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ABSTRACT: Abstract Objective. To investigate mucosal cytokine gene expression levels in healed mucosa after anti-tumor necrosis factor (TNF) therapy in patients with Crohn's disease (CD) as possible risk factors for relapse after discontinuation of therapy. Design. Thirty-seven CD patients treated with anti-TNF agents until complete mucosal healing, documented by endoscopy, discontinued anti-TNF treatment and entered a follow-up study. Levels of mRNA expression of interleukin (IL)17A (IL17A), IL23, interferon-gamma (IFNG), TNF-alpha (TNF), IL10 and Forkhead Box P3 (FOXP3) were measured in biopsies from healed mucosa and analyzed as possible risk factors of relapse. Mucosal cytokine transcript levels from patients without CD served as controls. Results. Patients were followed after therapy withdrawal until relapse. Median time to relapse was 20 and 68 weeks for patients with elevated and normalized IL17A and TNF expression levels, respectively (p = 0.02 for IL17A and p = 0.003 for TNF, log-rank). Expression levels of TNF, IL17A and FOXP3 were significantly higher in patients who relapsed before 26 weeks than in those who did not relapse, and also higher in patients with relapse before week 52 versus non-relapsers. Elevated expression levels of TNF and IL17A in healed mucosa significantly increased the risk of relapse (HR = 3.4, p = 0.03, sensitivity 80%, specificity 38% and HR = 4.1, p = 0.008, sensitivity 81%, specificity 61%, respectively). Conclusions. Normalization of mucosal gene expression of cytokines after anti-TNF therapy does not occur in all patients with healed mucosa as judged by endoscopy. Normalization of TNF and/or IL17A expression predicts long-term remission.
Scandinavian journal of gastroenterology 01/2013; · 2.08 Impact Factor
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ABSTRACT: Angiogenesis is essential for the growth, expansion and metastasis of human colorectal cancers (CRCs). Histamine produced by mast cells is a potent proangiogenic factor. However, the significance of non-mast cell expressing histamine in the tumor microenvironment remains unknown. In this study, we evaluated the histamine positive microvessels with the specific marker for biosynthesis of histamine L-histidine decarboxylase (HDC) in the CRC tumor microenvironment. The relationship between HDC positive microvessel density (HDC-MVD) and clinical pathological parameters was assessed. The results revealed that HDC-MVD in the tumor microenvironment of CRCs was significantly increased as compared with the controls. CRC patients with lymph node invasion had a particularly higher density of HDC-MVD than those without. The density of HDC-MVD accounted for ~79 % of CD34 positive MVD in CRCs and double IHC analysis demonstrated that these HDC positive microvessels were mostly CD34 positive microvessels and with a high proliferative activity. Our results suggest that histamine expressed in microvessels could be an additional cellular source and involved in the cancer invasion through promoting angiogenesis in human CRCs.
Pathology & Oncology Research 12/2012; · 1.37 Impact Factor
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ABSTRACT: Abstract Objectives. Interleukin (IL)-17A is an important pro-inflammatory cytokine and involved in the colorectal carcinogenesis. In this study, the authors evaluated the dynamic change of IL-17A expression in the tumor microenvironment throughout the colorectal adenoma-carcinoma sequence. Materials & methods. Using quantitative real-time PCR (polymerase chain reaction) and semi-quantitative immunohistochemistry, the authors examined the expression level of IL-17A in 50 of human colorectal adenoma tissues, 50 of colorectal cancer (CRC) tissues and 15 controls. The relationship between IL-17A expression and clinicopathological parameters throughout the sequence was also evaluated. Results. The results revealed a step-up increased IL-17A mRNA level throughout the colorectal adenoma-carcinoma sequence, which began to increase in the adenomas and became even higher in the CRCs; notably, the increase of IL-17A mRNA level in the adenomatous tissues was associated with the severity of dysplasia. Immunohistochemical analysis confirmed the real-time PCR results and revealed gradually increasing IL-17A cells in both the stroma and adenomatous/cancerous epithelium. In addition, the quantitative real-time PCR result has also revealed an increased expression of TH17-stimulating factors throughout the sequence. Conclusions. IL-17A and TH17 are highly activated throughout the colorectal adenoma-carcinoma sequence.
