Colorectal Tumor Progression Research Articles

Immediate Postablation 18F-FDG Injection and Corresponding SUV Are Surrogate Biomarkers of Local Tumor Progression After Thermal Ablation of Colorectal Carcinoma Liver Metastases.

The aim of this study was to determine whether intraprocedural 18F-FDG PET/CT can be used as a predictor of local tumor progression after percutaneous ablation of colorectal liver metastases. Methods: In this institutional review board-approved prospective study, 39 patients (19 men and 20 women; median age, 56 y) underwent split-dose 18F-FDG PET/CT-guided ablation followed by immediate biopsy and contrast-enhanced CT imaging of the ablation zone. Binary categorization of biopsy tissues was performed on the basis of the presence of only nonviable coagulation necrosis or viable tumor cells. Minimum ablation margin measurements from contrast-enhanced CT imaging were categorized as 0 mm, 1-4 mm, 5-9 mm, or greater than or equal to 10 mm. SUVs were obtained from PET/CT imaging, and SUV ratios were calculated from 3-dimensional regions of interest located in the ablation zone and surrounding normal liver. All predictive variables (biopsy, minimum margin distance, and SUV ratio) were evaluated as predictors of time to local tumor progression identified on imaging using competing-risks regression models (uni- and multivariate analyses). Results: A total of 62 consecutive ablations were evaluated. The mean SUV ratio was significantly higher for viable tumor-positive immediate postablation biopsies (n = 10) than for tumor-negative biopsies (n = 52) (85.8 ± 92.2 vs. 42.3 ± 45.5) (P = 0.03) and for a minimum margin size of less than 5 mm (n = 15) than for a minimum margin size of greater than or equal to 5 mm (n = 47) (78.5 ± 99.1 vs. 38.3 ± 78.5) (P = 0.01). After a median follow-up period of 22.5 (range, 7-52) months, 23 of 62 ablated tumors showed local tumor progression (37.1%). The local tumor progression rate was significantly higher for viable tumor-positive biopsies (8/10) than for negative biopsies (15/52) (80% vs. 29%) (P = 0.001) and for a minimum margin size of less than 5 mm (9/15) than for a minimum margin size of greater than or equal to 10 mm (2/15) (60% vs. 13%) (P = 0.02) but not 5-9 mm (37.5%; 12/32) (P = 0.5). In a competing-risks analysis, biopsy results (P = 0.07) and the minimum margin size (P = 0.08) were borderline significant, but the SUV ratio was not (P = 0.22). However, for negative biopsy ablations, the minimum margin size and SUV ratio were predictive imaging factors for local tumor progression; subdistribution hazard ratios were 0.564 (0.325-0.978) (P = 0.04) and 1.005 (1.001-1.009) (P = 0.005), respectively. Conclusion: The SUV ratio and minimum margin size can independently predict colorectal metastasis local tumor progression after liver ablation when there are no viable tumor cells on immediate postablation biopsies.

Intertwining DNA-RNA nanocapsules loaded with tumor neoantigens as synergistic nanovaccines for cancer immunotherapy

Nanomedicines that co-deliver DNA, RNA, and peptide therapeutics are highly desirable yet remain underdeveloped for cancer theranostics. Herein, we report self-assembled intertwining DNA-RNA nanocapsules (iDR-NCs) that efficiently delivered synergistic DNA CpG and short hairpin RNA (shRNA) adjuvants, as well as tumor-specific peptide neoantigens into antigen presenting cells (APCs) in lymph nodes for cancer immunotherapy. These nanovaccines were prepared by (1) producing tandem CpG and shRNA via concurrent rolling circle replication and rolling circle transcription, (2) self-assembling CpG and shRNA into DNA-RNA microflowers, (3) shrinking microflowers into iDR-NCs using PEG-grafted cationic polypeptides, and (4) physically loading neoantigen into iDR-NCs. CpG and shRNA in iDR-NCs synergistically activate APCs for sustained antigen presentation. Remarkably, iDR-NC/neoantigen nanovaccines elicit 8-fold more frequent neoantigen-specific peripheral CD8+ T cells than CpG, induce T cell memory, and significantly inhibit the progression of neoantigen-specific colorectal tumors. Collectively, iDR-NCs represent potential DNA/RNA/peptide triple-co-delivery nanocarriers and synergistic tumor immunotherapeutic nanovaccines.

