Special Issue "Exploring Inflammation in Cancers"

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A special issue of Cancers (ISSN 2072-6694).

Deadline for manuscript submissions: closed (30 May 2011)

Special Issue Editor

Guest Editor
Prof. Dr. Masanobu Oshima

Division of Genetics, Cancer Research Institute, Kanazawa University, Kakuma-machi, Kanazawa 920-1192, Japan
Fax: +81-76-234-4519
Interests: cancer genetics; molecular pathology of gastrointestinal cancers; cancer stem cell and Wnt signaling

Special Issue Information

Dear Colleagues,

Epidemiological studies have shown that regular use of non-steroidal anti-inflammatory drugs (NSAIDs) is associated with a reduced risk of cancer development. NSAIDs exert their anti-inflammatory activity through the inhibition of cyclooxygenase-2 (COX-2), resulting in suppression of prostaglandin E2 (PGE2) biosynthesis. Consistently, genetic studies using mouse models have demonstrated that a proinflammatory prostaglandin PGE2 plays an essential role in gastrointestinal cancer development through induction of angiogenesis or suppression of tumor immunity. On the other hand, NF-kB and Stat3 are two major transcription factors in the inflammatory response, which are activated by TNF-a and IL-6, respectively. It has been shown that activation of both NF-kB and Stat3 is required for colitis-associated cancer development in mouse models through inhibition of apoptosis and acceleration of cell proliferation. These results, taken together, indicate that inflammatory signaling networks promote tumor development through multiple pathways. Moreover, recent studies have also indicated that inflammation causes tumor initiation by induction of epigenetic or genetic alterations, and malignant progression through remodeling the metastatic microenvironment. Accordingly, it is possible that targeting inflammation is an effective therapeutic strategy against cancer initiation, promotion and progression. This special issue on “Exploring Inflammation in Cancers” will include original research articles and review papers in the field of inflammation and cancer, including, but not limited to, infection-associated cancer (H. pylori, HCV etc.), cytokine/chemokine signaling in cancer development, innate immunity and acquired immunity (Th1, Th2 or Th17) in cancer development, tumor-associated macrophages (TAMs) in tumorigenesis, and inflammation and epigenetics. Thank you for your collaboration.

Prof. Dr. Masanobu Oshima
Guest Editor

Keywords

  • inflammation
  • COX-2
  • PGE2
  • TNF-alpha
  • NF-kappa B
  • Stat3
  • tumor-associated macrophages
  • colitis-associated cancer
  • innate immunity

Published Papers (10 papers)

