Role Of Inflammation In Carcinogenesis Research Articles

Lipoxygenases at the Intersection of Infection and Carcinogenesis.

The persisting presence of opportunistic pathogens like Pseudomonas aeruginosa poses a significant threat to many immunocompromised cancer patients with pulmonary infections. This review highlights the complexity of interactions in the host's defensive eicosanoid signaling network and its hijacking by pathogenic bacteria to their own advantage. Human lipoxygenases (ALOXs) and their mouse counterparts are integral elements of the innate immune system, mostly operating in the pro-inflammatory mode. Taking into account the indispensable role of inflammation in carcinogenesis, lipoxygenases have counteracting roles in this process. In addition to describing the structure-function of lipoxygenases in this review, we discuss their roles in such critical processes as cancer cell signaling, metastases, death of cancer and immune cells through ferroptosis, as well as the roles of ALOXs in carcinogenesis promoted by pathogenic infections. Finally, we discuss perspectives of novel oncotherapeutic approaches to harness lipoxygenase signaling in tumors.

The Utility of Pre-Treatment Inflammation Markers as Associative Factors to the Adverse Outcomes of Vulvar Cancer: A Study on Staging, Nodal Involvement, and Metastasis Models

Given the role of inflammation in carcinogenesis, this study investigated the utility of pre-treatment inflammatory markers as associative indicators for advanced-stage disease, lymph node metastasis (LNM), and distant metastasis (DM) in vulvar cancer (VC). A cross-sectional study was conducted on 86 women with VC in a single centre in Jakarta, Indonesia. The laboratory data was based on C-reactive protein (CRP), procalcitonin, the erythrocyte sedimentation rate (ESR) and fourteen derived, recorded and calculated ratios: leukocyte-to-platelet (LPR), neutrophil-to-lymphocyte (NLR), derived neutrophil-to-lymphocyte (dNLR), neutrophil-to-monocyte (NMR), platelet-to-monocyte (PLR), lymphocyte-to-monocyte (LMR), basophil-to-monocyte (BLR), systemic immune-inflammation index (SII), body mass index, albumin, and NLR (BAN) score, haemoglobin-to-platelet (HPR), prognostic nutritional index (PNI), modified Glasgow Prognostic Score (mGPS), CRP-to-albumin, and CRP-to-procalcitonin. The optimal cut-off for each marker was determined using receiver operating characteristic (ROC) curve analysis, and their diagnostic indicator performances were assessed. The utility of these ratios as associative factors for three endpoints was further evaluated in multivariate regression models. Investigated inflammatory markers exhibited specific performances for individual adverse outcomes, proving a fair to excellent ability in case finding and screening. After adjustment, the BAN score ≤ 334.89 (OR 9.20, p = 0.001) and ESR ≥ 104 (OR 4.18, p = 0.048) become two advanced-stage associative factors with AUC: 0.769. LNM was solely determined by higher NLR ≥ 2.83 (OR 4.15, p = 0.014) with AUC: 0.615. Meanwhile, BLR ≥ 0.035 (OR 5.67, p = 0.001) and ESR ≥ 84 (OR 6.01, p = 0.003) were contributing factors for DM, with AUC: 0.765. Inflammatory markers are crucial for identifying the deleterious outcomes of VC. Accordingly, yielded models require external validation.

Preoperative neutrophil-lymphocyte ratio/platelet-lymphocyte ratio: A potential and economical marker for renal cell carcinoma.