Filamin A upregulation correlates with Snail-induced epithelial to mesenchymal transition (EMT) and cell adhesion but its inhibition increases the migration of colon adenocarcinoma HT29 cells

Filamin A (FLNA) is actin filament cross-linking protein involved in cancer progression. Its importance in regulating cell motility is directly related to the epithelial to mesenchymal transition (EMT) of tumor cells. However, little is known about the mechanism of action of FLNA at this early stage of cancer invasion.Using immunochemical methods, we evaluated the levels and localization of FLNA, pFLNA[Ser2152], β1 integrin, pβ1 integrin[Thr788/9], FAK, pFAK[Y379], and talin in stably transfected HT29 adenocarcinoma cells overexpressing Snail and looked for the effect of Snail in adhesion and migration assays on fibronectin-coated surfaces before and after FLNA silencing.Our findings indicate that FLNA upregulation correlates with Snail-induced EMT in colorectal carcinoma. FLNA localizes in the cytoplasm and at the sites of focal adhesion (FA) of invasive cells. Silencing of FLNA inhibits Snail-induced cell adhesion, reduces the size of FA sites, induces the relocalization of talin from the cytoplasm to the membrane area and augments cell migratory properties. Our findings suggest that FLNA may not act as a classic integrin inhibitor in invasive carcinoma cells, but is involved in other pro-invasive pathways. FLNA upregulation, which correlates with cell metastatic properties, maybe an additional target for combination therapy in colorectal carcinoma tumor progression.

Abstract 2690: MK2 pathway blockade inhibits inflammatory cytokine production and colorectal cancer growth and invasion

Abstract Introduction: Colorectal cancer is the third most common malignancy diagnosed for both men and women in the United States of America. High levels of inflammatory cytokines in colorectal tumors cause increased growth and invasion and carry a higher risk of metastasis. Identifying new targets to control inflammation is important for developing improved treatment approaches. Mitogen-activated protein kinase-activated protein kinase 2 (MK2) is a regulator of pro-inflammatory cytokines that may promote colorectal tumor progression. MK2 signaling is known to induce IL-1, IL-6, and TNF-α production. These pro-inflammatory cytokines are associated with CRC development, invasion, and metastasis. We hypothesized that the MK2 pathway could be an important component of CRC growth, invasion and tumor regrowth. Methods: To investigate this pathway, CT26 CRC cells were examined. Cells were flank-injected into Balb/c mice with and without MK2 inhibitor treatment. At day 19 after tumor injection, tumors were harvested and measured using calipers. Cytokines were quantitated by multiplex bead array in organ culture supernatants and in supernatants from tumor cells plated in fibronectin coated wells. In culture, tumor cell invasion was measured in scratch wound assays containing matrigel. Results: Treating CT26 cells with MK2 inhibitors markedly reduced tumor growth in mice by a mean of 60% compared to vehicle control treated cells. Inflammatory cytokines were also dramatically decreased with MK2 inhibition compared to controls by up to 80%. Cytokines affected included both known MK2 downstream cytokines (IL-1, IL-6, and TNF-α) and also chemokines such as MIP-1α and MCP-1 in both supernatants from cultured tumor cells and in organ culture supernatants. MK2 inhibition also decreased invasion of tumor cells in a cytokine dependent manner. Conclusions: The MK2 pathway regulates production of multiple pro-inflammatory cytokines in colorectal tumors, including several previously unreported chemokines. Inhibition of this pathway markedly decreases tumor growth and invasion. Thus, MK2 may be a promising tumor target to prevent colorectal cancer progression. Citation Format: Anita L. Ray, Amanda S. Peretti, Wade Johnson, Gregory Gan, Ellen J. Beswick. MK2 pathway blockade inhibits inflammatory cytokine production and colorectal cancer growth and invasion [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2690. doi:10.1158/1538-7445.AM2017-2690

Detection of BRAF Gene in Some Iraqi Bowel Inflammation and Colorectal Cancer Patients

