Macrophage arginine metabolism and the inhibition or stimulation of cancer.

The potential of the immune system to inhibit or stimulate tumor growth is a vivid example of the "two-edged sword" nature of immune responses. Our results provide evidence that this dual capacity can be attributed, in part, to the dual pathways of arginine metabolism exhibited by intratumor macrophages. Specifically, i.p. tumor rejection in P815-preimmunized mice is accompanied by an upshift in intratumor macrophage arginine metabolism to the nitric oxide (NO) synthase pathway that yields citrulline and NO. A rapid and marked local increase in IFN-gamma (both mRNA and protein) in preimmunized mice during tumor rejection suggests that this cytokine plays a role in up-regulating nitric oxide production in vivo. Unlike tumor rejection, progressive i.p. P815 tumor growth in naive mice is associated with a marked decline in the production of citruline/NO by intratumor macrophages. Examination of macrophage arginine metabolism via arginase revealed a pattern opposite that of NO synthase. The local production of ornithine/urea markedly increases during progressive tumor growth whereas arginase activity decreases during tumor rejection. Inasmuch as nitric oxide inhibits tumor cell replication whereas ornithine is the precursor of polyamines required for cell replication, these results are consistent with the conclusion that the pathway macrophages use to metabolize arginine can influence the type of host immune responses against cancer and other conditions.     

Effects in chicks of arsenic,arginine, and zinc and their interaction on body weight,plasma uric acid,plasma urea,and kidney arginase activity

The interaction among arsenic, zinc, and arginine was studied in chicks using two fully crossed, three-way, two-by-two-by-two experiments. Arsenic at levels of 0 and 2 μg/g zinc at levels of 2.5 (zinc-deficient) and 25 (zinc-adequate) μg/g, and arginine at levels of 0 and 16 mg/g were supplemented to the diet. After 28 d in both experiments, growth was depressed in chicks fed diets either supplemented with arginine or deficient in zinc. Arsenic deprivation depressed growth of chicks fed diets containing the basal level of arginine and 25 μg supplemental Zn/g. Arsenic deprivation had little or no effect on growth of zinc-deprived chicks fed diets containing the basal level of arginine, or in zinc-deprived or zinc-adequate chicks fed supplemental arginine. Zinc-deficiency elevated urea in plasma and arginase activity in kidney. Those elevations, however, were more marked in arsenic-supplemented than in arsenic-deprived chicks. Also, plasma urea and kidney arginase activity were markedly elevated in chicks fed supplemental arginine; the elevations were more marked in zinc-deficient chicks. These findings support the concept that arsenic has a physiological role, associated with zinc, that can influence arginine metabolism in the chick.     

Overview of mechanisms of cancer chemopreventive agents

Epidemiological data provide evidence that it is possible to prevent cancer and other chronic diseases, some of which share common pathogenetic mechanisms, such as DNA damage, oxidative stress, and chronic inflammation. An obvious approach is avoidance of exposure to recognized risk factors. As complementary strategies, it is possible to render the organism more resistant to mutagens/carcinogens and/or to inhibit progression of the disease by administering chemopreventive agents. In a primary prevention setting, addressed to apparently healthy individuals, it is possible to inhibit mutation and cancer initiation by triggering protective mechanisms either in the extracellular environment or inside cells, e.g., by modifying transmembrane transport, modulating metabolism, blocking reactive species, inhibiting cell replication, maintaining DNA structure, modulating DNA metabolism and repair, and controlling gene expression. Tumor promotion can be counteracted by inhibiting genotoxic effects, favoring antioxidant and anti-inflammatory activity, inhibiting proteases and cell proliferation, inducing cell differentiation, modulating apoptosis and signal transduction pathways, and protecting intercellular communications. In a secondary prevention setting, when a premalignant lesion has been detected, it is possible to inhibit tumor progression via the same mechanisms, and in addition by affecting the hormonal status and the immune system in various ways, and by inhibiting tumor angiogenesis. Although tertiary prevention, addressed to cancer patients after therapy, is outside the classical definition of chemoprevention, it exploits similar mechanisms. It is also possible to affect cell-adhesion molecules, to activate antimetastasis genes, and to inhibit proteases involved in basement membrane degradation.     