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Research

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Open AccessArticle Infiltration of M2 Tumor-Associated Macrophages in Oral Squamous Cell Carcinoma Correlates with Tumor Malignancy
Cancers 2011, 3(4), 3726-3739; doi:10.3390/cancers3043726
Received: 13 September 2011 / Revised: 20 September 2011 / Accepted: 22 September 2011 / Published: 28 September 2011
Cited by 4 | PDF Full-text (1757 KB) | HTML Full-text | XML Full-text
Abstract
Tumor-associated macrophages (TAMs) are a major cellular component in the tumor microenvironment of many solid tumors. The functional competence of TAMs varies depending on the type of tumors and their respective microenvironments. The classically activated M1 macrophages exhibit antitumor functions, whereas the [...] Read more.
Tumor-associated macrophages (TAMs) are a major cellular component in the tumor microenvironment of many solid tumors. The functional competence of TAMs varies depending on the type of tumors and their respective microenvironments. The classically activated M1 macrophages exhibit antitumor functions, whereas the alternatively activated M2 macrophages exhibit protumor functions that contribute to tumor development and progression. Although TAMs have been detected in oral squamous cell carcinoma (OSCC), little is known about their phenotype. In the present study, we performed an immunohistochemical analysis to identify TAMs in surgically resected specimens from 50 patients with OSCC and evaluated the relationship between infiltrated TAMs and the pathological grade of OSCC. Positive staining for CD163, which has been used as a marker for M2 macrophages, was observed in OSCC specimens, and the percentages of CD163+ cells were significantly increased based on the pathological grade. CD163+ cells were detected in the tumor stroma in grade I tumors, whereas an increase in the CD163+ cells in the tumor nest was observed in higher grades of tumors. Although infiltrated CD4+ and CD8+ T cells were detected in all pathological grades of OSCC, no correlation between the infiltrated T cells and the CD163+ TAMs was observed. These results indicate that the infiltrated TAMs in OSCC have an M2 phenotype and that the M2 macrophages may participate in the development of OSCC. Full article
(This article belongs to the Special Issue Exploring Inflammation in Cancers)
Open AccessArticle Upregulation of Leukotriene Receptors in Gastric Cancer
Cancers 2011, 3(3), 3156-3168; doi:10.3390/cancers3033156
Received: 10 June 2011 / Revised: 2 August 2011 / Accepted: 4 August 2011 / Published: 8 August 2011
Cited by 2 | PDF Full-text (390 KB) | HTML Full-text | XML Full-text
Abstract
Background: Leukotrienes (LT) mediate allergic and inflammatory processes. Previously, we identified significant changes in the expression pattern of LT receptors in the gastric mucosa after eradication of Helicobacter pylori infection. The aim of the present study was to evaluate the expression of 5-lipoxygenase (5-LOX) and LT receptors in gastric cancer (GC). Methods: The expression of 5-LOX and receptors for LTB4 (BLT-1, BLT-2) and cysteinyl-LT (CysLT-1, CysLT-2) were analyzed by immunohistochemistry (IHC) in GC samples of 35 consecutive patients who underwent gastrectomy and in 29 tumor-free tissue specimens from gastric mucosa. Results: Male-to-female ratio was 24:11. The median age was 70 years (range 34–91). Twenty-two patients had GC of intestinal, six of diffuse, six of mixed and one of undifferentiated type. The IHC analysis showed a nearly ubiquitous expression of studied proteins in GC (88–97%) and in tumor-free specimens as well (89–100%). An increase in the immunoreactive score of both BLT receptors and CysLT-1 was observed in GC compared to tumor-free gastric mucosa (p < 0.001 for BLT-1; p < 0.01 for BLT-2 and CysLT-1, Mann-Whitney U-test). No differences in the IHC expression of 5-LOX and CsyLT-2 were observed between GC and tumor-free mucosa. The expression of BLT-2, CysLT-1 and CysLT-2 was increased in GC of intestinal type when compared to the diffuse type (p < 0.05; Mann-Whitney U-test). Conclusions: LTB4 receptors and CysLT-1 are up-regulated in GC tissue implying a role in gastric carcinogenesis. Full article
(This article belongs to the Special Issue Exploring Inflammation in Cancers)
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Open AccessArticle Acquisition of Genetic Aberrations by Activation-Induced Cytidine Deaminase (AID) during Inflammation-Associated Carcinogenesis
Cancers 2011, 3(2), 2750-2766; doi:10.3390/cancers3022750
Received: 13 May 2011 / Revised: 9 June 2011 / Accepted: 14 June 2011 / Published: 22 June 2011
Cited by 3 | PDF Full-text (297 KB) | HTML Full-text | XML Full-text
Abstract
Genetic abnormalities such as nucleotide alterations and chromosomal disorders that accumulate in various tumor-related genes have an important role in cancer development. The precise mechanism of the acquisition of genetic aberrations, however, remains unclear. Activation-induced cytidine deaminase (AID), a nucleotide editing enzyme, [...] Read more.
Genetic abnormalities such as nucleotide alterations and chromosomal disorders that accumulate in various tumor-related genes have an important role in cancer development. The precise mechanism of the acquisition of genetic aberrations, however, remains unclear. Activation-induced cytidine deaminase (AID), a nucleotide editing enzyme, is essential for the diversification of antibody production. AID is expressed only in activated B lymphocytes under physiologic conditions and induces somatic hypermutation and class switch recombination in immunoglobulin genes. Inflammation leads to aberrant AID expression in various gastrointestinal organs and increased AID expression contributes to cancer development by inducing genetic alterations in epithelial cells. Studies of how AID induces genetic disorders are expected to elucidate the mechanism of inflammation-associated carcinogenesis. Full article
(This article belongs to the Special Issue Exploring Inflammation in Cancers)