The impacts of the inflammatory process on neoplasia development were observed in many cancer, it has a great role in the etiology, development and progression of invasive colorectal tumors. This study was designed to investigate the BRAF mutation and assist the clinicopathological parameter in some Iraqi bowel inflammation and colorectal cancer patients. Thirty patients were enrolled in this study (15 suffering bowel inflammation and 15 having colorectal cancer). BRAF gene was screened for the presence of mutations using PCR technique and direct sequencing. .The results revealed no BRAF mutation in position 1799 for exon fifteen in both samples of bowel inflammation and colorectal cancer. These results were confirmed previous articles regarding low rate of BRAF gene mutation in Asian countries. These results indicate the possibility of colorectal patients treatment with monoclonal antibodies. Several heterogeneity mutations were found in 3 out of 30 patients (10%) including transition two mutations G>A and one mutation was transversion mutation A>T in different sites as silent mutations

Su1825 - MecP2-Mediated Epigenetic Silencing of miR-137 Contributes to Colorectal Adenoma-Carcinoma Sequence and Tumor Progression via Relieving the Suppression of C-met

Su1825 - MecP2-Mediated Epigenetic Silencing of miR-137 Contributes to Colorectal Adenoma-Carcinoma Sequence and Tumor Progression via Relieving the Suppression of C-met

Mecp2-mediated Epigenetic Silencing of miR-137 Contributes to Colorectal Adenoma-Carcinoma Sequence and Tumor Progression via Relieving the Suppression of c-Met

The molecular mechanisms underlying colorectal cancer (CRC) development remain elusive. In this study, we examined the miRNA and mRNA expressions in the adenoma-carcinoma sequence (ACS), a critical neoplastic progression in CRC development. We found that miR-137 was down-regulated in all adenoma and carcinoma tissues. Low miR-137 levels were correlated negatively with tumor progression and metastasis. Then we identified the inhibition effect of the miR-137 in CRC development, both in CRC cell lines and mouse models. MiR-137 was shown to control CRC cell proliferation, colony formation, migration and invasion and to control tumor growth and metastasis. We further confirmed the negative association between miR-137 and c-Met expression and thus validated this important oncogene as the target of miR-137 in CRC. In addition, we found a DNA methyl-CpG-binding protein, Mecp2, was up-regulated in ACS tissues via mRNA sequencing. Further experiment showed that miR-137 expression in CRC was subjected to epigenetic regulation mediated by Mecp2. We also confirmed c-Met expression can be up-regulated by silencing of miR-137 and suppressed by coexpression of Mecp2 and miR-137. These findings highlight the critical role of miR-137-c-Met nexus in CRC development and reveal Mecp2-regulated epigenetic silence causes the downregulation of miR-137 in colorectal adenoma and carcinoma.

Pharmacological inhibition of MAGL attenuates experimental colon carcinogenesis

Colorectal cancer (CRC) is a major health problem in Western countries. The endocannabinoid 2-arachidonoyl-glycerol (2-AG) exerts antiproliferative actions in a number of tumoral cell lines, including CRC cells. Monoacylglycerol lipase (MAGL), a serine hydrolase that inactivates 2-AG, is highly expressed in aggressive human cancer cells. Here, we investigated the role of MAGL in experimental colon carcinogenesis. The role of MAGL was assessed in vivo by using the xenograft and the azoxymethane models of colon carcinogenesis; MAGL expression was evaluated by RT-PCR and immunohistochemistry; 2-AG levels were measured by liquid chromatography mass spectrometry; angiogenesis was evaluated in tumor tissues [by microvessel counting and by investigating the expression of vascular endothelial growth factor (VEGF) and fibroblast growth factor-2 (FGF-2) proteins] as well as in human umbilical vein endothelial cells (HUVEC); cyclin D1 was evaluated by RT-PCR. MAGL and 2-AG were strongly expressed in tumor tissues. The MAGL inhibitor URB602 reduced xenograft tumor volume, this effect being associated to down-regulation of VEGF and FGF-2, reduction in the number of vessels and down-regulation of cyclin D1. In HUVEC, URB602 exerted a direct antiangiogenic effect by inhibiting FGF-2 induced proliferation and migration, and by modulating pro/anti-angiogenic agents. In experiments aiming at investigating the role of MAGL in chemoprevention, URB602 attenuated azoxymethane-induced preneoplastic lesions, polyps and tumors. MAGL, possibly through modulation of angiogenesis, plays a pivotal role in experimental colon carcinogenesis. Pharmacological inhibition of MAGL could represent an innovative therapeutic approach to reduce colorectal tumor progression.