Signal transduction in monocytes: the role of zinc ions

The availability of zinc has a regulatory role in the immune system. It can have either pro- or anti-inflammatory effects, which both seem to be a consequence of a direct interaction of zinc with the cytokine secretion by monocytes. In this review, the molecular basis for this effect, the interaction of zinc with the signal transduction of monocytes, is discussed. In particular, zinc seems to activate or inhibit several signaling pathways that interact with the signal transduction of pathogen sensing receptors, the so-called Toll-like receptors (TLR), which sense pathogen-derived molecular structures and, upon activation, lead to secretion of pro-inflammatory cytokines. The interaction of zinc with protein tyrosine phosphatases and protein kinase C, and a direct modulation of lipopolysaccharide binding to its receptor (TLR-4) all result in enhanced cytokine production. On the other hand, a complex interaction between zinc, NO and cyclic nucleotide signaling, and inhibition of interleukin-1 receptor associated kinase-1, and inhibitor of kappa B kinase all counteract the production of pro-inflammatory cytokines. A role for the zinc binding protein metallothionein as a regulator for intracellular zinc signaling is discussed. By acting on all these signaling molecules, the zinc status of monocytes can have a direct effect on inflammation.     

Involvement of stromal p53 in tumor-stroma interactions

p53 is a major tumor-suppressor gene, inactivated by mutations in about half of all human cancer cases, and probably incapacitated by other means in most other cases. Most research regarding the role of p53 in cancer has focused on its ability to elicit apoptosis or growth arrest of cells that are prone to become malignant owing to DNA damage or oncogene activation, i.e. cell-autonomous activities of p53. However, p53 activation within a cell can also exert a variety of effects upon neighboring cells, through secreted factors and paracrine and endocrine mechanisms. Of note, p53 within cancer stromal cells can inhibit tumor growth and malignant progression. Cancer cells that evolve under this inhibitory influence acquire mechanisms to silence stromal p53, either by direct inhibition of p53 within stromal cells, or through pressure for selection of stromal cells with compromised p53 function. Hence, activation of stromal p53 by chemotherapy or radiotherapy might be part of the mechanisms by which these treatments cause cancer regression. However, in certain circumstances, activation of stromal p53 by cytotoxic anti-cancer agents might actually promote treatment resistance, probably through stromal p53-mediated growth arrest of the cancer cells or through protection of the tumor vasculature. Better understanding of the underlying molecular mechanisms is thus required. Hopefully, this will allow their manipulation towards better inhibition of cancer initiation, progression and metastasis.     

Mutations and regulatory anomalies effecting tumor cell immune functions

The immune system is capable of interacting with tumor cells in such a way as to lead to tumor cell death, and this knowledge has inspired therapies to manipulate patient immune systems to eradicate cancer. However, tumor cells are able to mitigate the antitumor immune response, a fact that has rarely been addressed in the design of immunotherapies. There are many different tumor cell immune functions that play a role in mitigating the antitumor immune response. In some cases, these functions appear to be intimately associated with the tumor cell abnormalities that lead to loss of growth control, such as the cases where classical tumor suppressor proteins regulate tumor cell immune function genes. In other cases, tumor cell mutations appear to affect only the antitumor response, such as tumor cell mutations that eliminate MHC class I expression. Here I review the bases for tumor cell immune functions, noting in particular where tumor cell mutations, the gold standard for identifying a tumor-specific function, are known to be responsible for the tumor cell immune function. This review also discusses other known regulatory anomalies, in the absence of a known mutation, that are apparently important for tumor development and that regulate tumor cell immune functions. Surprisingly, in many cases where the tumor cell immune function is well understood in terms of its effect on the antitumor immune response, the tumor abnormality underlying the tumor cell immune function is completely uncharacterized.     

Das Miteinander im Tumor

Interactions in the tumor Cancer has long been regarded as a mass of cells growing aberrantly due to mutations leading to constant cell proliferation and inhibition of cell death. Meanwhile, it has been acknowledged that not only tumor cells but also stroma plays an important role in tumorigenesis and progression. Although infiltrating immune cells are found in many tumors, an effective response to the tumor often seems to fail. One of the reasons discussed in this context is the modulation and suppression of immune cells by the tumor environment. Tumor cells show an altered metabolism leading to the secretion of metabolites that have been shown to act on stromal cells such as immune cells. Therefore, tumor metabolism is a promising therapeutic target to inhibit tumor growth and reactivate an effective anti‐tumor immune response.     