Emerging evidences have elucidated the crucial role of inflammation in carcinogenesis and tumor progression. In the recent years, many inflammatory biomarkers showed promising prognostic factors in renal cell carcinoma (RCC). We intended to evaluate the significance of one such inflammatory factor which is potential, noninvasive, simple, as well as economical. The preoperative neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) in RCC patients have shown favorable results. The objective was to assess the prognostic role of NLR/PLR in the advanced stage and high-grade RCC. This is a retrospective study. Ethical clearance was obtained from the institute ethics committee. One hundred and fifty histopathologically proven RCC cases during the period of January 2010-September 2018 were chosen from the pathology department and corresponding blood reports were obtained from the medical records department. We divided the cases based on their staging and grading. NLR/PLR values were calculated using formulas. Statistical analysis was done using R software. Data were expressed as mean ± standard deviation, median, and percentage. Independent t-test, Mann-Whitney test, and Chi-square test were used. P < 0.05 was considered statistically significant. The receiver operating characteristic curve (ROC) was plotted to assess the sensitivity of NLR/PLR. The elevated NLR/PLR values showed a significant relation with high-grade and advanced stage RCC. The ROC curve proved the accuracy of NLR/PLR in the advanced stage and high-grade RCC. A multicentric, prospective study can be planned in the future. Follow-up studies are needed to assess their prognostic role. NLR/PLR values can become part of routine investigations for all RCC patients. The values may help to estimate pathological outcomes, chance of recovery, recurrence, and survival rates.

Lung carcinomas induced by NNK and LPS.

Cigarette smoking is the major culprit of chronic lung diseases and the most dominant risk factor for the development of both lung cancer and chronic obstructive pulmonary disease (COPD). In addition, chronic inflammation has been shown to increase the risk of lung cancer and COPD in clinical and epidemiological studies. For pulmonary disease-related research, mice are the most commonly used model system. Multiple lung cancer mouse models driven by targeted genetic alterations are used to evaluate the critical roles of oncogenes and tumor suppressor genes. These models are useful in addressing lung tumorigenesis associated with specific genetic changes, but they are not able to provide a global insight into cigarette smoke-induced carcinogenesis. To fill this knowledge gap, we developed a lung cancer model by treating mice with cigarette smoke carcinogen nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) with/without repeated lipopolysaccharides (LPS) exposure in order to determine the role of chronic inflammation in lung tumorigenesis. Notably, combined LPS/NNK treatment increased tumor number, tumor incidence, and tumor area compared to NNK treatment alone. Therefore, this model offers a feasible approach to investigate lung cancer development on a more global level, determine the role of inflammation in carcinogenesis, and provide a tool for evaluating chemoprevention and immunotherapy.

Prognostic Value of Neutrophil to Lymphocyte Ratio in Patients Who Received Defintive Radiation Therapy for Head and Neck Squamous Cell Carcinoma

With growing evidence on the role of inflammation in carcinogenesis, the presence of a systemic inflammatory response has been proposed as having prognostic significance in a wide range of cancers. The purpose of this study was to investigate the prognostic value of pre-treatment neutrophil/lymphocyte ratio (NLR) in head and neck squamous cell carcinoma (HNSCC) patients treated with definitive radiotherapy (RT). We retrospectively analyzed 498 patients with stage I-IVB HNSCC including oral cavity, nasopharyngeal, oropharyngeal, hypopharyngeal and laryngeal cancer who received definitive RT with (62.7%) or without (37.3%) chemotherapy between 2006 and 2015. The median age of all patients was 60 years. Patients with high NLR had more advanced stage (p<0.001) and they received induction or concurrent chemotherapy more frequently (76.2% vs. 52.5%, p <0.001). progression free survival (PFS) and overall survival (OS) were calculated by the Kaplan-Meier method and compared by the log-rank test. Cox’s regression model was used for multivariate analysis of selected variables (p<0.05 in univariate analysis) as prognostic factors. The median follow up time was 38 months and 5-year PFS and OS for all patients were 62.3% and 72.1%. With NLR >2.7 considered as high according to receiver operating characteristic curve using PFS as an endpoint, 172 patients had a high NLR. Patients with high NLR showed significantly higher regional failure rate (37.8% vs, 28.6%, p <0.001) while incidence of local and distant failure were comparable to those with low NLR. PFS and OS were significantly lower in high NLR patients (5-year PFS 39.7% vs. 74.8%; 5-year OS. 51.0% vs. 83.7%, p <0.001, respectively). In subgroup analysis according to subsite of HNSCC, patients with high NLR showed significantly better PFS and OS in oral cavity, nasopharyngeal, hypopharyngeal and laryngeal cancer as well, while difference between two groups showed borderline significance in oropharyngeal cancer. In multivariate analysis, high NLR still remained as a independent prognostic factor for PFS and OS (HR for PFS 2.863, 95% CI 1.755-4.670, p<0.001; HR for OS 2.863, 95% CI 1.755-4.670, p<0.001). The patients with high NLR showed poorer survival and different patterns of failure. The optimal therapeutic approaches should be considered for these patients.

