interleukin-8 and Rectal-Neoplasms

Radiotherapy is a very effective adjuvant treatment for rectal cancer with little side effects. Its killing effect on tumor cells seems to be more profound than the effect on normal tissue. The molecular events caused by irradiation are mainly analyzed in in vitro and animal models; investigations on human material are rare. In the current study, we analyzed the effects of irradiation on gene expression in normal and tumor tissue of rectal cancer patients.. Normal and carcinoma tissue of patients from a randomized clinical trial of the benefits of preoperative radiotherapy were analyzed using the Affymetrix Human Cancer Gene Chip. Preoperative radiotherapy was given within 5 days prior to surgery. Results for normal tissue and tumor were compared to investigate the radiation-related differences between normal and tumor cells. We clustered the differentially expressed genes based on their functional annotation. Results were compared with immunohistochemical and literature data.. The majority of the investigated cancer-related genes remained unchanged by irradiation (92% in tumor tissue and 93% in normal tissue). The differentially expressed genes varied between tumor and normal tissue except for maspin and IL-8. Both in tumor and normal tissue, differentially expressed genes were present related to cell signaling and cycle control, apoptosis and cell survival and tissue response and repair. However, the spectrum of affected genes was totally different.. Pre-existing differences in gene expression between normal tissue and tumor tissue might explain the differences in their responses to radiation. This change in response may explain the clinical beneficial effect of radiotherapy on tumor cells (low local recurrence rate) and the less severe effects on normal tissue (minor side effects).

Topics: Apoptosis; Cell Adhesion Molecules; Cytokines; Gene Expression; Gene Expression Regulation, Neoplastic; Genes, Tumor Suppressor; Humans; Immunohistochemistry; Interleukin-8; Ki-67 Antigen; Metalloproteases; Oligonucleotide Array Sequence Analysis; Preoperative Care; Prospective Studies; Radiotherapy, Adjuvant; Rectal Neoplasms; Rectum; Serpins

Not all RAS wild-type metastatic colorectal cancer (mCRC) patients experience the same benefit from anti-epidermal growth factor receptor (EGFR) treatments. Studies have shown that nuclear factor-κB (NF-κB), hypoxia-inducible factor-1α (HIF-1α), interleukin 8 (IL-8) and transforming growth factor β (TGF-β) may be therapeutic targets for mCRC. The aim of this study was to clarify the prognostic value of NF-κB, HIF-1α, IL-8, and TGF-β expression in patients with left-sided mCRC receiving EGFR inhibitors.. Patients with RAS wild-type, left-sided mCRC treated with anti-EGFR on the first line between September 2013 and April 2022 were included. Immunohistochemical staining for NF-κB, HIF-1α, IL-8 and TGF-β was performed from tumor tissues of 88 patients. Patients were divided into NF-κB, HIF-1α, IL-8 and TGF-β expression positive and negative group, moreover, expression positive group were also divided into two group as expression intensity low and high group. The median follow-up was 25.2 months.. Median progression-free survival (PFS) was 8.1 (6-10.2) months in the cetuximab group, 11.3 (8.5-14) months in the panitumumab group (p = 0.09). Median overall survival (OS) was 23.9 (4.3-43.4) months in the cetuximab group, 26.9 (15.9-31.9) months in the panitumumab group (p = 0.8). Cytoplasmic NF-κB expression was present in all patients. The mOS was 19.8 (11-28.6) months in NF-κB expression intensity low group and 36.5 (20.1-52.8) months in high group (p = 0.03). The mOS of the HIF-1α expression negative group was significantly longer compared with expression positive group (p = 0.014). There was no significant difference in IL-8 and TGF-β expression status on mOS and mPFS (for all, p > 0.05). Positive expression of HIF-1α was poor prognostic for mOS in the univariate analysis (HR:2.7, 95% CI 1.18-6.52, p = 0.02) and in multivariate analysis (HR 3.69, 95% CI 1.41-9.6, p = 0.008). High cytoplasmic expression intensity of NF-κB was found to have a good prognostic value for mOS (HR 0.47, 95% CI 0.26-0.85, p = 0.01).. High cytoplasmic expression intensity of NF-κB and negative expression of HIF-1α could be a good prognostic marker for mOS in RAS wild-type left-sided mCRC.