Abstract A07: Detection of structural variants and recurrent breakpoint genes in colorectal adenoma-to-carcinoma progression

Abstract Background and Aim: The transition of pre-malignant colorectal adenomas (CRAs) into malignant colorectal carcinomas (CRCs) is accompanied by accumulation of somatic genetic alterations. The contribution of small nucleotide variants (SNVs, such as gene point mutations) and numerical DNA copy number aberrations (CNAs, such as gains and losses of large chromosomal segments) in tumor genomes has been studied extensively. In contrast, studies that systematically detect recurrent structural variants (SVs, such as chromosomal breaks) across large series of clinically well-defined samples are scarce. We recently developed “GeneBreak”, a computational method to identify genes that are recurrently affected by the genomic location of CNA-associated chromosomal breaks, and demonstrated high prevalence and clinical relevance of recurrent breakpoint genes in advanced CRCs (PLoS One 2015;10(9):e0138141). Using a similar approach, the present study aimed to determine what recurrent breakpoint genes contribute to colorectal adenoma-to-carcinoma progression. Methods: Differences in somatic CNA-associated gene breakpoint frequencies in 466 CRC and 118 CRA samples were examined using high-resolution array-comparative genomic hybridization (aCGH) profiles. Pearson's Chi-square statistic was applied to determine differences in gene breakpoint frequencies between CRC and CRA samples. Results: In total 21 recurrent breakpoint genes were more frequently affected in CRCs compared to CRAs (p<0.05). MACROD2 was affected by chromosomal breakpoints in 40% of CRCs while not being affected in CRAs. The frequencies of SVs in the other 20 recurrent breakpoint genes ranged from 5% to 29% in CRCs, and from 0% to 2% in CRAs. Conclusion: We identified 21 recurrent breakpoint genes that are frequently affected by SVs in CRCs but not in CRAs. Additional studies are needed to further elaborate the biological and clinical role of these 21 candidate driver genes for colorectal tumor progression. Citation Format: Evert van den Broek, Maurits J.J. Dijkstra, Quirinus J.M. Voorham, Beatriz Carvalho, Mark A. van de Wiel, Sanne Abeln, Gerrit A. Meijer, Remond J.A. Fijneman. Detection of structural variants and recurrent breakpoint genes in colorectal adenoma-to-carcinoma progression. [abstract]. In: Proceedings of the AACR Special Conference on Colorectal Cancer: From Initiation to Outcomes; 2016 Sep 17-20; Tampa, FL. Philadelphia (PA): AACR; Cancer Res 2017;77(3 Suppl):Abstract nr A07.

The critical role of mast cell-derived hypoxia-inducible factor-1α in regulating mast cell function.

During colorectal tumour progression, the tumour microenvironment becomes hypoxic, and infiltration of a large number of inflammatory cells occurs. The mast cells (MCs) are a type of immune cells plays an important role in tumour angiogenesis. However, it is unclear whether the role of MC in colorectal cancer is to promote or to inhibit tumour growth. Immunohistochemical analysis of clinical colorectal cancer samples and a colorectal carcinoma model were used. We found the carcinomas and the adjacent tissues were infiltrated with large numbers of mast cells, and the MC infiltration quantity increased with the Dukes' stage. After tumour inoculation, the survival time of MC-deficient mice was remarkably longer than wild-type C57BL/6 mice, and the tumour growth rate of MC-deficient mice was slower than wild type. In addition, the survival time and tumour growth rate can be recovered in MC reconstruction mice. Furthermore, inhibition of the expression of hypoxia-inducible factor-1α (HIF-1α) using siRNA reduced the release of inflammatory factors and the degree of MC degranulation. Mast cells promote the development of colorectal cancer, and MC-derived HIF-1α plays an important role in regulating MC function. Our study reveals a novel role of MC-derived HIF-1α in the colorectal carcinoma microenvironment.

Activin pathway enhances colorectal cancer stem cell self-renew and tumor progression

Activin belongs to transforming growth factor (TGF)-β super family of growth and differentiation factors and activin pathway participated in broad range of cell process. Studies elaborated activin pathway maintain pluripotency in human stem cells and suggest that the function of activin/nodal signaling in self-renew would be conserved across embryonic and adult stem cells. In this study, we tried to determine the effect of activin signaling pathway in regulation of cancer stem cells as a potential target for cancer therapy in clinical trials. A population of colorectal cancer cells was selected by the treatment of activin A. This population of cell possessed stem cell character with sphere formation ability. We demonstrated activin pathway enhanced the colorectal cancer stem cells self-renew and contribute to colorectal cancer progression in vivo. Targeting activin pathway potentially provide effective strategy for colorectal cancer therapy.