INFLAMMATION AS A THERAPEUTIC TARGET IN THE COMPLEX TREATMENT OF MALIGNANT TUMORS

In this review, we analyzed the role of inflammation in carcinogenesis, tumor development, and metastasis. In addition, the mechanisms of non-steroidal anti-inflammatory drugs (NSAIDs) and the reasons of their contradictory influence on cancers were discussed. We summarized the numerous data about effectiveness of anti-inflammatory drugs for the prevention and additional therapy of tumor diseases. In particular, divergent effects of NSAIDs may be due to the peculiarities of immune-inflammatory responses that are realized in carcinogenesis and tumor development that have yet to be studied. We also discussed the selectivity of NSAID effects on different cancers and opposite effects of anticancer drugs with similar mechanisms of action. Apparently, the unsuccessful use of NSAIDs in cancer prevention and therapy are more specific for squamous cell carcinomas. Based on the literature, we provided significant clinical findings regarding the need of NSAID use in the current therapy of certain cancers and the determination of molecular predictors of the drug effect. In fact, anti-inflammatory therapy could eliminate the factors that contribute to the appearance of invasive and metastatic tumor cells, cancer and premetastatic niches and thus prevent metastasis and recurrence. At present, some non-selective (aspirin) and selective (celecoxib) NSAIDs are highly promising in the therapy of solid tumors.

A prospective follow-up study of the relationship between C-reactive protein and human cancer risk in the Chinese Kailuan Female Cohort.

C-reactive protein (CRP) has been associated with cancer risk in some prospective studies. However, the associations have not been entirely consistent and have not been evaluated in Chinese females. We conducted a large population-based cohort study to investigate whether elevated levels of CRP at baseline are associated with an increased risk of cancer among Chinese females. A total of 19,437 women from the Chinese Kailuan Female Cohort were enrolled in the study in July 2006. Levels of high-sensitivity CRP (hsCRP) were tested at baseline for all subjects. Multivariable Cox proportional hazards regression models were used to evaluate the association between levels of hsCRP and risk of all cancers, including breast cancer, lung cancer, colorectal cancer, and other cancers. By December 31, 2011, a total of 322 incident cancer cases accrued. Compared with women with lower hsCRP levels (<1 mg/L), women with higher hsCRP (>3 mg/L) had a significantly increased risk of all incident cancers [HR, 1.62; 95% confidence intervals (CI), 1.23-2.14; P(trend) = 0.001] and breast cancer (HR, 1.74; 95% CI, 1.01-2.97; P(trend) = 0.047). The significant association between hsCRP levels and breast cancer risk was apparent among younger women (<50 years; HR, 2.76; 95% CI, 1.18-6.48). Elevated levels of hsCRP at baseline may be associated with an increased risk of cancer, especially breast cancer, and particularly in younger Chinese women. Our findings provide additional evidence for a role of inflammation in carcinogenesis and suggest that CRP may be a potentially useful biomarker of cancer risk in this population.

Mononuclear cells phagocytic activity affects the crosstalk between immune and cancer cells

The “professional phagocytes”, i.e. monocytes and macrophages, play an important role as eliminators of pathogens and as essential components of the immune system. It is well established that monocytes induced for phagocytosis by various stimulators, produce cytokines that are closely related to inflammation. Considering the role of inflammation in carcinogenesis and the existence of an immune dialog between mononuclear and cancer cells, the aim of the present work was to examine cytokine production by immune cells stimulated for phagocytosis by latex particles and incubated with cells from HT-29 and RKO human cancer lines. Human peripheral blood mononuclear cells (PBMC) were incubated with various numbers of polysterene latex beads, 0.8μm in diameter and the secretion of the following cytokines: TNF-α, IL-1β and IL-6, IL-10 and IL-1ra was examined before and after further incubation with cells of the both cancer lines. Phagocytosis of latex beads by PBMC caused an increased production of TNF-α, IL-1β and IL-10, whereas that of IL-6 declined. PBMC activated by latex beads and co-cultured with cancer cells generated lesser amount of the three pro-inflammatory cytokines TNF-α, IL-1β and IL-6, while that of the anti-inflammatory IL-10 and IL-1ra remained unchanged. The results indicate that phagocytosis of polystyrene latex beads by human PBMC alters the dialogue between immune and cells of human colon carcinoma lines, an observation that may clarify the role of the immune cells in attenuating inflammation and restraining carcinogenesis.

