate the different molecular mechanisms and catabolic mediators (mainly cytokines) involved in cancer cachexia since they may represent targets for future promising clinical investigations.

In advanced cancer patients, energy metabolism is severely compromised by the occurrence, during the disease progression, of symptoms such as anorexia, nausea and vomiting, which do not allow for a normal nutrition and so a regular supply of carbohydrates, proteins, amino acids and vitamins. In addition to the reduced food intake, important changes of energy metabolism and biochemical/metabolic abnormalities in carbohydrate, protein and lipid biochemistry and metabolism have been observed. The most important carbohydrate abnormalities observed in cachectic cancer patients are increased glucose synthesis, gluconeogenesis and Cory cycle activity, insulin resistance, and decreased glucose tolerance. Protein metabolism changes seem to depend mainly from the lack of body adjustment to the increased energy demands and the inadequate food intake, which determines the activation of glucogenesis starting in particular from protein substrates. From a clinical point of view this metabolic condition is characterized by skeletal muscle atrophy and hypoalbuminemia. Moreover, hypertrigliceridemia, increase of free fatty acids, depletion of fat stores and decrease of LPL concentrations and activity, which is closely related with weight loss, have been constantly observed in advanced cancer patients. It has been suggested that the chronic action of mediators released by tumour cells and immune cells counteracting tumour is the main cause of the metabolic abnormalities characterising the cachectic neoplastic patient. In particular, proinflammatory cytokines IL-1, TNF-α and IL-6 play a central role in the pathogenesis of metabolic derangements associated with cancer-related cachexia. It may be hypothesised that, during the initial phases of neoplastic disease, the synthesis of proinflammatory cytokines leads to an efficient antineoplastic effect. However, their chronic activity leads to severe alterations of cell metabolism, with deleterious effects on body composition, nutritional status and immune system efficiency.

Chronic and acute overproduction of reactive oxygen species (ROS) under pathophysiologic conditions characterises the development of oxidative stress and diseases including cancer and diabetes. These ROS are released principally from mitochondria but also from other sources. Oxidative stress seems to play an important role in mitochondria-mediated disease processes, though the exact molecular mechanisms responsible remain elusive. ROS are generally necessary for the proper functioning of the cell, but excessive ROS production can be harmful, and so antioxidant defenses are required. Diabetes and cancer are heterogeneous, multifactorial, severe and chronic diseases. Epidemiological studies clearly indicate that the risk of several types of cancer (including that of the breast, colorectum, female reproductive organs, liver, pancreas and urinary tract) is higher in diabetic patients. Hyperinsulinemia appears to promote cancer in diabetic patients, as insulin is a growth factor with metabolic and mitogenic effects and its action in malignant cells is favoured by mechanisms that act at both receptor and post-receptor levels. Obesity, hyperglycemia and increased oxidative stress may also contribute to an increased risk of cancer in diabetes patients. In conclusion, diabetes and cancer are conditions related with oxidative stress; a complex relationship that requires clinical attention.

Anemia is a common cause of morbidity in the general population as it contributes to diminished quality of life and reduced physical and cognitive function. Inflammation is a major factor in the pathogenesis of anemia and thus, anemia is commonly observed in patients with acute and chronic infection, and other inflammatory conditions including cancer, arthritis, atherosclerosis, and diabetes. The mechanisms whereby inflammation may result in anemia are complex and incompletely understood although the recent discovery of the importance of a hepcidin production by the liver in response to inflammatory (among other) signals has improved our understanding as this cytokine is an important regulator of iron trafficking and utilization. Thus, although the anemia of inflammation remains difficult to reverse, optimism is high that we will soon have therapies directed at the mediators of anemia and these hold the promise of affording a major therapeutic advance.

Cachexia is a complex metabolic syndrome associated with many chronic or end-stage diseases, especially cancer, and is characterized by loss of muscle with or without loss of fat mass. The management of cancer-related anorexia/cachexia syndrome (CACS) is a complex challenge that should address the different causes underlying this clinical event with an integrated or multimodal treatment approach targeting the different factors involved in its pathophysiology. Among the treatments proposed in the literature for CACS, some proved to be ineffective, namely, cyproheptadine, hydrazine, metoclopramide, and pentoxifylline. Among effective treatments, progestagens are currently considered the best available treatment option for cancer-related cachexia, and they are the only drugs approved in Europe. Drugs with a strong rationale that have failed or have not shown univocal results in clinical trials so far include eicosapentaenoic acid, cannabinoids, bortezomib, and anti-TNF-α MoAb. Several emerging drugs have shown promising results but are still under clinical investigation (thalidomide, selective cyclooxygenase-2 (COX-2) inhibitors, ghrelin mimetics, insulin, oxandrolone, and olanzapine). However, to date, despite several years of co-ordinated efforts in basic and clinical research, practice guidelines for the prevention and treatment of cancer-related muscle wasting are lacking, mainly because of the multifactorial pathogenesis of the syndrome. From all the data presented, one can speculate that one single therapy may not be completely successful in the treatment of cachexia. A more effective approach might be a combination therapy targeting the different mechanisms contributing to CACS.