Chronic inflammation, the tumor microenvironment and carcinogenesis

Gonda, Tamas A.; Tu, Shuiping; Wang, Yichen

doi:10.4161/cc.8.13.8985

Cited by 226 publications

(168 citation statements)

References 70 publications

(80 reference statements)

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“…Thus, the progress from atrophy and intestinal metaplasia to cancer might be an autonomous, H. pylori-independent process (de Vries et al 2009). Simultaneously, the slightly but significantly greater residual inflammation in the non-acid-secreting areas could also be responsible for the carcinogenesis in the areas after eradication through the sustained pro-carcinogenic actions of sustained inflammatory cytokines (Gonda et al 2009).…”

Section: Discussionmentioning

confidence: 99%

Gastric Cancers Emerging after H. pylori Eradication Arise Exclusively from Non-Acid-Secreting Areas

Iijima

Abe

Koike

et al. 2012

Tohoku J. Exp. Med.

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Although Helicobacter pylori (H. pylori) eradication has some inhibitory effects on the subsequent development of gastric cancer, there are sporadic cases of gastric cancer even after successful eradication. The pathogenesis of gastric cancer emerging after H. pylori eradication remains to be clarified. In this study, employing Congo-red chromoendoscopy, which is capable of visualizing the acid-secreting fundic mucosa, we investigated the topographic relationship of the acid secretion pattern to the occurrence site of gastric cancers emerging after eradication. Fourteen consecutive patients who suffered from new gastric cancer after eradication, defined as lesions that were discovered at least 2 years after the eradication, were prospectively enrolled. Whether the neoplasias arose from acid-secreting or nonacid-secreting areas was evaluated with Congo-red chromoendoscopy. Biopsy specimens taken from the two areas were subjected to histologic evaluation and immunohistochemistry for Ki-67 and p53. The mean period from the eradication to the subsequent occurrence of gastric cancer was 74 (44) months. There were two cancer lesions in 5 cases, and thus there was a total 19 lesions from 14 cases. Congo-red chromoendoscopy revealed that all 19 lesions arose exclusively from non-acid-secreting areas. Histological examination revealed sustained hyperproliferation and accumulation of p53 protein was frequently detectable in non-acid-secreting areas. Genetic alteration such as p53 mutation seems to be already present in the residual non-acid-secreting areas after eradication, areas that could be the origin of gastric carcinogenesis after eradication. Identification of such high-risk areas should be a promising approach for estimating the individual cancer risk after eradication.

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Section: Discussionmentioning

confidence: 99%

Gastric Cancers Emerging after H. pylori Eradication Arise Exclusively from Non-Acid-Secreting Areas

Iijima

Abe

Koike

et al. 2012

Tohoku J. Exp. Med.

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“…The development of gastric cancer is a multistep, sequential process that initiates from chronic gastritis, atrophy, intestinal metaplasia, dysplasia, and finally malignant transformation to invasive gastric cancer. 2 One mechanistic connection between chronic inflammation and gastric cancer may account for the generation of excessive reactive oxygen species (ROS) 3 induced by Helicobacter pylori-infected gastric epithelial cells, 4 activated inflammatory cells, and physical or chemical agents. 3 Low levels of ROS are crucial in maintaining normal cellular physiologic functions, such as proliferation, apoptosis, cell cycle arrest, and senescence; whereas increased levels of ROS induce oxidative stress and cause an imbalanced hemostatic microenvironment, leading to DNA damage, tumorigenesis, and cancer progression.…”

Section: Introductionmentioning

confidence: 99%

Clinical significance of SOD2 and GSTP1 gene polymorphisms in Chinese patients with gastric cancer