Gist of Dr. Katsusaburo Yamagiwa's papers entitled "Experimental study on the pathogenesis of epithelial tumors" (I to VI reports).

The concept of cancer and inflammation has a long history. Virchow's irritation theory based on human cancer engendered the essential role of inflammation in carcinogenesis. Drs. Yamagiwa and Ichikawa first published a comprehensive paper entitled “Experimental study on the pathogenesis of epithelial tumors” (I report) in 1915 in German, and went on to publish five more reports (1915–1924) under the same title. They succeeded in demonstrating that inflammation is an important carcinogenic factor, and the mechanisms are now being investigated by numerous scientists all over the world. In order to introduce Yamagiwa's work to modern cancer researchers, the essentials of their six reports have been translated into English as a short review. Scientists' comments on Yamagiwa's contribution are attached by way of introduction.

High neutrophil-to-lymphocyte ratio is an independent marker of poor disease-specific survival in patients with oral cancer

With growing evidence on the role of inflammation in carcinogenesis, the presence of a systemic inflammatory response has been proposed as having prognostic significance in a wide range of cancers. The aim of the study was to assess the value of pretreatment neutrophil-to-lymphocyte ratio (NLR) in predicting disease-specific survival (DSS) in patients with oral cancer undergoing preoperative chemoradiotherapy. A cohort of 97 patients with locally advanced oral squamous cell carcinoma receiving preoperative chemoradiotherapy was retrospectively examined. The impact of NLR and other potential prognostic factors on DSS was assessed with the Kaplan-Meier method and multivariate Cox regression analysis. Sixty-nine patients had a high pretreatment NLR, with NLR > 1.9 considered as high according to receiver operating characteristic curve analysis. In univariate analysis, high pretreatment NLR (p = 0.018), positive perineural invasion (p < 0.001) and advanced pathologic TNM stage after neoadjuvant therapy (p < 0.001) were predictive of shorter DSS. In multivariate analysis, advanced pathologic TNM stage after neoadjuvant therapy (HR 1.71, 95 % CI 1.17-2.48, p = 0.005), positive perineural invasion (HR 3.67, 95 % CI 1.11-12.13, p = 0.033) and high pretreatment NLR (HR 10.37, 95 % CI 1.28-84.08, p = 0.029) remained independently associated with poor DSS. A high pretreatment NLR is a significant independent predictor of shorter DSS in patients with oral cancer receiving preoperative chemoradiotherapy.

1α,25-dihydroxyvitamin D3 modulates the interaction between immune and colon cancer cells

Following observations indicating the existence of a relationship between immune and cancer cells in the course of tumor development, it was the aim of the study to establish the role of 1α,25-dihydroxyvitamin D3 (vit. D) in the functional equilibrium between cells from two human colon carcinoma lines-induced cytokine production by peripheral blood mononuclear cells (PBMC). PBMC were incubated with HT-29 and RKO human colon cancer cells with and without vit. D at final concentrations of 10−8, 10−7 or 10−6M. The production of the cytokines TNF-α, IL-6 and IL-10, as well as the effect of the vitamin on tumor cell proliferation were evaluated. Incubation of PBMC with either HT-29 or RKO cells caused a significant stimulation of both pro- and anti-inflammatory cytokine generation. Addition of vit. D to the incubation mixture containing PBMC and cells of both colon carcinoma lines caused a marked inhibition of the generation of the pro-inflammatory cytokines TNF-α and IL-6 and to a lesser extent–of the IL-10. Vit. D did not affect the proliferation of the cancer cells. The results indicate the existence of a functional “dialog” between immune and cancer cells expressed by an alteration of their capacity for cytokine production and support the role of inflammation in carcinogenesis. The ability of vit. D to attenuate production of the pro-inflammatory cytokines when added to the incubation mixture containing PBMC and cancer cells endorses observations as for the beneficial role of the vitamin in suppressing inflammation with subsequent colon cancer prevention.