Topics: Cetuximab; Colonic Neoplasms; Colorectal Neoplasms; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Interleukin-8; NF-kappa B; Panitumumab; Prognosis; Rectal Neoplasms

Several biomarkers have been established for metastatic colorectal cancer (mCRC). We investigated whether plasma angiogenesis factors could predict the efficacy of biologics combined with chemotherapy in first-line (1L) treatment in patients with RAS wild-type mCRC and the dynamics of plasma angiogenesis factors at progression during 1L treatment.. In this multicenter prospective observational study, serial plasma samples were prospectively collected at pretreatment and progression stages; 17 plasma angiogenesis factors were analyzed using the multiplex assay with Luminex® technology. Interactions between the pretreatment measurements and treatment groups on progression-free survival (PFS) and overall survival (OS) in patients with RAS wild-type were assessed using the propensity-score weighted Cox proportional hazards model.. From February 2018 to September 2020, 202 patients were enrolled in the 1L cohort; 133 patients had RAS wild-type (chemotherapy plus bevacizumab [BEV group, n = 33] and plus anti-epidermal growth factor receptor monoclonal antibodies [aEGFR group, n = 100]). A trend of strong interaction on PFS was observed for interleukin-8 (IL-8) (p = 0.0752) and soluble vascular cell adhesion molecule-1 (sVCAM-1) (p = 0.0156). Regarding OS, IL-8 (p = 0.0283), soluble vascular endothelial growth factor-receptor-1 (sVEGFR-1) (p = 0.0777) and sVCAM-1 (p = 0.0011) tended to differentiate the treatment effect. In 112 patients, plasma samples were evaluable for dynamic analysis (57 and 55 from the BEV and aEGFR groups, respectively). In the BEV group, six factors significantly increased during progression, whereas two decreased. In the aEGFR group, three factors significantly increased, and six decreased.. Pretreatment plasma IL-8 and sVCAM-1 levels could be predictive biomarkers to distinguish BEV and anti-EGFR mAbs when combined with chemotherapy in the 1L treatment of RAS wild-type mCRC. Several plasma angiogenesis factors showed significant change at progression in 1L chemotherapy plus biologics for RAS wild-type mCRC, which are potential biomarkers for selecting an optimal angiogenesis inhibitor in second-line treatment.

Topics: Antibodies, Monoclonal; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Biological Products; Biomarkers; Colonic Neoplasms; Colorectal Neoplasms; Fluorouracil; Humans; Interleukin-8; Rectal Neoplasms; Vascular Endothelial Growth Factor A

Aflibercept plus 5-fluorouracil/levofolinate/irinotecan (FOLFIRI) is a second-line treatment for metastatic colorectal cancer. This ancillary exploratory analysis of data in Japanese people was aimed at exploring the relationship between a set of potential prognostic biomarkers and efficacy endpoints following aflibercept plus FOLFIRI therapy. Sixty-two patients with metastatic colorectal cancer received aflibercept (4 mg/kg) plus FOLFIRI every 2 weeks. Seventy-eight potential protein biomarkers were chosen for analysis based on their roles in angiogenesis, tumor progression, and tumor-stroma interaction. Plasma levels of biomarkers at baseline and at pre-dose 3 (day 1 of treatment cycle 3) were measured in all patients by ELISA. Relationships between these levels and efficacy endpoints were assessed. Ten potential biomarkers had a ±30% change from baseline to pre-dose 3 (adjusted P < .001), with the greatest changes occurring in placental growth factor (median: +4716%) and vascular endothelial growth factor receptor 1 (+2171%). Baseline levels of eight potential biomarkers correlated with overall survival in a univariate Cox regression analysis: extracellular newly identified receptor for advanced glycation end-products binding protein, insulin-like growth factor-binding protein 1, interleukin-8, kallikrein 5, pulmonary surfactant-associated protein D, tissue inhibitor of metalloproteinases 1, tenascin-C, and tumor necrosis factor receptor 2. None correlated with progression-free survival or maximum tumor shrinkage. Pre-dose 3 levels did not correlate with any efficacy endpoints. Preliminary data show that these eight biomarkers could be associated with overall survival. ClinicalTrials.gov identifier: NCT01882868.