Zhu

Luk

et al. 2012

Cancer

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BACKGROUND: Excessive reactive oxygen species (ROS) accumulation is a common phenomenon in carcinogenesis. However, the rationale behind ROS involvement in gastric cancer is unclear. In this study, the authors investigated the clinical significance of the single nucleotide polymorphisms (SNPs) of 2 ROS metabolic process-related genes: superoxide dismutase 2 (SOD2) and glutathione Stransferase p (GSTP1). METHODS: In total of 929 patients with gastric cancer who had definitive clinicopathologic and follow-up data were collected. SOD2 reference SNP 4880 (rs4880) and GSTP1 rs1695 genotyping were examined in DNA samples extracted from paraffin-embedded tumor tissue. Association of the 2 SNPs with each clinicopathologic feature was analyzed using the Pearson chisquare test and the independent Student t test. Gastric cancer-specific overall survival was analyzed using Kaplan-Meier curves and log-rank tests. Multivariate Cox regression analyses of these SNPs also were performed. RESULTS: The SOD2 rs4880 CT þ CC genotypes were significantly associated with a high level of lymph node metastasis (P ¼ .023), whereas the GSTP1 rs1695 GA þ GG genotypes were significantly associated with larger tumor size (>5 cm long; P ¼ .048). Kaplan-Meier and Cox regression data indicated that the SOD2 rs4880 CT þ CC genotypes alone (hazard ratio, 1.299; 95% confidence interval, 1.053-1.603; P ¼ .015) and the GSTP1 rs1695 GA þ GG combined genotypes (hazard ratio, 1.496; 95% CI, 1.078-2.074; P ¼ .016) were independent predictors for overall survival. CONCLUSIONS: The current data, based on a large cohort (n ¼ 929) of Chinese patients with gastric cancer, suggested that the presence of SOD2 rs4880 and GSTP1 rs1695 genotypes may contribute to cancer progression as well as tumor aggressiveness. The components of ROS metabolism pathways may be potential therapeutic targets for this aggressive malignancy.

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“…Indeed, it appears that chronic inflammation stimulates tumor development and plays a critical role in initiating, sustaining and promoting tumor growth. 35,36 Consistent with this hypothesis, many of the receptors and cytokines involved in innate immune responses, such as TNFα, IL-1, IL-6 and IL-8, have also been linked to tumor progression processes.…”

Section: Intestinal Inflammation and Colorectal Cancermentioning

confidence: 74%

Netrin-1, a missing link between chronic inflammation and tumor progression

Paradisi

Mehlen²

2010

Cell Cycle

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N etrin-1, discovered as a neuronal navigation cue, has been recently proposed to play a crucial role during colorectal tumorigenesis by regulating apoptosis. This survival activity is mediated via the inhibition of the so-called netrin-1 dependence receptors. The netrin-1 receptors, DCC (for Deleted in Colorectal Cancer) and UNC5H (UNC5 homologues), indeed belong to the functional family of dependence receptors that share the ability to induce apoptosis in the absence of their ligands and such a trait has been hypothesized to confer these receptors a tumor suppressor activity as their presence render cell survival dependent on ligand availability. As a consequence, human tumors show either a loss of dependence receptors or a gain of netrin-1, allowing tumors to escape this safeguard mechanism. We recently found that netrin-1 is a direct transcriptional target of the transcription factor NFκB, and that a fraction of colorectal tumors show a netrin-1 gain parallel to NFκB activation. Moreover, colorectal cancers from patients affected by inflammatory bowel diseases (IBD) show upregulation of netrin-1. Several evidences suggest a tight link between chronic inflammation and tumorigenesis, mainly through NFκB activation. We propose that induction of netrin-1 expression via NFκB in IBD patients could affect colorectal tumor promotion and progression and that inhibition of netrin-1 could be an innovative target for drug therapy in inflammation-driven colorectal cancers.

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Chronic inflammation, the tumor microenvironment and carcinogenesis

Cited by 226 publications

References 70 publications

Gastric Cancers Emerging after H. pylori Eradication Arise Exclusively from Non-Acid-Secreting Areas

Gastric Cancers Emerging after H. pylori Eradication Arise Exclusively from Non-Acid-Secreting Areas

Clinical significance of SOD2 and GSTP1 gene polymorphisms in Chinese patients with gastric cancer

Netrin-1, a missing link between chronic inflammation and tumor progression

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