Is 15-LOX-1 a Tumor Suppressor?

A number of enzymes in the cyclooxygenase and lipoxygenase pathways process fatty acids to generate a variety of bioactive lipids. Recent findings that link inflammation to carcinogenesis have started to reveal how these bioactive lipids function in cellular signaling pathways as lipid messengers that mediate responses to cellular injury through inflammatory processes (1). Downstream effects of these bioactive lipids are determined by tissue-specific isomerases and specific receptors present in different organs. Two main pathways lead to the generation of bioactive lipids, which differ markedly in their biological activities. The cyclooxygenases lead mostly to the generation of prostaglandins and thromboxanes, whereas the lipoxygenases lead to the formation of leukotrienes and lipoxins among other products (Figure 1). Collectively, these signaling 20-carbon fatty acids are termed eicosanoids. They act by autocrine and paracrine mechanisms to regulate the dynamics of inflammation, immunity, and smooth muscle contraction and as messengers in the central nervous system (1,2). It is not surprising that many of these bioactive molecules play a critical role in inflammation, but their opposing functions are often underappreciated. The role of inflammation in carcinogenesis is well established and has been summarized by Wang and Dubois (1); however, important questions remain. It is still not clear which specific component(s) or which phase(s) of the inflammatory process are involved in carcino genesis or at which stage of carcinogenesis the primary effects of inflammation occur. Furthermore, the key question of whether inflam mation alone is sufficient and necessary to promote carcinogenesis in some settings is still unanswered. If so, a strategy that reverses inflam mation might be used to prevent and treat some types of cancer. Unsaturated fatty acids and metabolites of arachidonic and linoleic acids form bioactive lipids that function in the initiation, maintenance, and resolution of inflammation. Colorectal epithelium may be espe cially susceptible to the effects of bioactive lipids because of its direct proximity to their dietary sources. Lipoxygenases are lipid-peroxidizing enzymes that catalyze the dioxygenation of polyunsaturated fatty acids. More work is needed to fully understand the complex nature of these bioactive lipids in diverse biologic processes, but more and more evidence is emerging that suggests that lipoxygenases have many important roles in human diseases including cancer. Two different 15-lipoxygenase enzymes, 15-LOX-1 and 15-LOX-2, are found in humans, with distinct expression patterns throughout the body. The functions of the 15-LOX-1 enzyme and its products, 15-S-hydroxyeicosatetraenoic acid (15-S-HETE) and 13-S-hydroxyoctadecadienoic acid (13-S-HODE), are diverse; reportedly, they are chemoattractants for neutrophils (3), inhibit the production of superoxide by macrophages, affect the expression of adhesion molecules (4), and inhibit nuclear factor-kB (NF-kB), whereas they activate peroxisome proliferator–activated receptorg (PPAR-g) (5). Expression of 15-LOX-1 in cancer cell lines has

Das hepatozelluläre Karzinom – von der Immunbiologie zur Immuntherapie

Hepatocellular carcinoma (HCC) is the fifth most common malignancy worldwide with an increasing incidence. The clinical outcome is influenced by the underlying liver cirrhosis, the size of the tumour at the time of diagnosis and the few therapeutic options currently available. In recent years there has been a lot of progress in the understanding of HCC immunobiology. This review summarizes our current knowledge of HCC biology, the role of chronic inflammation in carcinogenesis and the role of tumour-specific immune responses. Furthermore, we will present potentially new, immune-based therapies that might open up new avenues for the treatment of HCC.

Detouring the Undesired Route of Helicobacter pylori-Induced Gastric Carcinogenesis

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.