Scandinavian journal of gastroenterology 09/2012; 47(11):1304-12. · 2.08 Impact Factor
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ABSTRACT: Mucosal cytokine profile determines T cell differentiation and may play an important role in the clinical course of inflammatory bowel disease (IBD). Cytokines from different T helper (Th) cell subsets are elevated in inflamed mucosa of patients with ulcerative colitis (UC), contributing to the inflammation. The aim of this study was to determine the predictive value of pre-treatment mucosal cytokine profile in response to therapy with the anti-TNF agent infliximab (IFX).
The expression of Th1, Th17, Th2 and T-regulatory (Treg)-related cytokines was quantified by real-time PCR in mucosal biopsies from 74 UC patients before initiation of IFX induction therapy. Clinical and endoscopic effects were assessed after three infusions. Remission was defined as ulcerative colitis disease activity index (UCDAI) below 3.
Higher gene expression levels of IL-17A and IFN-γ were significantly associated with remission after three IFX infusions (OR = 5.4, p = 0.013 and OR = 5.5, p = 0.011, respectively). IL-17A and IFN-γ mRNA expression showed positive correlation. Th2 and Treg-related mediators were not significantly associated with clinical outcome, but were expressed at higher levels in UC patients compared with the controls. Immunohistochemistry (IHC) confirmed the presence of cells expressing both IL-17A and IFN-γ.
High expression of Th1- and Th17-related cytokines in the mucosa of UC patients can potentially predict a favorable outcome of IFX induction therapy. Th2 and Treg-related mediators do not appear useful as predictive markers.
Scandinavian journal of gastroenterology 05/2012; 47(5):538-47. · 2.08 Impact Factor
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ABSTRACT: Human colorectal carcinoma (CRC) is one of the leading cancers. Every year, the WHO estimates a total of 945,000 new CRC cases, with 492,000 deaths worldwide. Most CRCs arise from the main premalignant lesion, colorectal adenomas, and the progression of colorectal adenoma to CRCs may take a long-term time course. The development of human CRCs is not only determined by the adenomatous cells, but also by the interaction between adenomatous cells and host immune environment. In response to tumor initiation or invasion, many inflammatory cells and components will be inevitably activated and form an inflammatory microenvironment surrounding the CRC tumors. Accumulative evidence has revealed that inflammatory response plays a key role in the development of human CRCs by implicating in many aspects including in determining the microenvironmental immune function shift from immunosurveillance to immunosuppression and significantly influences the progression of precancerous lesions to cancers. In this review, the functional changes of immune microenvironment from precancerous stage (adenoma) to cancer stage are summarized, and their potential as predictive biomarkers and biotherapeutic significance in preventing the development of CRCs are discussed.
Scandinavian journal of gastroenterology 01/2012; 47(4):367-77. · 2.08 Impact Factor
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ABSTRACT: The growth, invasiveness, and metastasis of human cancers are not only determined by the cancer cells but also by their microenvironment. The purpose of this study was to extend our previous studies and to examine the cellular changes in tumor microenvironment (stroma) of esophageal squamous cell carcinomas (ESCCs). The proliferative activity, cellular components, and angiogenesis status in different compartments (non-tumor stroma, tumor stroma, and tumor periphery stroma) of ESCCs were evaluated by immunohistochemistry. The results revealed a hyperproliferative rate labeled by Ki-67 in stromal cells in tumor area as compared with that in stromal cells in non-tumor area, which resulted in the increased densities of myofibroblasts (labeled by smooth muscle actin (SMA)-alpha), lymphocytes (labeled by CD3), macrophages (labeled by CD68), and the activation of angiogenesis characterized by increased microvessel density (MVD) and the increased expression of the proangiogenic factors (vascular endothelial growth factor and interleukin 8) in the tumor stroma. Further analysis showed that the changes of stromal cell density were more significant in the area of periphery tumor stroma than that of stroma between tumor nests. Most cellular changes were significantly associated with lymph node involvement. Double immunohistochemistries with PCNA/CD3, PCNA/CD68, and PCNA/SMA-alpha revealed that these cells present in the ESCC tumor stroma had a proliferative capacity. The cells present in the tumor microenvironment of ESCCs were greatly activated, suggesting that microenvironmental components may be involved in the cancer growth and progression.