Review

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Open AccessReview The Crosstalk of PTGS2 and EGF Signaling Pathways in Colorectal Cancer
Cancers 2011, 3(4), 3894-3908; doi:10.3390/cancers3043894
Received: 13 September 2011 / Revised: 7 October 2011 / Accepted: 9 October 2011 / Published: 14 October 2011
Cited by 15 | PDF Full-text (231 KB) | HTML Full-text | XML Full-text
Abstract
Colorectal cancer (CRC) is now the second-leading cause of cancer deaths in the USA. Colorectal cancer progression and metastasis depends on the orchestration of the aberrant signaling pathways that control tumor cell proliferation, survival and migration/invasion. Epidemiological, clinical, and animal studies have [...] Read more.
Colorectal cancer (CRC) is now the second-leading cause of cancer deaths in the USA. Colorectal cancer progression and metastasis depends on the orchestration of the aberrant signaling pathways that control tumor cell proliferation, survival and migration/invasion. Epidemiological, clinical, and animal studies have demonstrated that prostaglandin-endoperoxide synthase 2 (PTGS2) and epithelial growth factor (EGF) signaling pathways play key roles in promoting colorectal cancer growth and metastasis. In this review, we highlight major advances in our understanding of the roles of PTGS2 and EGF signaling in colorectal cancer. Full article
(This article belongs to the Special Issue Exploring Inflammation in Cancers)
Open AccessReview Tumor-Associated Macrophages as Incessant Builders and Destroyers of the Cancer Stroma
Cancers 2011, 3(4), 3740-3761; doi:10.3390/cancers3043740
Received: 31 August 2011 / Revised: 15 September 2011 / Accepted: 19 September 2011 / Published: 28 September 2011
Cited by 12 | PDF Full-text (1493 KB) | HTML Full-text | XML Full-text
Abstract
Tumor-Associated Macrophages (TAM) are key components of the reactive stroma of tumors. In most, although not all cancers, their presence is associated with poor patient prognosis. In addition to releasing cytokines and growth factors for tumor and endothelial cells, a distinguished feature [...] Read more.
Tumor-Associated Macrophages (TAM) are key components of the reactive stroma of tumors. In most, although not all cancers, their presence is associated with poor patient prognosis. In addition to releasing cytokines and growth factors for tumor and endothelial cells, a distinguished feature of TAM is their high-rate degradation of the extra-cellular matrix. This incessant stroma remodelling favours the release of matrix-bound growth factors and promotes tumor cell motility and invasion. In addition, TAM produce matrix proteins, some of which are typical of the neoplastic tissues. The gene expression profile of TAM isolated from human tumors reveals a matrix-related signature with the up-regulation of genes coding for different matrix proteins, as well as several proteolytic enzymes. Among ECM components are: osteopontin, osteoactivin, collagens and fibronectin, including also a truncated isoform of fibronectin termed migration stimulation factor. In addition to serve as structural proteins, these matrix components have key functions in the regulation of the vessel network, in the inductionof tumor cell motility and degradation of cellular debris. Among proteolytic enzymes are: matrix metalloproteases, cathepsins, lysosomal and ADAM proteases, and the urokinase-type plasminogen activator. The degrading activity of TAM, coupled to the production of bio-active ECM proteins, co-operate to the build-up and maintenance of an inflammatory micro-environment which eventually promotes tumor progression. Full article
(This article belongs to the Special Issue Exploring Inflammation in Cancers)
Open AccessReview Inflammation-Related Carcinogenesis and Prevention in Esophageal Adenocarcinoma Using Rat Duodenoesophageal Reflux Models
Cancers 2011, 3(3), 3206-3224; doi:10.3390/cancers3033206
Received: 17 May 2011 / Revised: 2 August 2011 / Accepted: 4 August 2011 / Published: 10 August 2011
Cited by 3 | PDF Full-text (890 KB) | HTML Full-text | XML Full-text
Abstract
Development from chronic inflammation to Barrett’s adenocarcinoma is known as one of the inflammation-related carcinogenesis routes. Gastroesophageal reflux disease induces regurgitant esophagitis, and esophageal mucosa is usually regenerated by squamous epithelium, but sometimes and somewhere replaced with metaplastic columnar epithelium. Specialized columnar [...] Read more.
