Wednesday, May 6, 2015

Zinc and its deficiency consequence

INCREASE search

subject: Increase in Th2 activity
object_opposite: Diminished Thi In face of Zn +2 deficiency
misc: Includes Th2 Cytokines
author_year: J.E. Sprietsma/july 97
journal_volume_page: Medical hypothesis/Volume 4/Issue 1/ Pages 1–14

Friday, April 10, 2015

Arginase vs. i NOS regulation of TH1 Th2 response

subject: Inlammatory factors in colorectal Ca Inflammatory pathways in the early steps of colorectal cancer development arginase/ Macrophages Francesco Mariani, Paola Sena, and Luca Roncucci
object_opposite: Inflammatory pathways in the early steps of colorectal cancer developmentColorectal cancer is a major cause of cancer-related death in many countries. Colorectal carcinogenesis is a stepwise process which, from normal mucosa leads to malignancy. Many factors have been shown to influence this process, however, at present, several points remain obscure. In recent years some hypotheses have been considered on the mechanisms involved in cancer development, expecially in its early stages. Tissue injury resulting from infectious, mechanical, or chemical agents may elicit a chronic immune response resulting in cellular proliferation and regeneration. Chronic inflammation of the large bowel (as in inflammatory bowel diseases), has been associated with the subsequent development of colorectal cancer. In this review we examine the inflammatory pathways involved in the early steps of carcinogenesis, with particular emphasis on colorectal. Firstly, we describe cells and proteins recently suggested as central in the mechanism leading to tumor development. Macrophages and neutrophils are among the cells mostly involved in these processes and proteins, as cyclooxygenases and resolvins, are crucial in these inflammatory pathways. Indeed, the activation of these pathways establishes an oxidative and anaerobic microenvironment with DNA damage to epithelial cells, and shifting from an aerobic to an anaerobic metabolism. Many cellular mechanisms, such as proliferation, apoptosis, and autophagy are altered causing failure to control normal mucosa repair and renewal Francesco Mariani, Paola Sena, and Luca Roncucci
misc: Macrophages (Mfs) represent 10%-20% of all mononuclear cells found in the intestinal lamina propria making the intestine the largest reservoir of Mfs in humans. Type I macrophages (M1) (classical activated) as cells able to produce large amounts of proinflammatory cytokines, are implicated in the mechanism of killing pathogens and tumor cells by secreting agents such as tumor necrosis factor α (TNF-α), interleukin (IL)-12, reactive nitrogen (iNOS), and oxygen intermediates (ROS). In contrast, Type II macrophages (M2) (alternative activated), generated by various signals which include IL-4, IL-13, IL-10, and glucocorticoid hormones, moderate the inflammatory response, eliminate cell wastes, promote angiogenesis and tissue remodeling, and release cytokines, including IL-10[1-4]. Macrophages in tumors, usually termed tumor-associated macrophages (TAMs), play important roles in determining the clinical outcome, and often express the M2 phenotype. M1 macrophages are often abundant in chronic inflammatory sites, and where tumors are initiated and start to develop. Moreover, it is possible that the macrophages switch to an M2-like phenotype as the tumor begins to invade, vascularize, and develop [5,6]. IL-23 is produced by macrophages within a few hours after the activation. This, in turn, triggers rapid IL-17 responses from tissue-resident macrophages. IL-17 promotes the production of IL-1, IL-6, IL-8, CXC ligand 1 and TNF-α in stromal, epithelial and endothelial cells, and also in a subset of monocytes. Together, these proinflammatory cytokines rapidly recruit neutrophils to the site of infection. Neutrophils normally traffic to peripheral tissues, where they are phagocytosed by Mfs after transmigration and apoptosis. Apoptotic cell phagocytosis might downregulate IL-23 secretion and then curb IL-17 and granulocyte colony stimulating factor (G-CSF) production and eventually granulopoiesis. If this processes were interrupted, tissue Mfs would continue to express IL-23. This could drive IL-17 expression and increase neutrophils retrieval in peripheral tissues[7-9]. The production of arginase has been associated with M2 type macrophages. The switch from (nitric oxide) NO production to induction of arginase in these “alternatively activated” cells up-regulates polyamine and proline biosynthesis, that can stimulate cell replication, collagen deposition, and tissue repair[10,11]. Some in vivo evidences indicate that an exacerbated local M1 macrophage-like inflammation favors oxidative microenvironment, while M2 macrophage-like inflammation sustains progressive tumor growth[12-14]
author_year: Francesco Mariani/ Paola Sena/ Luca Roncucci /2014
journal_volume_page: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4123361/ World J Gastroenterol/ Aug 7/ 20(29)/ 9716–9731

Friday, March 13, 2015

Inflammation and Colon Cancer

2004 Jul;287(1):G7-17.

Inflammation and cancer IV. Colorectal cancer in inflammatory bowel disease: the role of inflammation.