Topics: Antineoplastic Combined Chemotherapy Protocols; Asian People; Biomarkers, Tumor; Camptothecin; Colonic Neoplasms; Fluorouracil; Humans; Insulin-Like Growth Factor Binding Protein 1; Interleukin-8; Japan; Kallikreins; Leucovorin; Placenta Growth Factor; Prognosis; Progression-Free Survival; Prospective Studies; Pulmonary Surfactant-Associated Protein D; Receptor for Advanced Glycation End Products; Receptors, Tumor Necrosis Factor, Type II; Receptors, Vascular Endothelial Growth Factor; Recombinant Fusion Proteins; Rectal Neoplasms; Regression Analysis; Tenascin; Tissue Inhibitor of Metalloproteinase-1; Vascular Endothelial Growth Factor Receptor-1

Chemoradiation (CRT) has been shown to lead to downsizing of an important portion of rectal cancers. In order to tailor treatment at an earlier stage during treatment, predictive models are being developed. Adding blood biomarkers may be attractive for prediction, as they can be collected very easily and determined with excellent reproducibility in clinical practice. The hypothesis of this study was that blood biomarkers related to tumor load, hypoxia and inflammation can help to predict response to CRT in rectal cancer.. 295 patients with locally advanced rectal cancer who were planned to undergo CRT were prospectively entered into a biobank protocol (NCT01067872). Blood samples were drawn before start of CRT. Nine biomarkers were selected, based on a previously defined hypothesis, and measured in a standardized way by a certified lab: CEA, CA19-9, LDH, CRP, IL-6, IL-8, CA IX, osteopontin and 25-OH-vitamin D. Outcome was analyzed in two ways: pCR vs. non-pCR and responders (defined as ypT0-2N0) vs. non-responders (all other ypTN stages).. 276 patients could be analyzed. 20.7% developed a pCR and 47.1% were classified as responders. In univariate analysis CEA (p=0.001) and osteopontin (p=0.012) were significant predictors for pCR. Taking response as outcome CEA (p<0.001), IL-8 (p<0.001) and osteopontin (p=0.004) were significant predictors. In multivariate analysis CEA was the strongest predictor for pCR (OR 0.92, p=0.019) and CEA and IL-8 predicted for response (OR 0.97, p=0.029 and OR 0.94, p=0.036). The model based on biomarkers only had an AUC of 0.65 for pCR and 0.68 for response; the strongest model included clinical data, PET-data and biomarkers and had an AUC of 0.81 for pCR and 0.78 for response.. CEA and IL-8 were identified as predictive biomarkers for tumor response and PCR after CRT in rectal cancer. Incorporation of these blood biomarkers leads to an additional accuracy of earlier developed prediction models using clinical variables and PET-information. The new model could help to an early adaptation of treatment in rectal cancer patients.

Topics: Adult; Aged; Aged, 80 and over; Biomarkers, Tumor; Carcinoembryonic Antigen; Chemoradiotherapy; Female; Humans; Interleukin-8; Male; Middle Aged; Multivariate Analysis; Neoplasm Staging; Osteopontin; Predictive Value of Tests; Prognosis; Prospective Studies; Rectal Neoplasms; Reproducibility of Results; Young Adult