Development from chronic inflammation to Barrett’s adenocarcinoma is known as one of the inflammation-related carcinogenesis routes. Gastroesophageal reflux disease induces regurgitant esophagitis, and esophageal mucosa is usually regenerated by squamous epithelium, but sometimes and somewhere replaced with metaplastic columnar epithelium. Specialized columnar epithelium, so-called Barrett’s epithelium (BE), is a risk factor for dysplasia and adenocarcinoma in esophagus. Several experiments using rodent model inducing duodenogastroesophageal reflux or duodenoesophageal reflux revealed that columnar epithelium, first emerging at the proliferative zone, progresses to dysplasia and finally adenocarcinoma, and exogenous carcinogen is not necessary for cancer development. It is demonstrated that duodenal juice rather than gastric juice is essential to develop esophageal adenocarcinoma in not only rodent experiments, but also clinical studies. Antireflux surgery and chemoprevention by proton pump inhibitors, nonsteroidal anti-inflammatory drugs, selective cyclooxygenase-2 inhibitors, green tea, retinoic acid and thioproline showed preventive effects on the development of Barrett’s adenocarcinoma in rodent models, but it remains controversial whether antireflux surgery could regress BE and prevent esophageal cancer in clinical observation. The Chemoprevention for Barrett's Esophagus Trial (CBET), a phase IIb, multicenter, randomized, double-masked study using celecoxib in patients with Barrett's dysplasia failed to prove to prevent progression of dysplasia to cancer. The AspECT (Aspirin Esomeprazole Chemoprevention Trial), a large multicenter phase III randomized trial to evaluate the effects of esomeprazole and/or aspirin on the rate of progression to high-grade dysplasia or adenocarcinoma in patients with BE is now ongoing. Full article
(This article belongs to the Special Issue Exploring Inflammation in Cancers)
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Open AccessReview Inflammatory Alterations of the Extracellular Matrix in the Tumor Microenvironment
Cancers 2011, 3(3), 3189-3205; doi:10.3390/cancers3033189
Received: 4 July 2011 / Revised: 28 July 2011 / Accepted: 4 August 2011 / Published: 9 August 2011
Cited by 12 | PDF Full-text (670 KB) | HTML Full-text | XML Full-text
Abstract
Complex interactions between cancer cells and host stromal cells result in the formation of the “tumor microenvironment”, where inflammatory alterations involve the infiltration of tumor-associated fibroblasts and inflammatory leukocytes that contribute to the acquisition of malignant characteristics, such as increased cancer cell [...] Read more.
Complex interactions between cancer cells and host stromal cells result in the formation of the “tumor microenvironment”, where inflammatory alterations involve the infiltration of tumor-associated fibroblasts and inflammatory leukocytes that contribute to the acquisition of malignant characteristics, such as increased cancer cell proliferation, invasiveness, metastasis, angiogenesis, and avoidance of adaptive immunity. The microenvironment of a solid tumor is comprised not only of cellular compartments, but also of bioactive substances, including cytokines, growth factors, and extracellular matrix (ECM). ECM can act as a scaffold for cell migration, a reservoir for cytokines and growth factors, and a signal through receptor binding. During inflammation, ECM components and their degraded fragments act directly and indirectly as inflammatory stimuli in certain cases and regulate the functions of inflammatory and immune cells. One such ECM component, hyaluronan, has recently been implicated to modulate innate immune cell function through pattern recognition toll-like receptors and accelerate the recruitment and activation of tumor-associated macrophages in inflamed cancers. Here, we will summarize the molecular mechanism linking inflammation with ECM remodeling in the tumor microenvironment, with a particular emphasis on the role of hyaluronan in controlling the inflammatory response. Full article
(This article belongs to the Special Issue Exploring Inflammation in Cancers)
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Open AccessReview Toll-Like Receptor 4 Signaling Integrates Intestinal Inflammation with Tumorigenesis: Lessons from the Murine Model of Colitis-Associated Cancer
Cancers 2011, 3(3), 3104-3113; doi:10.3390/cancers3033104
Received: 9 June 2011 / Revised: 25 July 2011 / Accepted: 26 July 2011 / Published: 2 August 2011
PDF Full-text (832 KB) | HTML Full-text | XML Full-text
Abstract
Chronic inflammation has long been implicated as a predisposition for cancer, but the underlying mechanism for how this occurs has remained obscure. Ulcerative colitis (UC) is a chronic inflammatory disorder of the large intestine which is known to be highly linked to [...] Read more.