EpiGeNet: A Graph Database of Interdependencies Between Genetic and Epigenetic Events in Colorectal Cancer.

The development of colorectal cancer (CRC)-the third most common cancer type-has been associated with deregulations of cellular mechanisms stimulated by both genetic and epigenetic events. StatEpigen is a manually curated and annotated database, containing information on interdependencies between genetic and epigenetic signals, and specialized currently for CRC research. Although StatEpigen provides a well-developed graphical user interface for information retrieval, advanced queries involving associations between multiple concepts can benefit from more detailed graph representation of the integrated data. This can be achieved by using a graph database (NoSQL) approach. Data were extracted from StatEpigen and imported to our newly developed EpiGeNet, a graph database for storage and querying of conditional relationships between molecular (genetic and epigenetic) events observed at different stages of colorectal oncogenesis. We illustrate the enhanced capability of EpiGeNet for exploration of different queries related to colorectal tumor progression; specifically, we demonstrate the query process for (i) stage-specific molecular events, (ii) most frequently observed genetic and epigenetic interdependencies in colon adenoma, and (iii) paths connecting key genes reported in CRC and associated events. The EpiGeNet framework offers improved capability for management and visualization of data on molecular events specific to CRC initiation and progression.

The Role of RUNX3 in Colorectal Tumor Progression

Objectives: RUNX3 (runt-related-transcription-factor3) is a putative tumor suppressor in colorectal carcinoma (CRC) and other cancers. Recent evidence also suggests that RUNX3 localization to the cytoplasm may play an oncogenic role. We investigated the role of cytoplasmic and nuclear expression of RUNX3 in CRC tumor progression from adenoma to carcinoma. Methods: We compared expression of RUNX3 in CRC and tubulovillous adenomas (TVAs) in …

Proteomics analysis of up-regulated NPM1 protein in colorectal cancer

In order to identify potential protein targets involved in colorectal cancer(CRC), we used a liquid chromatography coupled with mass spectrometry(LC-MS)/MS-based proteomics approach to characterize global protein expression patterns in malignant tissues and their adjacent healthy tissues from Dukes C stage CRC patients. A total number of 34 differentially expressed proteins were detected and identified by LC-MS/MS and database searching, which are supposed to be relevant to progression of colorectal tumor. Among these proteins, nucleophosmin 1(NPM1) was found to be remarkably up-regulated in colorectal carcinoma tissues, as compared with that in their normal counterparts. The results presented here could provide clues to elucidate the pathological significance of NPM1 in regulation of carcinogenesis of Dukes C stage colorectal tumors.

OVOL2, an Inhibitor of WNT Signaling, Reduces Invasive Activities of Human and Mouse Cancer Cells and Is Down-regulated in Human Colorectal Tumors