Itzkowitz SH¹, Yio X.

Abstract

Patients with ulcerative colitis and Crohn's disease are at increased risk for developing colorectal cancer. To date, no known genetic basis has been identified to explain colorectal cancer predisposition in these inflammatory bowel diseases. Instead, it is assumed that chronic inflammation is what causes cancer. This is supported by the fact that colon cancer risk increases with longer duration of colitis, greater anatomic extent of colitis, the concomitant presence of other inflammatory manifestations such as primary sclerosing cholangitis, and the fact that certain drugs used to treat inflammation, such as 5-aminosalicylates and steroids, may prevent the development of colorectal cancer. The major carcinogenic pathways that lead to sporadic colorectal cancer, namely chromosomal instability, microsatellite instability, and hypermethylation, also occur in colitis-associated colorectal cancers. Unlike normal colonic mucosa, however, inflamed colonic mucosa demonstrates abnormalities in these molecular pathways even before any histological evidence of dysplasia or cancer. Whereas the reasons for this are unknown, oxidative stress likely plays a role. Reactive oxygen and nitrogen species produced by inflammatory cells can interact with key genes involved in carcinogenic pathways such as p53, DNA mismatch repair genes, and even DNA base excision-repair genes. Other factors such as NF-kappaB and cyclooxygenases may also contribute. Administering agents that cause colitis in healthy rodents or genetically engineered cancer-prone mice accelerates the development of colorectal cancer. Mice genetically prone to inflammatory bowel disease also develop colorectal cancer especially in the presence of bacterial colonization. These observations offer compelling support for the role of inflammation in colon carcinogenesis.

Estrogen receptor (ER) negative ductal carcinomas Breast Cancer lowered survivAL with higher CD4 counts

CD4⁺lymphocytes were more prevalent than FOXP3⁺TILs whereas IL-17⁺TILs were rare. Increased numbers of total CD4⁺and FOXP3⁺TIL were observed in ductal, as compared with lobular carcinomas. High grade (G3) and estrogen receptor (ER) negative ductal carcinomas displayed significantly (p < 0.001) higher CD4⁺and FOXP3⁺lymphocyte infiltration while her2/neu over-expression in ductal carcinomas was significantly (p < 0.001) associated with higher FOXP3⁺TIL counts. In contrast, lymphocyte infiltration was not linked to any clinico-pathological parameters in lobular cancers. In univariate but not in multivariate analysis CD4⁺infiltration was associated with significantly shorter survival in patients bearing ductal, but not lobular cancers. However, a FOXP3⁺/CD4⁺ratio > 1 was associated with improved overall survival even in multivariate analysis (p = 0.033).

Note that if they were TH1 cells. MORE TNF was produced which lowered survival,
This is why the ratio is important with CD4 cells are in minority. INCREASING THIS RATIO
CAN INCREASE SURVIVAL

Breast Cancer : Th1/ Th2 balance impairments ART 1

subject: Survival: However, a FOXP3+/CD4+ ratio > 1 was associated with improved overall survival even in multivariate analysis (p = 0.033)/Raoul Droeser/Inti Zlobec/ Ergin Kilic / Uwe Güth/ Michael Heberer/ Giulio Spagnoli/ Daniel Oertli1 / Coya Tapia/
object_opposite: CD4+ infiltration was associated with significantly shorter survival in patients bearing ductal, but not lobular cancers.
misc: In univariate but not in multivariate analysis CD4+ infiltration was associated with significantly shorter survival in patients bearing ductal, but not lobular cancers. However, a FOXP3+/CD4+ ratio > 1 was associated with improved overall survival even in multivariate analysis (p = 0.033)./Differential pattern and prognostic significance of CD4+, FOXP3+ and IL-17+ tumor infiltrating lymphocytes in ductal and lobular breast cancers Raoul Droeser12, Inti Zlobec34, Ergin Kilic5, Uwe Güth6, Michael Heberer2, Giulio Spagnoli2, Daniel Oertli1 and Coya Tapia34*author_year: Raoul Droeser/Inti Zlobec/ Ergin Kilic / Uwe Güth/ Michael Heberer/ Giulio Spagnoli/ Daniel Oertli1 / Coya Tapia/2012journal_volume_page: BMC Cancer / 10.1186/1471-2407-12-134

Differential pattern and prognostic significance of CD4⁺, FOXP3⁺and IL-17⁺tumor infiltrating lymphocytes in ductal and lobular breast cancers