Tumor-host interactions: the role of inflammation

It is well established that interactions between tumor cells and the host tissue stroma play a key role in determining whether and how any given solid malignancy will develop. In most cases, tumor cells hijack stromal cell functions for their own benefit and ultimately dictate the rules of engagement to the host tissue microenvironment. However, the contribution of the different stromal cell components to tumor growth remains to be clarified. Because most solid tumors are accompanied by a local inflammatory response, it has long been thought that inflammation and carcinogenesis are related. If formal proof that cancer can be initiated by inflammation in the absence of exogenous carcinogens is still lacking, there is abundant evidence that the inflammatory response can play a central role in modulating tumor growth and progression. This review will discuss some of the mechanisms whereby inflammation can both enhance and inhibit tumor growth.     

Inflammatory microenvironment and human papillomavirus-induced carcinogenesis

More than 15% of the global cancer burden is attributable to infectious agents. Pathogens that cause persistent infections are strongly associated with cancer, inflammation being a major component of the chronic infections as revealed by basic, clinical and epidemiological studies.Persistent infection and viral oncoproteins induce specific cellular pathways modifications that promote tumorigenesis. Deregulated and continuous immune response leads to severe tissue and systemic damage, impaired tumor surveillance and consequent carcinogenesis promotion by selecting for metastatic and therapeutically resistant tumor phenotypes.In this review, the role of inflammatory microenvironment in the HPV-induced carcinogenesis is addressed, with a specific focus on the involvement of the immune molecules and microRNAs as well as their delivery through the microvesicle cargo.     

Immunoediting: evidence of the multifaceted role of the immune system in self-metastatic tumor growth

ABSTRACT: BACKGROUND: The role of the immune system in tumor progression has been subject to discussion for many decades. Numerous studies suggest that a low immune response might be beneficial, if not necessary, for tumor growth, and only a strong immune response can counter tumor growth and thus inhibit progression. METHODS: We implement a cellular automaton model previously described that captures the dynamical interactions between the cancer stem and non-stem cell populations of a tumor through a process of self-metastasis. By overlaying on this model the diffusion of immune reactants into the tumor from a peripheral source to target cells, we simulate the process of immune-system-induced cell kill on tumor progression. RESULTS: A low cytotoxic immune reaction continuously kills cancer cells and, although at a low rate, thereby causes the liberation of space-constrained cancer stem cells to drive self-metastatic progression and continued tumor growth. With increasing immune system strength, however, tumor growth peaks, and then eventually falls below the intrinsic tumor sizes observed without an immune response. With this increasing immune response the number and proportion of cancer stem cells monotonically increases, implicating an additional unexpected consequence, that of cancer stem cell selection, to the immune response. CONCLUSIONS: Cancer stem cells and immune cytotoxicity alone are sufficient to explain the three-step "immunoediting" concept - the modulation of tumor growth through inhibition, selection and promotion.     

GDF11 as a friend or an enemy in the cancer biology?

The Growth and Differential Factor 11 (GDF11) is a recently discovered representative of Transforming Growth Factor β superfamily. The highest expression of GDF11 is detected in the nervous system, bladder, seminal vesicles and muscles whereas the lowest in the testis, liver or breast. GDF11 role in physiology is still not clear. GDF11 is a crucial factor in embryogenesis, cell cycle control and apoptosis, inasmuch it mainly targets cell retain stemness features, managing to the cell differentiation and the maturation. GDF11 is entangled in lipid metabolism, inflammatory processes and aging. GDF11 is strongly related to carcinogenesis and its expression in tumors is intruded. GDF11 can promote cancer growth in the colon or inhibit the cell proliferation in breast cancer. The aberrated expression is probably allied with the impaired maturation. In this article we summarized an impact of GDF11 on the tumor cells and review the all attitudes connecting GDF11 with carcinogenesis.     

Influence of antioxidative vitamins A, C and E on lipid peroxidation in BOP-induced pancreatic cancer in Syrian hamsters.

Persistent oxidative stress is thought to play an important role in carcinogenesis. Vitamins may influence oxygen radical metabolism and thus inhibit tumor growth. In the present trial the effects of Vitamins (Vit.) A, C and E on neoplastic growth and lipid peroxidation in pancreatic tissue were evaluated on chemically-induced pancreatic adenocarcinoma in the Syrian hamster. The incidence of pancreatic cancer was decreased by Vit. A (64.3%) and Vit. C (71.4%) as compared to the control group (100%, P<0.05). All vitamins increased the activity of superoxidedismutase (SOD) in pancreatic carcinomas. Accumulation of vitamins in tumor cells seems to be responsible for high levels of SOD and consecutive intracellular increase of hydrogen peroxide levels. Since this effect is selectively toxic for tumor cells it might be one of the mechanisms decreasing the incidence of pancreatic cancer in our trial.     