Interleukins are a group of cytokines that contribute to growth and differentiation, cell migration, and inflammatory and anti-inflammatory responses by the immune system. In our study, we examined genetic variation in genes from various anti-inflammatory and proinflammatory interleukins to determine association with colon and rectal cancer risk and overall survival. Data from two population-based incident studies of colon cancer (1,555 cases and 1,956 controls) and rectal cancer (754 cases and 954 controls) were used. After controlling for multiple comparisons, single nucleotide polymorphisms (SNPs) from four genes, IL3, IL6R, IL8, IL15, were associated with increased colon cancer risk, and CXCR1 and CXCR2 were significantly associated with increased rectal cancer risk. Only SNPs from genes within the IL-8 pathway (IL8, CXCR1 and CXCR2) showed a significant association with both colon and rectal cancer risk. Several SNPs interacted significantly with IL8 and IFNG SNPs and with aspirin/non-steroidal anti-inflammatory drug (NSAID), cigarette smoking, estrogen use and BMI. For both colon and rectal cancer, increasing numbers of risk alleles were associated with increased hazard of death from cancer; the estimated hazard of death for colon cancer for the highest category of risk alleles was 1.74 (95% confidence interval [CI] 1.18-2.56) and 1.96 (95% CI 1.28-2.99) for rectal cancer. These data suggest that interleukin genes play a role in risk and overall survival for colon and rectal cancer.

Topics: Adult; Aged; Anti-Inflammatory Agents, Non-Steroidal; Aspirin; Biomarkers, Tumor; Body Mass Index; Colonic Neoplasms; Genetic Predisposition to Disease; Genetic Variation; Genotype; Humans; Interferon-gamma; Interleukin-15; Interleukin-3; Interleukin-8; Interleukins; Middle Aged; Polymorphism, Single Nucleotide; Receptors, Interleukin-6; Receptors, Interleukin-8A; Receptors, Interleukin-8B; Rectal Neoplasms; Risk; Risk Factors; Signal Transduction; Smoking

Preoperative clinical diagnosis of lymph node involvement guides treatment decisions for rectal cancer. Unfortunately, clinical staging still suffers from a lack of accuracy.. The aim of this study was to evaluate objective genetic differences in primary rectal cancers with and without associated lymph node metastasis.. cDNA microarrays were generated from fresh-frozen tumors. Normalized data underwent global unsupervised hierarchical clustering analysis, and discriminating genes were mapped. Top discriminating genes were compared between stage II and III rectal cancers by use of an empirical Bayes 2 group t test with the Statistical Analysis of Microarrays and the Reproducibility-Optimized Test Statistic software separately to guide data reduction and deal with the difficulties of simultaneous statistical inference. Ingenuity Pathways Analysis software was used to analyze discriminating genes in terms of function and biological processes.. Fifty-five patients with stage II and 22 patients with stage III rectal adenocarcinomas not treated with chemoradiation were included.. Two major unsupervised clusters emerged representing stage II and III cancers. In 1 cluster, 11 of 12 patients (92%) had stage III cancer; in the other cluster, 54 of 65 patients (83%) had stage II (p < 0.001). Five significantly differentially expressed genes characterized the stage III cluster: interleukin-8, 3-hydroxy-3-methylglutaryl coenzyme A synthase, carbonic anhydrase, ubiquitin, and cystatin (all p < 0.05). Of the 12 patients with differential expression of the 5 marker genes, only one had stage II cancer. Fifty-four of 55 stage II patients clustered with alternative expression patterns of the predictor genes. Differentially expressed genes are related to cancer-associated processes, pathways, and networks.. The identified gene signatures have not yet been validated in independent patient populations.. Distinct gene expression signatures from primary rectal adenocarcinomas can help differentiate the presence or absence of lymph node metastases. These data are informative, and validation of this gene signature may provide a novel approach for more appropriate individualized treatment selection.