Activation of WNT signaling promotes the invasive activities of several types of cancer cells, but it is not clear if it regulates the same processes in colorectal cancer (CRC) cells, or what mechanisms are involved. We studied the expression and function of OVOL2, a member of the Ovo family of conserved zinc-finger transcription factors regulated by the WNT signaling pathway, in intestinal tumors of mice and human beings. We analyzed the expression of OVOL2 protein and messenger RNA in CRC cell lines and tissue arrays, as well as CRC samples from patients who underwent surgery at Xiamen University in China from 2009 to 2012; clinical information also was collected. CRC cell lines (SW620) were infected with lentivirus expressing OVOL2, analyzed in migration and invasion assays, and injected into nude mice to assess tumor growth and metastasis. Tandem affinity purification was used to purify the OVOL2-containing complex from CRC cells; the complex was analyzed by liquid chromatography, tandem mass spectrometry, and immunoprecipitation experiments. Gene promoter activities were measured in luciferase reporter assays. We analyzed mice with an intestine-specific disruption of Ovol2 (Ovol2(flox/+) transgenic mice), as well as Apc(min/+) mice; these mice were crossed and analyzed. Analysis of data from patients indicated that the levels of OVOL2 messenger RNA were significantly lower in colon carcinomas than adenomas, and decreased significantly as carcinomas progressed from grades 2 to 4. Immunohistochemical analysis of a tissue array of 275 CRC samples showed a negative association between tumor stage and OVOL2 level. Overexpression of OVOL2 in SW620 cells decreased their migration and invasion, reduced markers of the epithelial-to-mesenchymal transition, and suppressed their metastasis as xenograft tumors in nude mice; knockdown of OVOL2 caused LS174T cells to transition from epithelial to mesenchymal phenotypes. OVOL2 bound T-cell factor (TCF)4 and β-catenin, facilitating recruitment of histone deacetylase 1 to the TCF4-β-catenin complex; this inhibited expression of epithelial-to-mesenchymal transition-related genes regulated by WNT, such as SLUG, in CRC cell lines. OVOL2 was a downstream target of WNT signaling in LS174T and SW480 cells. The OVOL2 promoter was hypermethylated in late-stage CRC specimens from patients and in SW620 cells; hypermethylation resulted in OVOL2 down-regulation and an inability to inhibit WNT signaling. Disruption of Ovol2 in Apc(min/+) mice increased WNT activity in intestinal tissues and the formation of invasive intestinal tumors. OVOL2 is a colorectal tumor suppressor that blocks WNT signaling by facilitating the recruitment of histone deacetylase 1 to the TCF4-β-catenin complex. Strategies to increase levels of OVOL2 might be developed to reduce colorectal tumor progression and metastasis.

Fasting induces anti-Warburg effect that increases respiration but reduces ATP-synthesis to promote apoptosis in colon cancer models.

Tumor chemoresistance is associated with high aerobic glycolysis rates and reduced oxidative phosphorylation, a phenomenon called "Warburg effect" whose reversal could impair the ability of a wide range of cancer cells to survive in the presence or absence of chemotherapy. In previous studies, Short-term-starvation (STS) was shown to protect normal cells and organs but to sensitize different cancer cell types to chemotherapy but the mechanisms responsible for these effects are poorly understood. We tested the cytotoxicity of Oxaliplatin (OXP) combined with a 48hour STS on the progression of CT26 colorectal tumors. STS potentiated the effects of OXP on the suppression of colon carcinoma growth and glucose uptake in both in vitro and in vivo models. In CT26 cells, STS down-regulated aerobic glycolysis, and glutaminolysis, while increasing oxidative phosphorylation. The STS-dependent increase in both Complex I and Complex II-dependent O(2) consumption was associated with increased oxidative stress and reduced ATP synthesis. Chemotherapy caused additional toxicity, which was associated with increased succinate/Complex II-dependent O(2) consumption, elevated oxidative stress and apoptosis .These findings indicate that the glucose and amino acid deficiency conditions imposed by STS promote an anti-Warburg effect characterized by increased oxygen consumption but failure to generate ATP, resulting in oxidative damage and apoptosis.

Contextual niche signals towards colorectal tumor progression by mesenchymal stem cell in the mouse xenograft model.

The role of mesenchymal stem/stromal cells (MSCs) in tumorigenesis remains controversial. This study aimed to determine whether heterotypic interactions between MSCs and colon cancer cells can supply contextual signals towards tumor progression. Xenografts consisting of co-implanted human colorectal cancer cells with rat MSCs in immunodeficient mice were evaluated by tumor progression, angiogenic profiles, and MSC fate. Furthermore, we investigated how MSCs function as a cancer cell niche by co-culture experiments in vitro. Tumor growth progressed in two ways, either independent of or dependent on MSCs. Such cell line-specific dependency could not be explained by host immune competency. COLO 320 xenograft angiogenesis was MSC-dependent, but less dependent on vascular endothelial growth factor (VEGF), whereas HT-29 angiogenesis was not MSC-dependent, but was VEGF-dependent. MSCs and COLO 320 cells established a functional positive feedback loop that triggered formation of a cancer cell niche, leading to AKT activation. Subsequently, MSCs differentiated into pericytes that enhanced angiogenesis as a perivascular niche. In contrast, the MSC niche conferred an anti-proliferative property to HT-29 cells, through mesenchymal-epithelial transition resulting in p38 activation. In conclusion, MSCs demonstrate pleiotropic capabilities as a cancer cell or perivascular niche to modulate colorectal cancer cell fate in a cell line-dependent manner in a xenogeneic context.