Tumor Biology 12/2011; 33(2):495-505. · 1.94 Impact Factor
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ABSTRACT: Crohn's disease (CD) and ulcerative colitis (UC) have been associated with a T helper1 (TH1) and a TH2 cytokine profile, respectively. Recently, a TH17 lineage has been introduced, but their role in the inflammation of CD and UC is not fully understood.
To characterize the cytokines directing the TH17 cells and their interactions with TH1 cells in the mucosa of untreated patients with CD and UC.
Seventy-nine patients with untreated UC, 32 patients with untreated CD and 23 controls with no signs of colon disease were included in the study. Clinical indices for ulcerative colitis (UCDAI) and Crohn's disease (CDAI) were assessed. Biopsies for measurements of interleukin (IL)-17A, IL-23, IL-6, transforming growth factor-beta (TGF-β), interferon-gamma (IFN-γ), mRNA levels as well as immunohistochemical (IHC) analyses were performed.
The gene expression for all cytokines in UC and for all cytokines except for TGF-β in CD were significantly increased compared with the controls. The immunohistochemical analysis showed significantly increased number of IL-17A positive cells in lamina propria and epithelium of both UC and CD compared to controls. The levels of IL-17A and IL-23 mRNA were significantly higher in UC than in CD while the levels of IL-6 were significantly higher in CD compared with UC. The levels of IL-17A, IL-6 and IL-23 mRNA were associated with the disease activity score in both UC and CD. IFN-γ was associated with the disease activity in UC, but did not reach significant level in CD.
Increased levels of IL-17A and IL-23 were found in both UC and CD compared to controls. Association to the grade of inflammation and clinical activity was also observed. IL-17A and IL-23 were significantly higher in UC than in CD. TH1 and TH17 cytokines seem to act synergistically in inflammatory bowel disease (IBD) with no apparent polarization between UC and CD.
Cytokine 09/2011; 56(3):633-40. · 3.02 Impact Factor
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Shui Ping Tu,
Michael Quante,
Govind Bhagat,
Shigeo Takaishi, Guanglin Cui,
Xiang Dong Yang,
Sureshkumar Muthuplani,
Wataru Shibata,
James G Fox,
D Mark Pritchard,
Timothy C Wang
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ABSTRACT: IFN-γ mediates responses to bacterial infection and autoimmune disease, but it is also an important tumor suppressor. It is upregulated in the gastric mucosa by chronic Helicobacter infection; however, whether it plays a positive or negative role in inflammation-associated gastric carcinogenesis is unexplored. To study this question, we generated an H(+)/K(+)-ATPase-IFN-γ transgenic mouse that overexpresses murine IFN-γ in the stomach mucosa. In contrast to the expected proinflammatory role during infection, we found that IFN-γ overexpression failed to induce gastritis and instead inhibited gastric carcinogenesis induced by interleukin-1beta (IL-1β) and/or Helicobacter infection. Helper T cell (Th) 1 and Th17 immune responses were inhibited by IFN-γ through Fas induction and apoptosis in CD4 T cells. IFN-γ also induced autophagy in gastric epithelial cells through increased expression of Beclin-1. Finally, in the gastric epithelium, IFN-γ also inhibited IL-1β- and Helicobacter-induced epithelial apoptosis, proliferation, and Dckl1(+) cell expansion. Taken together, our results suggest that IFN-γ coordinately inhibits bacterial infection and carcinogenesis in the gastric mucosa by suppressing putative gastric progenitor cell expansion and reducing epithelial cell apoptosis via induction of an autophagic program.