Topics: Adenocarcinoma; Aged; Bayes Theorem; Carbonic Anhydrases; Chi-Square Distribution; Cystatins; Female; Gene Expression Regulation, Neoplastic; Humans; Hydroxymethylglutaryl-CoA Synthase; Interleukin-8; Lymphatic Metastasis; Male; Middle Aged; Neoplasm Staging; Oligonucleotide Array Sequence Analysis; Rectal Neoplasms; Software; Statistics, Nonparametric; Ubiquitin

Rectal cancer is often clinically resistant to radiotherapy (RT) and identifying molecular markers to define the biologic basis for this phenomenon would be valuable. The nuclear factor κ-light chain-enhancer of activated B cells (NF-κB) is a potential anti-apoptotic transcription factor that has been associated with resistance to RT in model systems. The present study was designed to evaluate NF-κB activation in patients with rectal cancer undergoing chemoradiotherapy to determine whether NF-κB activity correlates with the outcome in rectal cancer patients.. A total of 22 patients underwent biopsy at multiple points in a prospective study and the data from another 50 were analyzed retrospectively. The pretreatment tumor tissue was analyzed for multiple NF-κB subunits by immunohistochemistry. Serial tumor biopsy cores were analyzed for NF-κB-regulated gene expression using reverse transcriptase polymerase chain reaction and for NF-κB subunit nuclear localization using immunohistochemistry.. Several NF-κB target genes (Bcl-2, cellular inhibitor of apoptosis protein [cIAP]2, interleukin-8, and tumor necrosis factor receptor-associated-1) were significantly upregulated by a single fraction of RT at 24 h, demonstrating for the first time that NF-κB is activated by RT in human rectal tumors. The baseline NF-κB p50 nuclear expression did not correlate with the pathologic response to RT. However, an increasing baseline p50 level was prognostic for overall survival (hazard ratio, 2.15; p = .040).. NF-κB nuclear expression at baseline in rectal cancer was prognostic for overall survival but not predictive of the response to RT. Larger patient numbers are needed to assess the effect of NF-κB target gene upregulation on the response to RT. Our results suggest that NF-κB might play an important role in tumor metastasis but not to the resistance to chemoradiotherapy.

Topics: Adult; Aged; Aged, 80 and over; Combined Modality Therapy; Female; Genes, bcl-2; Humans; Inhibitor of Apoptosis Proteins; Interleukin-8; Male; Middle Aged; Neoplasm Proteins; NF-kappa B; Prognosis; Prospective Studies; Radiation Tolerance; Rectal Neoplasms; Retrospective Studies; TNF Receptor-Associated Factor 1; Treatment Outcome

Stage II and III adenocarcinoma of the rectum has an overall 5-year survival rate of approximately 50%, and tumor recurrence remains a major problem despite an improvement in local control through chemotherapy and radiation. The efficacy of chemoradiation therapy may be significantly compromised as a result of interindividual variations in clinical response and host toxicity. Therefore, it is imperative to identify those patients who will benefit from chemoradiation therapy and those who will develop recurrent disease. In this study, we tested whether a specific pattern of 21 polymorphisms in 18 genes involved in the critical pathways of cancer progression (i.e., drug metabolism, tumor microenvironment, cell cycle regulation, and DNA repair) will predict the risk of tumor recurrence in rectal cancer patients treated with chemoradiation.. A total of 90 patients with Stage II or III rectal cancer treated with chemoradiation were genotyped using polymerase chain reaction (PCR)-based techniques for 21 polymorphisms.. A polymorphism in interleukin (IL)-8 was individually associated with risk of recurrence. Classification and regression tree analysis of all polymorphisms and clinical variables developed a risk tree including the following variables: node status, IL-8, intracellular adhesion molecule-1, transforming growth factor-beta, and fibroblast growth factor receptor 4.. Genomic profiling may help to identify patients who are at high risk for developing tumor recurrence, and those who are more likely to benefit from chemoradiation therapy. A larger prospective study is needed to validate these preliminary data using germline polymorphisms on tumor recurrences in rectal cancer patients treated with chemoradiation.