Targeting the inflammation in HCV-associated hepatocellular carcinoma: a role in the prevention and treatment

Epidemiological, preclinical and clinical studies demonstrated that chronic inflammation induced by hepatitis C virus (HCV) is crucial in hepatocellular carcinogenesis. The interaction between hepatocytes and microenvironment regards virus, inflammatory and immunocompetent cells, chemo- and cyto-kines, reactive oxygen species (ROS) and nitric oxide (NO), generating cell transformation. We suggest hepatocarcinoma (HCC) as a model in which the targeting of microenvironment determine neoplastic transformation. The present review focuses on: the role of inflammation in carcinogenesis, the clinical impact of HCC and the inadequacy of the actual therapy, the chemoprevention targeting the microenvironment.

Endotoxin and Cancer

ObjectiveExposure to endotoxin, a component of gram-negative bacterial cell walls, is widespread in many industrial settings and in the ambient environment. Heavy-exposure environments include livestock farms, cotton textile facilities, and saw mills. Concentrations are highly variable in non-occupational indoor and outdoor environments. Endotoxin is a potent inflammagen with recognized health effects, including fever, shaking chills, septic shock, toxic pneumonitis, and respiratory symptoms. Somewhat paradoxically, given the putative role of inflammation in carcinogenesis, various lines of evidence suggest that endotoxin may prevent cancer initiation or limit tumor growth. The hypothesis that components of bacteria may retard cancer progression dates back to William B. Coley’s therapeutic experiments (“bacterial vaccine”) in the 1890s.Data sourcesIn this article, we review epidemiologic, clinical trial, and experimental studies pertinent to the hypothesis that endotoxin prevents cancer. Since the 1970s, epidemiologic studies of cotton textile and other endotoxin-exposed occupational groups have consistently demonstrated reduced lung cancer risks. Experimental animal toxicology research and some limited therapeutic trials in cancer patients offer additional support for an anticarcinogenic potential. The underlying biological mechanisms of anticarcinogenesis are not entirely understood but are thought to involve the recruitment and activation of immune cells and proinflammatory mediators (e.g., tumor necrosis factor α and interleukin-1 and -6).ConclusionsIn view of the current state of knowledge, it would be premature to recommend endotoxin as a cancer-chemopreventive agent. Nonetheless, further epidemiologic and experimental investigations that can clarify further dose–effect and exposure–timing relations could have substantial public health and basic biomedical benefits.

Inflammation: its role and interplay in the development of cancer, with special focus on gynecological malignancies

The relationship between inflammation and cancer is intriguing. Mechanisms contributing to the pathobiology of carcinogenesis are multiple and complex. Many aspects still elude researchers and are subjects of intense speculation and debate, for example, the triggering factor for malignant transformation in inflammation. A comprehensive literature search was conducted from the Web sites of the National Library of Medicine and Pubmed Central, the US National Library of Medicine's digital archive of life sciences literature. The data were accessed from books and journals that published recent articles in this field. Several recent studies have identified nuclear factor-kappa B as a key modulator in driving inflammation to cancers. An inflammatory microenvironment inhabiting various inflammatory cells and a network of signaling molecules is essential for the malignant progression of transformed cells. This is attributed to the mutagenic predisposition of persistent infection-fighting agents at sites of chronic inflammation. The appreciation of the role of inflammation in carcinogenesis provides a mechanistic framework to understand clinical benefits of newer therapeutic strategies An in-depth knowledge about various pathogenic mechanisms involved in cancer will help clinicians in better management of the disease.

Expression of COX-2 in Normal and Pyelonephritic Kidney, Renal Intraepithelial Neoplasia, and Renal Cell Carcinoma

ObjectivesThe role of inflammation in carcinogenesis is unknown. To determine the relationship between cyclooxygenase 2 (COX-2) expression, inflammation, and carcinogenesis in human renal cell carcinoma (RCC), we looked for COX-2 expression in normal and pyelonephritic kidney, renal intratubular neoplasia (RIN), and RCC tissues. MethodsCOX-2 expression was assessed immunohistochemically in tissues obtained from 20 pyelonephritic kidneys, 16 normal kidneys, 19 RIN, and 75 RCC cases. ResultsCOX-2 expression was found to be positive in 64% of RCCs. It was positive in 13 chronic pyelonepritic (65%), 9 normal (56%), and 15 RIN (79%) cases. COX-2 expression was significantly higher in RCC and RIN than the normal and pyelonepritic cases (p<0.001 and p<0.001, respectively). No statistically significant difference was noted between RCC and RIN cases. ConclusionsAlthough the function of COX-2 in tumor development has not been exactly elucidated, the increased expression of COX-2 in RIN and RCC might be a factor that may play a role in the development of RIN or progression to RCC, which warrants further research.