Cancer Research 06/2011; 71(12):4247-59. · 7.86 Impact Factor
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ABSTRACT: Dendritic cells (DCs) play a critical role in generating anti-tumor immunity. DC functional defect has been related to the growth and progression of various human cancers. In esophageal squamous cell carcinoma (ESCC), the examination of DCs using immunohistochemistry (IHC) with anti-S100 antibody has demonstrated an increased infiltration of DCs into the tumor mass, however, the distribution patterns of DCs at different maturation states in ESCC are not fully evaluated. In this study, we immunohistochemically analyzed the DC maturation status by examining the S100-positive DCs, CD1alpha-positive immature DCs (iDCs), and CD208-positive mature DCs (mDCs) and their distribution patterns in 45 ESCCs and 10 control tissues. The IHC analysis showed that the number of S100-positive DCs was increased in both the cancer epithelium and tumor stroma. Further phenotypic analyses revealed that intraepithelial DCs in the cancer mass were predominantly CD1alpha-positive iDCs. Whereas DCs presented in the tumor stroma were exclusively CD208-positive mDCs, CD208-positive mDCs were particularly dense in the margin of cancerous lesions and formed clusters with CD3-positive lymphocytes. The number of CD208-positive mDCs in the tumor mass was significantly lower than the number of CD1alpha-positive iDCs. The current results suggest that ESCC tissue comprises a high frequency of iDCs in the cancerous epithelium and a low density of mDCs in the tumor stroma. Such a distinct distribution pattern may reflect the ongoing DC tracking in ESCCs.
Pathology - Research and Practice 09/2010; 206(9):602-6. · 1.21 Impact Factor
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ABSTRACT: Patients with locally advanced rectal cancer often receive preoperative radio-chemotherapy (RCT). The mechanisms of tumour response to radiotherapy are not understood. The aim of this study was to identify the effects of RCT on gene expression in rectal tumour and normal rectal tissue. For that purpose tissue samples from 21 patients with resectable adenocarcinomas were collected for use in whole genome-microarray based gene expression analysis. A factorial experimental design allowed us to determine the effect of RCT on tumour tissue alone by removing the effect of radiation on normal tissue. This resulted in 1327 differentially expressed genes in tumour tissue with p<0.05. In addition to known markers for radio-chemotherapy, a Gene Set Enrichment Analysis (GSEA) showed a significant enrichment in gene sets associated with cell adhesion and leukocyte transendothelial migration. The profound change of cell adhesion molecule expression in rectal tumour tissue could either increase the risk of metastasis, or decrease the tumour's invasive potential.
Molecular oncology 11/2009; 4(1):52-64. · 4.10 Impact Factor
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ABSTRACT: Immunosuppressive factors derived from the tumor and nontumor cells present in the tumor microenvironment contribute to tumor escape from host immune attack. Recently, the tryptophan-catabolizing enzyme indoleamine 2,3-dioxygenase (IDO) derived from both the tumor cells and surrounding nontumor cells was found to function as a critical immunosuppressive factor. While the expression of IDO is intensively under investigation in many types of cancers, little information is available in esophageal squamous cell carcinomas (ESCC) thus far. In this study, we have therefore investigated the cellular localization of IDO in 45 ESSCs and ten morphologically normal esophageal tissues; the correlation of IDO with clinicopathological parameters was also analyzed. Immunohistochemistry (IHC) analysis revealed that the density of IDO-positive cells was increased in ESCCs relative to controls (P < 0.01). These cells were distributed as clusters and formed a patchy pattern in both the cancerous epithelium and the surrounding noncancerous cells. Double IHC further confirmed that many IDO-positive cells in the tumor stroma were smooth-muscle-actin-alpha-positive myofibroblasts, CD68-positive macrophages, and S100-positive dendritic cells. Statistical analysis showed that the densities of IDO-positive cells were not significantly correlated with tumor clinical parameters (tumor invasion depth, node metastasis, and TNM stages) and lymphocytic infiltration. Our current findings suggested that the increased IDO expression in ESCCs is from a mixed cellular source (both cancer cells and noncancerous cells). Further studies on immune cell functional analysis are required in the future.