Topics: Antineoplastic Agents; Cell Cycle; Combined Modality Therapy; Cyclooxygenase 2; Disease Progression; DNA Repair; DNA-Binding Proteins; Endonucleases; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Genes, p53; Genotype; Glutathione S-Transferase pi; Humans; Interleukin-8; Polymorphism, Genetic; Predictive Value of Tests; Rectal Neoplasms; Recurrence; Transforming Growth Factor beta

Animal models and epidemiological observations suggest that a continuous inflammatory condition predisposes to colorectal cancer (CRC), but the roles of different elements participating in inflammatory responses have been little investigated in relation to CRC. We have studied the association between single nucleotide polymorphisms in the interleukin (IL)-6 (-174 G>C), IL8 (-251T>A), tumor necrosis factor alpha (-308G>A), and PPARG (Pro12Ala) genes and the risk of CRC in a group of 377 cases and 326 controls from Barcelona, Spain. These genes are known to be important for inflammation of the colorectum and common allelic variants have been shown to have a biological effect. The PPARG Ala12 and IL8-251A genotypes are associated with reduced risk of disease (0.56, 95% CI, 0.37-0.85, P = 0.0056, and 0.70, 95% CI, 0.50-0.99, P = 0.043, respectively), whereas the IL6-174C genotype is associated with increased risk (1.53, 95% CI, 1.12-2.09, P = 0.0073). We also studied a single nucleotide polymorphism in intron 11 of the NFKB1 gene (rs1020759), which probably lacks any functional role, and found no significant association with the disease. This is the first report that IL6, IL8, and PPARG genes are important in relation to inflammation-related risk of sporadic CRC.

Topics: Aged; Case-Control Studies; Colonic Neoplasms; Colorectal Neoplasms; Female; Genotype; Humans; Inflammation; Interleukin-6; Interleukin-8; Male; Middle Aged; Polymorphism, Genetic; Polymorphism, Single Nucleotide; Receptors, Cytoplasmic and Nuclear; Rectal Neoplasms; Risk Factors; Spain; Transcription Factors; Tumor Necrosis Factor-alpha

To describe the profile of potential chemotaxins C5a, interleukin 8 and tumour-necrosis factor alpha, and the peripheral blood leucocyte (PBL) response in five patients having uncomplicated operations for rectal cancer.. Prospective study.. University hospital, Norway.. Five patients, four men and one woman, median age 66 years (range 48-77) who were operated on for rectal cancer.. Four had low anterior resections and total mesorectal excision (TME) and one patient had a diverting end sigmoidostomy because of local perirectal spread of the cancer and liver metastases. Blood samples were taken at the start of the operation; peroperatively after 1, 2, and 3 hours; postoperatively at 5, 8, and 24 hours, for analysis of potential chemotaxins.. The number of PBL tripled between the start and end of the operation and declined to a slightly lower plateau between 5 and 24 hours. Peroperatively, the association of C5a with PBL increased six-fold resulting in a doubled concentration of C5a/PBL, whereas the corresponding concentration of C5a in plasma remained relatively constant. Postoperatively, the concentration of C5a associated with the PBL and in plasma fluctuated with the maximums being at 8 and 24 hours, respectively. In contrast to C5a in plasma, the concentration of cell-associated C5a correlated with number of PBL or polymorphonuclear leucocytes (PMN). The plasma concentration of IL-8 doubled during the operation, reached a six-fold maximum at 5 hours, and declined after 24 hours to twice the initial concentration. There were no correlations between plasma IL-8 and either number of PBL, plasma C5a, or PBL-associated C5a. No TNF alpha was detected in the plasma.. Tissue trauma caused by uncomplicated excision of rectal cancer leads to leucocyte mobilisation peroperatively, probably partly by complement activation and subsequent generation and binding of the chemotaxin C5a to PBL. However, other chemotaxins may also play a role.

Topics: Aged; Chemotaxis, Leukocyte; Complement C5a; Female; Humans; Interleukin-8; Leukocytes; Male; Middle Aged; Neutrophils; Prospective Studies; Rectal Neoplasms; Tumor Necrosis Factor-alpha