Update on the effects of vitamins A, C, and E and selenium on carcinogenesis

The effects of vitamins A, C, and E and of selenium on carcinogenesis are briefly summarized and updated. These vitamins and minerals were selected because they have been studied extensively in recent years with a variety of carcinogenesis models. The consumption of vitamin A and its precursors (carotenoids) has been negatively correlated with cancer at a number of sites, particularly the lung. Animal investigations on vitamin A involvement in carcinogenesis have generally been of three types: those assessing the effect of vitamin A deficiency, the effect of excess vitamin A, or the effect of supplementation with synthetic analogs of vitamin A. Vitamin A deficiency had no effect on salivary gland carcinogenesis, enhanced urinary bladder, lung, and liver carcinogenesis, and inhibited colon carcinogenesis. Excess of various forms of vitamin A enhanced or inhibited skin tumorigenesis, inhibited mammary carcinogenesis in rats (but not in mice), and carcinogenesis of the forestomach, liver, and urinary bladder (with one model, but not with another), or enhanced or did not influence lung carcinogenesis. Vitamin A analogs have enhanced or inhibited skin tumorigenesis, inhibited salivary gland, mammary, and urinary bladder carcinogenesis, enhanced tracheal and liver carcinogenesis, and either enhanced or inhibited pancreas carcinogenesis, depending upon the model employed. Although retinoids have been shown to inhibit carcinogenesis at many sites, numerous negative studies have been reported and some reports have indicated enhanced carcinogenesis. The most convincing evidence for the involvement of vitamin C in cancer prevention is the ability of ascorbic acid to prevent formation of nitrosamine and of other N-nitroso compounds. In addition vitamin C supplementation was shown to inhibit skin, nose, tracheal, lung, and kidney carcinogenesis, to either not influence or enhance skin, mammary gland, and colon carcinogenesis, and to enhance urinary bladder carcinogenesis, when given as sodium ascorbate, but not when given as ascorbic acid. Like vitamin C, vitamin E can inhibit nitrosation. Vitamin E was shown to inhibit skin, cheek pouch, and forestomach carcinogenesis, to enhance or inhibit colon carcinogenesis, and to have no effect on or to inhibit mammary gland carcinogenesis, depending upon the method of vitamin E administration or the level of dietary selenium or dietary fat. Selenium effects on carcinogenesis have been recently reviewed and the present discussion only updates this area by indicating that enhancement of carcinogenesis by dietary selenium supplements has been observed in the liver, pancreas, and skin.(ABSTRACT TRUNCATED AT 400 WORDS)     

Signaling pathways bridging microbial-triggered inflammation and cancer

Microbial-triggered inflammation protects against pathogens and yet can paradoxically cause considerable secondary damage to host tissues that can result in tissue fibrosis and carcinogenesis, if persistent. In addition to classical pathogens, gut microbiota bacteria, i.e. a group of mutualistic microorganisms permanently inhabiting the gastrointestinal tract and which plays a key role in digestion, immunity, and cancer prevention, can induce inflammation-associated cancer following the alterations of their microenvironment. Emerging experimental evidence indicates that microbiota members like Escherichia coli and several other genotoxic and mutagenic pathogens can cause DNA damage in various cell types. In addition, the inflammatory response induced by chronic infections with pathogens like the microbiota members Helicobacter spp., which have been associated with liver, colorectal, cervical cancers and lymphoma, for instance, can also trigger carcinogenic processes. A microenvironment including active immune cells releasing high amounts of inflammatory signaling molecules can favor the carcinogenic transformation of host cells. Pivotal molecules released during immune response such as the macrophage migration inhibitory factor (MMIF) and the reactive oxygen and nitrogen species' products superoxide and peroxynitrite, can further damage DNA and cause the accumulation of oncogenic mutations, whereas pro-inflammatory cytokines, adhesion molecules, and growth factors may create a microenvironment promoting neoplastic cell survival and proliferation. Recent findings on the implication of inflammatory signaling pathways in microbial-triggered carcinogenesis as well as the possible role of microbiota modulation in cancer prevention are herein summarized and discussed.