Chronic inflammation has long been implicated as a predisposition for cancer, but the underlying mechanism for how this occurs has remained obscure. Ulcerative colitis (UC) is a chronic inflammatory disorder of the large intestine which is known to be highly linked to colorectal cancer. During chronic inflammation the intestinal mucosa is in a constant cycle of injury and repair resulting in aberrant epithelial proliferation, a process that increases the risk of neoplastic transformation. In particular, the coexistence of commensal flora in the intestine plays an important role in the regulation of mucosal restitution after epithelial injury. It has become apparent that signaling through toll-like receptors (TLRs), the receptor family recognizing pathogen-associated molecular patterns, is crucial to intestinal epithelial proliferation and mucosal restitution. We have recently described two important downstream pathways underlying TLR4-mediated epithelial proliferation in a mouse model of colitis-associated cancer; i.e., cyclooxygenase 2 (COX-2)-mediated production of prostaglandin E2 (PGE2), and induction of specific ligands for epidermal growth factor receptor (EGFR). These two pathways are closely involved with mucosal levels of PGE2 and other prostanoids such as 15-deoxy-delta 12,14-prostaglandin-J2 (15d-PGJ2). Understanding the fine interplay between the TLR signaling and intestinal tumorigenesis in the setting of chronic inflammation can contribute to establishing a novel treatment strategy for inflammation-associated cancers. Full article
(This article belongs to the Special Issue Exploring Inflammation in Cancers)
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Open AccessReview Detouring the Undesired Route of Helicobacter pylori-Induced Gastric Carcinogenesis
Cancers 2011, 3(3), 3018-3028; doi:10.3390/cancers3033018
Received: 3 June 2011 / Revised: 12 July 2011 / Accepted: 19 July 2011 / Published: 25 July 2011
Cited by 3 | PDF Full-text (1164 KB) | HTML Full-text | XML Full-text
Abstract
Epidemiological and experimental evidence has emerged that a dysregulated inflammation is associated with most of the tumors, and many studies have begun to unravel the molecular pathways linking inflammation and cancer. As a typical example linking these associations, Helicobacter pylori (H. [...] Read more.
Epidemiological and experimental evidence has emerged that a dysregulated inflammation is associated with most of the tumors, and many studies have begun to unravel the molecular pathways linking inflammation and cancer. As a typical example linking these associations, Helicobacter pylori (H. pylori) infection-associated atrophic gastritis has been recognized as precursor lesion of gastric cancer. The identification of transcription factors such as NF-κB and STAT3, and their gene products such as IL-8, COX-2, iNOS, cytokines, chemokines and their receptors, etc have laid the molecular foundation for our understanding of the decisive role of inflammation in carcinogenesis. In addition to the role as the initiator of cancer, inflammation contributes to survival and proliferation of malignant cells, tumor angiogenesis, and even metastasis. In this review, the fundamental mechanisms of H. pylori-induced carcinogenesis as well as the possibility of cancer prevention through suppressing H. pylori-induced inflammation are introduced. We infer that targeting inflammatory pathways have a potential role to detour the unpleasant journey to H. pylori-associated gastric carcinogenesis. Full article
(This article belongs to the Special Issue Exploring Inflammation in Cancers)
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Open AccessReview Tumor Necrosis Factor (TNF) and Chemokines in Colitis-Associated Cancer
Cancers 2011, 3(3), 2811-2826; doi:10.3390/cancers3032811
Received: 23 May 2011 / Revised: 17 June 2011 / Accepted: 21 June 2011 / Published: 27 June 2011
Cited by 4 | PDF Full-text (512 KB) | HTML Full-text | XML Full-text
Abstract
The connection between inflammation and tumorigenesis has been well established, based on a great deal of supporting evidence obtained from epidemiological, pharmacological, and genetic studies. One representative example is inflammatory bowel disease, because it is an important risk factor for the development [...] Read more.
The connection between inflammation and tumorigenesis has been well established, based on a great deal of supporting evidence obtained from epidemiological, pharmacological, and genetic studies. One representative example is inflammatory bowel disease, because it is an important risk factor for the development of colon cancer. Moreover, intratumoral infiltration of inflammatory cells suggests the involvement of inflammatory responses also in other forms of sporadic as well as heritable colon cancer. Inflammatory responses and tumorigenesis activate similar sets of transcription factors such as NF-kB, Stat3, and hypoxia inducible factor and eventually enhances the expression of inflammatory cytokines including tumor necrosis factor (TNF) and chemokines. The expression of TNF and chemokines is aberrantly expressed in a mouse model of colitis-associated carcinogenesis as well as in inflammatory bowel disease and colon cancer in humans. Here, after summarizing the presumed actions of TNF and chemokines in tumor biology, we will discuss the potential roles of TNF and chemokines in chronic inflammation-associated colon cancer in mice. Full article
(This article belongs to the Special Issue Exploring Inflammation in Cancers)

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