Raoul Droeser/ Inti Zlobec/ Ergin Kilic/ Uwe Güth/ Michael Heberer/ Giulio Spagnoli/Daniel Oertli/ Coya Tapia/2012

Background

Tumor-infiltrating lymphocytes (TILs) are frequently considered to reflect host immune response against malignant tumors [1]. TILs have been shown to infiltrate a variety of tumors of diverse histological origin [2,3]. Their exquisite tumor specificity has been demonstrated in a number of cases and it has led to the characterization of tumor associated antigens. Although resident TILs have frequently been reported to be in a functionally "anergic" state [4,5], importantly, following "ex vivo" culture, TILs have been used to treat different types of cancers [6]. In line with these data, tumor infiltration by T lymphocytes has been shown to be associated with favorable prognosis, particularly in melanoma and colorectal cancers [2,7]. On the other hand, tumor infiltration by T-lymphocytes subsets endowed with immuno-regulatory or suppressive potential, e.g. CD4⁺T-cells expressing FOXP3 transcription factor, has been suggested to be associated with tumor progression and unfavorable prognosis [8]. More recently, a CD4⁺T-cell subset producing IL-17 has been implicated in the pathogenesis of several autoimmune diseases [9]. However, the role of the so-called Th17 in antitumor immunity is still debated [10-13]

In normal breast tissue small numbers of lymphocytes representing the mucosa-associated lymphoid tissue can be detected [14]. In contrast, increased numbers of lymphocytes are frequently detectable around and within breast cancers [15-18]. The clinical significance of TILs in breast cancer is still controversial. In some studies, TILs were associated with unfavorable characteristics such as high grade tumors, estrogen receptor negativity, basal-like molecular subtype as well as her2/neu positive tumors [19,20]. High CD4⁺and CD8⁺lymphocytic infiltration has been associated with positive lymph node status as well as worse overall survival [21]. Furthermore, in early stage breast cancer, CD8⁺lymphocytic infiltration has been suggested to correlate with lymph node involvement [22]. Other groups, however, have shown that breast cancers with increased TIL number display a better prognosis in comparison with breast cancers with lesser lymphocyte infiltration [23], as also confirmed by data from our institution for CD8⁺TILs in the ER negative subgroup [24]. Additionally, high TIL counts may represent an independent predictor of response to neo-adjuvant chemotherapy [25]. Notably, infiltration by FOXP3⁺lymphocytes in breast cancer has been proposed to represent an independent unfavorable prognostic factor, especially in the nodal positive subgroup [26] and to correlate with tumor invasiveness [27]. In contrast, a complete clinical response has been suggested to be associated with disappearance of tumor infiltrating FOXP3⁺T-cells during treatment [28].

While the clinical significance of TILs is controversial, their distribution within stromal and intratumoral compartments in breast cancers is largely unknown. Furthermore, T-cell infiltration in different histological subtypes as well as the occurrence of IL-17⁺lymphocytes in breast cancer tissue has not been reported to date. Here, we addressed these issues by using a tissue microarray (TMA) including a large number (> 1000) of breast cancers stratified according to ductal and lobular histological subtypes. By taking advantage of a comprehensive clinical follow-up database, numbers of CD4⁺, FOXP3⁺and IL-17⁺TILs and their occurrence in different tumor compartments was correlated with clinico-pathological features and survival data.

Discussion

The adaptive immune system is known to play a major role in the control of tumor progression in different types of cancer. Indeed, tumor infiltration by CD8⁺T-cells has been shown to represent an important prognostic factor in melanoma [7], and, more recently, in colorectal cancers [2,33].

Early studies have suggested a favorable prognostic effect of lymphocyte infiltration in breast cancers [34]. More recently, infiltration by CD3⁺T-cells has been suggested to predict responsiveness to neoadjuvant treatment in these tumors [25]. Furthermore, a predictive effect of breast cancer infiltration by FOXP3⁺cells has also been reported [35]. Breast cancers, however, comprise histologically different tumor entities characterized by molecular specificities and differential prognosis [36,37]. The expression of hormone receptors and her2/neu also represent important factors in the biology of breast cancers and in its prognosis [36]. Most importantly, phenotypes and location of tumor infiltrating lymphocytes are emerging as important issues in cancer immunobiology [7]. Therefore, a thorough assessment of the immunobiological relevance of lymphocyte infiltration in breast cancer needs to accurately take into account these parameters.

Our data, deriving from the study of a large cohort of cases, including > 1000 specimens, are consistent with a significantly different pattern of lymphocyte infiltration in ductal and lobular breast cancers. In the lobular histological type, there is a lower lymphocytic infiltration than in ductal cancers, particularly regarding CD4⁺and FOXP3⁺cells. Furthermore, in lobular breast cancers, lymphocyte infiltration is not correlated with tumor grade and expression of hormonal receptors and it has no prognostic relevance.