Gene Expression Profiling Reveals Cross-talk between Melanoma and Fibroblasts: Implications for Host-Tumor Interactions in Metastasis

Host-tumor interaction is considered critical in carcinogenesis, tumor invasion, and metastasis. To explore the reciprocal effects of host-tumor interaction, we developed a system to assess the gene expression patterns of A2058 human melanoma cells cocultured in fibrillar collagen with HS-68 primary human fibroblasts. The gene expression pattern of the cocultured A2058 cells was only modestly affected, whereas the HS-68 fibroblast gene expression pattern was significantly altered. Interleukin-11 and inhibitor of DNA-binding domain-1 gene expression in the cocultured A2058 cells was down-regulated, indicative of a proinflammatory response and resistance to apoptosis, respectively. The overall pattern of up-regulated genes indicated triggering of the proinflammatory process. In addition, the melanoma growth and migration stimulatory chemokines CXCL1 and CXCL2 were significantly up-regulated in the cocultured fibroblasts. These results were corroborated by additional coculture experiments with the melanoma cell lines WM-164, BLM, and SK-Mel-28 and immunohistochemistry on invasive human melanoma sections. Taken together, these results indicate that tumor cells cause a proinflammatory and melanoma growth-promoting response in stromal fibroblasts. The role of inflammation in carcinogenesis, tumor promotion, invasion, and metastasis is viewed as being increasingly important and the results of these studies underscore this as well as identify certain key proteins that are expressed as a result of the complex interactive processes in the host-tumor microenvironment.

Polymorphisms of interleukin (IL)-1α, IL-1β, IL-6, IL-10, and IL-18 and the risk of ovarian cancer

Objective. Recent studies of ovarian cancer have suggested a role for inflammation in carcinogenesis. Data from a population-based case-control study in Hawaii were examined to assess the relation between polymorphisms in cytokines involved with the inflammatory response, specifically members of the interleukin (IL) family and the incidence of ovarian cancer. Patients and methods. The analysis of 182 epithelial ovarian cancer cases and 219 controls focused on the polymorphisms in the following genes: IL-1α, IL-1β, IL-6, IL-10, and IL-18. Genotype data were obtained from blood samples collected in participants' homes, and reproductive, demographic, and lifestyle histories were collected during interview. Results. There were no significant odds ratios (ORs) for ovarian cancer by allelic variants in any of the IL genes after adjusting for age, ethnicity, education, oral contraceptive pill use, pregnancy, and history of tubal ligation. Although there was a significantly reduced risk of ovarian cancer risk among women with an IL-1α (− 4845) T allele compared to women with two G alleles (OR: 0.59; 95% confidence interval: 0.37–0.97) after adjustment for age and ethnicity, the trend was not significant ( p = 0.10). Further examination of the data suggested that women with at least one IL-18 variant allele (a G to C transition at position −137) were at significantly decreased risk of advanced ovarian cancer (OR: 0.51; 95% confidence interval: 0.28–0.90) compared to women with the IL-18 GG genotype. There was a significant difference in the risk of ovarian cancer associated with the IL-18 C allele by stage at diagnosis ( p = 0.04 for homogeneity in the ORs): cases with IL-18 GC or CC genotypes were less likely to be diagnosed at regional/distant stages. Analysis of the data within ethnic subgroups revealed a significant positive association of the heterozygous IL-18 GC genotype with ovarian cancer risk among Native Hawaiian women (OR: 9.96; 95% CI: 1.88–52.90). The OR for ovarian cancer was not significant for Native Hawaiian women homozygous for the IL-18 C allele, but only one case and control had the IL-18 CC genotype. Conclusions. Overall, this study does not support an association of selected IL-1α, IL-1β, IL-6, IL-10, or IL-18 polymorphisms with the risk for ovarian cancer. However, the IL-18 G137C variant may be a marker for ovarian cancer progression or metastasis.