Archiv für Pathologische Anatomie und Physiologie und für Klinische Medicin 10/2009; 455(5):441-8. · 2.49 Impact Factor
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ABSTRACT: The interleukin-8 (IL-8) network is involved in the colorectal cancer (CRC) progression. However, its role during the adenoma-carcinoma transition to date has not been fully investigated. To evaluate the dynamic changes of IL-8 network along the colorectal adenoma-carcinoma sequence, we examined the tissue IL-8 mRNA level in colorectal biopsies from 53 colorectal adenomas, 44 CRCs and 18 controls by quantitative real-time PCR (Q-PCR), and the expressions of IL-8 and its receptors (IL-8RA and IL-8RB) in the tumor microenvironment by immunohistochemistry (IHC) and double IHCs. The results showed that the tissue IL-8 mRNA level began to increase in the precancerous lesions (adenomas) as compared with the controls and became even higher in the CRCs. Significantly, the increase of IL-8 mRNA levels was associated with the increase of dysplastic grades in the adenomas, and also paralleled to the increase of Duke's stages in the CRCs. IHC results revealed that IL-8 and its receptors, IL-8RA and IL-8RB, were observed both in the stroma and in the adenomatous/cancerous cells. By double IHCs, the IL-8 expression was characterized in macrophages, lymphocytes and myofibroblasts in the tumor stroma. Further double IHC identified the co-expression of IL-8 receptors (IL-8RA and IL-8RB) with CD34 positive tumor-associated microvessels in both the adenomas and CRCs. We, therefore, conclude that activated IL-8 network in the tumor microenvironment may function as a significant regulatory factor for the adenoma progression and the adenoma-carcinoma transition.
Cancer Immunology and Immunotherapy 05/2009; 58(11):1897-905. · 3.70 Impact Factor
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ABSTRACT: The lamina propria is inevitably involved in epithelial transformation. The aim was to evaluate the dynamic cellular changes in the tumour lamina propria throughout the colorectal adenoma-carcinoma sequence.
Using immunohistochemistry and double immunohistochemistry, we examined lamina propria cellular changes in 41 colorectal adenomas, 25 colorectal cancers and 15 control tissues. The results showed that the proliferation labelling index in lamina propria cells began to increase in the precancerous lesions (adenomas) and became even higher in the colorectal cancers; these proliferative cells were primarily identified as myofibroblasts and lymphocytes. Phenotypic analysis revealed gradually increasing lymphocytic infiltration in both the lamina propria and adenomatous epithelium, as well as myofibroblasts in the lamina propria. However, the intraepithelial macrophage density also showed a tendency to increase gradually. Furthermore, cyclooxygenase-2-expressing cell density and microvessel density gradually increased in the tumour lamina propria throughout the adenoma-carcinoma sequence.
Progressive cellular responses in the lamina propria could be involved in the adenoma-carcinoma transition.
Histopathology 05/2009; 54(5):550-60. · 3.08 Impact Factor
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ABSTRACT: It has been documented that treatment with infliximab (IFX) induces remission in 1/3 of patients with moderate to severe ulcerative colitis (UC). Predictors of response could improve selection of patients with a higher probability of favorable outcome.
To determine predictor factors for the clinical outcome of IFX induction therapy in UC.
UC patients with moderate to severe disease who received 5mg/kg IFX at weeks 0, 2 and 6weeks were included. Ulcerative colitis disease activity index (UCDAI) score including endoscopic sub-scores were assessed before and after treatment. Several predictors, including TNF-alpha mRNA expression, were tested in a regression model.
Fifty-nine patients completed the study. Age, gender, steroid therapy, immunosuppressive, pancolitis, endoscopic sub-score, disease duration, C-reactive protein, interleukin-(IL)-4, IL-10 or interferon-gamma (IFN-gamma) did not predict mucosal or clinical remission. There was an inverse and independent association between pre-treatment TNF-alpha expression levels and clinical and endoscopic remission of IFX treatment (logistic regression, p=0.01 and p=0.003, odds ratio 2.5 and 4.8, respectively).
The clinical outcome of an induction therapy with IFX in UC is inversely associated with the pre-treatment gene expression levels of TNF-alpha in colorectal mucosa.
Cytokine 04/2009; 46(2):222-7. · 3.02 Impact Factor
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ABSTRACT: The mechanisms of action of infliximab (IFX) in the treatment of ulcerative colitis (UC) are poorly understood. The aim of the study was to investigate the changes in tissue expression of tumor necrosis factor-alpha (TNF-alpha) and other cytokines in UC patients receiving IFX treatment.