Interleukin-17FT7488 allele is associated with a decreased risk of colorectal cancer and tumor progression

BackgroundIL-17 family of cytokines and human IL-23R play important and sometimes contradictory roles in autoimmune and inflammatory diseases as well as human malignancies. Different alleles of this cytokine family may differentially affect IL-17 secretion. We sought to investigate the association of IL-17A, IL-17F and IL-23R gene polymorphisms with the susceptibility to colorectal cancer (CRC). MethodsThe IL-17A rs2275913 (G197A), IL-17F rs763780 (T7488C), IL-23R rs11209026 and IL-23R rs1088967 SNPs were detected in 202 patients with colorectal cancer and 203 healthy age/sex matched controls by PCR-RFLP method. For evaluation of the functional relevance of these SNPs with IL-17A and IL-17F production, the serum levels of IL-17A and IL-17F were investigated in 107 and 109 patients as well as 33 and 52 healthy individuals, respectively, by ELISA assays. ResultsThe IL-17F TT genotype [OR=0.44, 95% CI: 0.21–0.94, P=0.03] and T allele [OR=0.46, 95% CI: 0.21–1.1, P=0.03] were associated with a decreased risk of CRC compared with the TC genotype and C allele. Moreover, IL-17F TT genotype was significantly associated with well differentiation in tumors (P=0.02). We also observed a significant association between the AG genotype of IL-17A G197A SNP with increased risk of colorectal cancer as compared to AA genotype (P=0.001). The IL-17A concentrations in the sera of patients with CRC were significantly elevated compared to healthy individuals (P=0.008), and serum level of IL-17A was significantly related to tumor size (P=0.043). The A allele of IL-23R rs10889677 polymorphism was marginally associated with increased IL-17A levels in the sera of patients (P=0.08). The genotype distributions of IL-23R rs11209026 and IL-23R rs10889677 SNPs were not significantly different between CRC patients and controls. The haplotypes of IL-17A G197A/IL-17F T7488C and IL-23R were not significantly associated with CRC. No IL-17F was detected in the sera of patients and only one healthy individual had IL-17F in his serum. ConclusionOur findings suggest that the T allele of IL-17F T7488C polymorphism may be involved in reduced risk of CRC and IL-17A may be an attractive target for colorectal cancer immunotherapy.

Prognostic significance of E-Cadherin and CD44 expression in tumor tissue of colorectal carcinoma

Background Colorectal cancer (CRC) is a major cause of cancer-related mortality worldwide. Currently, tumor-node-metastasis staging system still remains the gold standard for prognosis of CRC patients, but it is no longer sufficient. Among the most important molecules involved in colorectal tumor growth, cell proliferation and progression are adhesive molecules such as CD44 and E-cadherin (EC). The aim of this study was to evaluete the expression of CD44 standard protein and EC in correlation with Ki-67 proliferative index and some other clinicopathological prognostic variables in patients with CRC.

Aurora kinase A gene copy number is associated with the malignant transformation of colorectal adenomas but not with the serrated neoplasia progression.

A crucial role for Aurora Kinase A (AURKA) gene has been demonstrated in the advanced steps of colorectal tumor progression. Little is known, however, about its role in the early phases of the adenoma-carcinoma sequence. Moreover, no data are currently available concerning AURKA involvement in the serrated tumorigenesis. Fluorescence in situ hybridization analysis and immunohistochemistry were used to assess gene copy number and protein expression in 40 colorectal adenomas, 20 cancerized adenomas, and 20 serrated polyps. An increased copy number was found either in adenomatous tissue or in early cancer in the vast majority of cancerized adenomas, but only in 5% of adenomas (P < .001). Protein expression strictly paralleled fluorescence in situ hybridization results. No changes in the gene copy number were observed in serrated polyps, regardless of their histotype and the presence of dysplasia, even if high percentages of immunostained cells were detected in all the subgroups. AURKA gene is associated with progressive colorectal adenomas but is uninvolved in the development of nonprogressive adenomas. The diploid status of the gene is maintained along the progression of serrated neoplasia. AURKA protein expression in serrated polyps is uncoupled from gene status and is likely to reflect apoptotic dysregulation.