In contrast, in ductal cancers, increased infiltration by CD4⁺or FOXP3⁺lymphocytes correlates significantly with histological grade, and ER loss. Her2/neu over-expression in ductal cancers is also significantly associated with increased numbers of FOXP3⁺infiltration. Puzzlingly, loss of PR expression appears to be associated with a decrease of CD4⁺infiltrate. In agreement with previous reports [27,38], we also found that FOXP3⁺infiltration is significantly increased in triple negative ductal, but not in lobular breast cancers.

Whereas the molecular background underlying these effects is unclear, they do impact the clinical course of the disease, since in ductal cancers, high infiltration by CD4⁺T-cells is associated with a significantly more severe prognosis, albeit only in univariate analysis.

On the other hand, in both ductal and lobular cancers only a modest infiltration by IL-17 producing cells was detectable.

Ductal breast cancers are more compactly growing tumors, sometimes characterized by a broad and pushing border, whereas lobular carcinomas mainly show indian file pattern, smoothly infiltrating the surrounding tissue. Interestingly, the detection of increasing numbers of TILs in high grade tumors with pushing borders was described earlier in medullary breast cancers [23]. In our study, higher counts of TILs are significantly (p < 0.001) associated with more aggressive tumor features such as loss of estrogen receptor, higher tumor grade (G3), or her2/neu over-expression in ductal breast cancers. More aggressive tumors are growing faster and may therefore present more necrotic areas while producing stroma damage possibly related to local hypoxia [39-42]. Indeed, increased numbers of CD4⁺and FOXP3⁺cells under hypoxic condition could be shown in several studies [43]. Therefore, the growth dynamics of the tumor could play a role in inducing lymphocyte infiltration.

FOXP3 represents a typical, although not exclusive, marker of regulatory CD4⁺T-cells. Tumor infiltration by T-cells expressing this marker has been associated to severe prognosis in different tumors, including ovarian and lung cancers [8]. However, in colorectal cancers FOXP3⁺T-cell infiltration has been found to correlate with significantly improved prognosis by us and others [44,45]. Our data clearly document that, although numbers of FOXP3⁺lymphocyte infiltration in ductal breast cancer are significantly associated with unfavourable clinico-pathological features, this marker alone does not appear to represent a prognostic marker. However, a high ratio (> 1) of total FOXP3⁺/CD4⁺TILs was independently associated with a better overall survival, thereby suggesting that FOXP3⁺cells other than CD4⁺T lymphocytes could be involved in the elicitation of the favorable prognostic effects. It is of note, that although FOXP3 still represents one of the most reliable Treg markers, it is known to be expressed by activated T-cells as well [8]. Indeed, FOXP3 has been shown to be expressed, albeit transiently, in activated CD8⁺T cells [46], in tonsillar suppressive CD8⁺T cells [47], and even in tumor cells [48].

Contrasting data have been reported regarding FOXP3 expression in tumor cells. In a mouse model FOXP3 could be identified as a X-linked tumor suppressor gene in breast cancer [49], but others have failed to detect expression of this gene in non hematopoietic tissues [50]. FOXP3 expression has also been reported in human breast cancer cells [26,51]. Other groups however, did not confirm these findings and only detected FOXP3 expression in breast cancer infiltrating lymphocytes [35,52]. Furthermore evidence has been reported that localization and activation status of FOXP3 positive cells might play a prognostic role in breast cancer [53,54]. Still unclear is the background underlying these discrepancies, possibly related to the use of different reagents and staining protocols. In our studies however, in keeping with previous results [55] expression of FOXP3 in breast cancer cells was found to be negligible while it was usually detectable as nuclear staining of TIL.

Accordingly, CD3 and CD163 specific staining data indicate that tumor infiltration by FOXP3⁺cells is highly correlated with infiltration by CD3⁺cells. Further studies are warranted to clarify nature, origin and functions of FOXP3⁺cells associated with improved survival in ductal breast cancer. Nevertheless, our data suggest that FOXP3 expression might reflect an activated state of specific T cell subsets.

Our study indicates that ductal and lobular breast cancers are characterized by a significantly different pattern of lymphocyte infiltration. Notably, in ductal cancers, total and, in particular, intratumoral lymphocyte infiltration is significantly associated with higher histological grade and severe prognosis, although not independently from known prognostic factors.

Further research is warranted to clarify whether these features are related to differential growth patterns of these tumor types, or to a differential immunogenicity of these tumors. Alternatively, variable tumor microenvironments might differentially favour lymphocyte chemoattraction and expansion.

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