The levels of TNF-alpha, interleukin (IL)-10, IL-4, and interferon-gamma (IFN-gamma) mRNA in colonic biopsies from 32 UC patients during IFX treatment were measured by real-time polymerase chain reaction (PCR) and compared with those of 19 controls. Immunohistochemistry was performed to characterize the changes of inflammatory cells during treatment.
IFX reduced the expression of TNF-alpha and IFN-gamma mRNA, but not that of IL-10 and IL-4 mRNA. Reductions in TNF-alpha mRNA were correlated to clinical and endoscopic improvements, and normalization of TNF-alpha mRNA was obtained in patients with healed mucosa. The numbers of T lymphocytes and macrophages were significantly decreased in patients with healed mucosa after IFX treatment, although compared to normal controls, there were still increased levels of TNF-alpha-positive cells after treatment.
IFX induced down-regulation of the mucosal TNF-alpha and IFN-gamma mRNA expression in UC patients. The numbers of T lymphocytes and macrophages were significantly decreased in patients with endoscopically healed mucosa after IFX treatment.
Scandinavian journal of gastroenterology 04/2009; 44(6):727-35. · 2.08 Impact Factor
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ABSTRACT: Histamine is produced by mast cells and many other types of cells. The role of histamine released from mast cells in promoting tumor angiogenesis has been intensively studied; however, the role of non-mast cell histamine in regulating tumor angiogenesis has been largely ignored. In this study, tissue specimen sections from 43 patients with esophageal squamous cell carcinoma (ESCC) and normal esophageal biopsies from 17 heath individuals obtained from a high incidence area of north China were used to assess changes in microvessel density (MVD) and non-mast cell L-histidine decarboxylase (HDC) (the only rate-limiting enzyme that catalyzes the formation of histamine from L-histidine) expression in the tumor microenvironment by immunohistochemistry (IHC). In addition, the cellular characterization of non-mast cell HDC-positive cells in microvessels was examined by double IHC combined with HDC/CD34 and HDC/PCNA antibodies. These IHC analyses revealed a significantly increased HDC-positive MVD in ESCC as compared with normal controls, which accounted for approximately 61% of CD34-labeled general MVD in ESCC. Furthermore, IHC in serial sections and double IHC showed that most of these HDC-positive cells were CD34-positive endothelial cells in microvessels with an increased proliferative capacity. Thus, our results suggest that non-mast cell histamine expressed in endothelial cells of microvessels could be an additional cellular source and might play a role in regulating angiogenesis in ESCC.
Apmis 01/2009; 116(12):1034-42. · 1.99 Impact Factor
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Shuiping Tu,
Govind Bhagat, Guanglin Cui,
Shigeo Takaishi,
Evelyn A Kurt-Jones,
Barry Rickman,
Kelly S Betz,
Melitta Penz-Oesterreicher,
Olle Bjorkdahl,
James G Fox,
Timothy C Wang
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ABSTRACT: Polymorphisms of interleukin-1beta (IL-1beta) are associated with an increased risk of solid malignancies. Here, we show that stomach-specific expression of human IL-1beta in transgenic mice leads to spontaneous gastric inflammation and cancer that correlate with early recruitment of myeloid-derived suppressor cells (MDSCs) to the stomach. IL-1beta activates MDSCs in vitro and in vivo through an IL-1RI/NF-kappaB pathway. IL-1beta transgenic mice deficient in T and B lymphocytes develop gastric dysplasia accompanied by a marked increase in MDSCs in the stomach. Antagonism of IL-1 receptor signaling inhibits the development of gastric preneoplasia and suppresses MDSC mobilization. These results demonstrate that pathologic elevation of a single proinflammatory cytokine may be sufficient to induce neoplasia and provide a direct link between IL-1beta, MDSCs, and carcinogenesis.
Cancer cell 12/2008; 14(5):408-19. · 25.29 Impact Factor
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ABSTRACT: The development of colorectal carcinoma (CRC) has been hypothesized to be raised mostly from the precancerous lesion of colorectal adenoma (CRA) through a multistep process and defined as the adenoma-carcinoma sequence. In response to the tumorigenesis, host cellular immunity acts as the most important defense factor with cytokines as the main regulator molecules. Therefore, changes of cytokines of the T helper 1 (Th1)/T helper 2 (Th2) type immune responses along this sequence may therefore reflect a functional switch of host anti-tumor immunity. This minireview focused on the recent knowledge of the Th1/Th2 balance in the adenoma-carcinoma sequence and its potential clinical and therapeutical significance.
Inflammation & Allergy - Drug Targets (Formerly ?Current Drug Targets - Inflammation & Allergy) 07/2008; 7(2):94-7.
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ABSTRACT: We have previously reported that the dendritic cell (DC) functional index cytokine interleukin-12 was significantly decreased in colorectal carcinoma (CRC) tissues. In this study, the DC infiltration pattern and the density of mature DCs (mDCs; labeled by anti-CD83 and anti-CD208) and immature DCs (iDCs; labeled by anti-CD1alpha) were characterized using immunohistochemistry (IHC) in tissue samples from 23 patients with CRC, 33 patients with colorectal adenoma (CRA), and 19 healthy controls. In addition, the DC function inhibitor cyclooxygenase-2 (COX-2) and the downstream signal molecule prostaglandin E2 (PGE2) and related receptors EP2/EP4 were measured by quantitative real-time PCR and double immunofluorescence staining. The IHC analyses revealed changed densities of mDCs and iDCs in the tumor microenvironment; in CRA and CRC, the density of mDCs was decreased, but the density of iDCs was gradually increased. Furthermore, the distribution patterns of DCs were also altered. In CRA, mDCs were abundantly distributed in the subepithelial stroma of the adenomatous mass. In CRC, the distribution of mDCs in the tumor stroma was not homogeneous, and mDCs residing in the stroma at invading edges were more frequently found compared with in the intratumoral stroma (P<0.05). Increased iDCs were found in the intratumoral mass in CRC, and some infiltrated into the malignant epithelium. By quantitative real-time PCR, a gradually increased level of COX-2 mRNA was demonstrated in the local tissues along the adenoma-carcinoma sequence, and double immunofluorescence staining showed a colocalization of PGE2 receptors EP2/EP4 with mDCs in the stroma of CRC. In conclusion, our current findings revealed an altered DC infiltration pattern along the adenoma-carcinoma sequence; gradually increased COX-2 expression might contribute to the DC functional defect.
Apmis 07/2008; 116(6):445-56. · 1.99 Impact Factor
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ABSTRACT: A promoting effect of gastrin on stimulating Barrett's oesophagus proliferation has been demonstrated, but whether it plays a regulating role for esophageal squamous cell carcinoma (ESCC) to date has not been fully investigated. The aim of this study is to examine the expressions of gastrin, gastrin precursors and gastrin/CCK-2 receptor in ESCC. Tissue specimen sections from 38 patients with ESSC obtained from a high incidence area of north China were assessed using immunohistochemistry for amidated gastrin, gastrin precursors (progastrin and glycine-extended gastrin) and gastrin/CCK-2 receptors. Their clinical histopathological significance was also analyzed. Of 38 ESCC, the immunoreactivities of gastrin, glycine-extended gastrin and progastrin were observed in 13.2% (5/38), 7.9% (3/38) and 23.68% (9/38) cases. The expression of progastrin was obviously higher than other gastrins, though not significantly (P > 0.05). In positive cases for gastrin or glycine-extended gastrin, the scores of positive tumor cell numbers were at a lower density (<10/abundant-distributed field). However, the scores of progastrin positive tumor cell density in five of nine positive cases were over 10/abundant-distributed field. The immunoreactivity of gastrin/CCK-2 receptor was also observed in 15.8% (6/38) ESCC cases. There was not significant correlation regarding immunohistochemical results with known histomorphological parameters i.e. gender, tumor location and TNM stages. Based on our current results, ESCC tumor cells could be a possible cellular source of gastrin precursors, which has been postulated to play a role in regulating the growth in some human tumor cells.
Pathology & Oncology Research 04/2008; 14(4):449-55. · 1.37 Impact Factor
