Role of TNFα and leptin signaling in colon cancer incidence and tumor growth under obese phenotype.

Epidemiological studies over the last few decades have shown a strong influence of obesity on colon cancer risk and its progression. These studies have primarily focussed on the role of adipokines in driving cancer progression. We investigated the incidence of cancerous polyp formation and tumor progression in presence and absence of functional leptin along with exploring the role of tumor necrosis factor α (TNFα), under obese condition. By utilizing diet induced obese and genetically obese mice, carcinogen induced colon polyp formation was investigated. Experiments were performed using tumor tissues and cell lines to delineate the inter-relationship between leptin and TNFα. Data shown in this report indicates that in leptin knockdown obese mice, AOM/DSS induced polyps are smaller and lesser in numbers as compared to AOM/DSS induced polyps in diet induced obese mice. Further in vitro experiments suggest that abrogation of leptin associated pathways promote TNFα induced apoptosis. Mechanistically, we report that TNFα induces p53 independent cell death through up regulation of p53 upregulated modulator of apoptosis (PUMA). TNFα induced PUMA was inhibited upon pre- exposure of cells to leptin, prior to TNFα treatment. Collectively these results indicate that obesity due to leptin non-functionality facilitates TNFα induced colon cancer cell death.

Calcium and vitamin D supplementation and increased risk of serrated polyps: results from a randomised clinical trial.

OBJECTIVE: Serrated lesions such as sessile serrated adenomas or polyps (SSA/Ps) are important colorectal cancer precursors, but aetiological factors for these lesions are largely unknown. We aimed to determine the effects of calcium and vitamin D supplementation on the incidence of serrated polyps (SPs) in general and hyperplastic polyps and SSA/Ps specifically. DESIGN: Participants with one or more adenoma at baseline were randomised to receive 1200 mg/day of elemental calcium, 1000 IU/day of vitamin D3, both or neither agent. Treatment continued for 3 or 5 years, when risk of polyps was determined from surveillance colonoscopy (treatment phase). Outcomes after treatment ceased were also assessed (observational phase). Adjusted risk ratios (aRRs) of SPs were determined via multivariable generalised linear models. RESULTS: SPs were diagnosed in 565 of 2058 (27.5%) participants during the treatment phase and 329/1108 (29.7%) during the observational phase. In total, 211 SSA/Ps were identified during follow-up. In the treatment phase, there was no effect of either calcium or vitamin D on incidence of SSA/Ps. However, during the later observational phase, we observed elevated risks of SSA/Ps associated with calcium alone and calcium+vitamin D treatment (aRR (95% CI): 2.65 (1.43 to 4.91) and 3.81 (1.25 to 11.64), respectively). CONCLUSION: In a large multicentre chemoprevention study, we found evidence that calcium and vitamin D supplementation increased the risk of SSA/Ps. This appeared to be a late effect: 6-10 years after supplementation began. These possible risks must be weighed against the benefits of calcium and vitamin D supplementation. : Trial registration NUMBER: NCT00153816; Results.

Association of colorectal polyps and cancer with low-dose persistent organic pollutants: A case-control study.

BACKGROUND: Low-dose persistent organic pollutants (POPs) have recently been linked to immunosenescence, a key mechanism in carcinogenesis, as well as many aging-related chronic diseases. Since feces are the main excretion route of POPs, the large intestine is a potential target organ for these pollutants. We performed a case-control study to evaluate whether exposure to low-dose POPs is related to the risk of colorectal polyps and cancer. METHODS: A total of 277 participants were recruited from one hospital: 99 cancer patients, 102 polyp patients, and 76 control subjects. As typical examples of POPs, we measured the serum concentrations of organochlorine pesticides (OCPs) and polychlorinated biphenyls (PCBs). RESULTS: Across the tertiles of the summary measure of POPs, the adjusted odds ratios (ORs) of colorectal polyps and cancer were 2.8 (1.2-6.8) (Ptrend = 0.01) and 3.0 (1.0-8.8) (Ptrend = 0.02), respectively, for subjects in the highest tertile. When OCPs and PCBs were analyzed separately, OCPs were linked to an increased risk of both polyps and cancer; the adjusted ORs were 2.3 (0.9-5.7) (Ptrend = 0.05) for polyps and 3.6 (1.1-11.8) (Ptrend< 0.01) for cancer. However, PCBs were only significantly associated with a high risk of polyps but not cancer; the adjusted OR was 2.8 (1.2-6.6) (Ptrend = 0.01). CONCLUSION: Chronic exposure to low-dose POPs may be associated with an increased risk of colorectal polyps and cancer. Our findings suggest the carcinogenic potential of strong lipophilic chemical mixtures such as POPs which are accumulated in adipose tissue, released to circulation, and eliminated through feces.

Gavage of Fecal Samples From Patients With Colorectal Cancer Promotes Intestinal Carcinogenesis in Germ-Free and Conventional Mice.

BACKGROUND & AIMS: Altered gut microbiota is implicated in development of colorectal cancer (CRC). Some intestinal bacteria have been reported to potentiate intestinal carcinogenesis by producing genotoxins, altering the immune response and intestinal microenvironment, and activating oncogenic signaling pathways. We investigated whether stool from patients with CRC could directly induce colorectal carcinogenesis in mice. METHODS: We obtained stored stool samples from participants in a metagenome study performed in Hong Kong. Conventional (male C57BL/6) mice were given azoxymethane to induce colon neoplasia after receiving a course of antibiotics in drinking water. Mice were gavaged twice weekly with stool from 5 patients with CRC or 5 healthy individuals (controls) for 5 weeks. Germ-free C57BL/6 mice were gavaged once with stool from 5 patients with CRC or 5 controls. We collected intestinal tissues from mice and performed histology, immunohistochemistry, expression microarray, quantitative polymerase chain reaction, immunoblot, and flow cytometry analyses. We performed 16S ribosomal RNA gene sequencing analysis of feces from mice. RESULTS: Significantly higher proportions of conventional mice fed with stool from individuals with CRC than control stool developed high-grade dysplasia (P < .05) and macroscopic polyps (P < .01). We observed a higher proportion of proliferating (Ki-67-positive) cells in colons of germ-free mice fed with stool from patients with CRC vs those fed with stool from controls (P < .05). Feces from germ-free and conventional mice fed with stool from patients with CRC vs controls contained different microbial compositions, with lower richness in mice fed with stool from patients with CRC. Intestines collected from conventional and germ-free mice fed with stool from patients with CRC had increased expression of cytokines that modulate inflammation, including C-X-C motif chemokine receptor 1, C-X-C motif chemokine receptor 2, interleukin 17A (IL17A), IL22, and IL23A. Intestines from conventional and germ-free mice fed with stool from patients with CRC contained higher proportions of T-helper 1 (Th1) cells (2.25% vs 0.44%) and Th17 cells (2.08% vs 0.31%) (P < .05 for each) than mice fed with stool from controls. Real-time polymerase chain reaction arrays revealed up-regulation of genes involved in cell proliferation, stemness, apoptosis, angiogenesis, invasiveness, and metastasis in mice fed with stool from patients with CRC. CONCLUSIONS: We fed stool samples from patients with CRC and heathy individuals to germ-free mice and conventional mice with azoxymethane. We found stool from patients with CRC to increase the numbers of polyps, levels of intestinal dysplasia and proliferation, markers of inflammation, and proportions of Th1 and Th17 cells in colon, compared with stool from individuals without CRC. This study provides evidence that the fecal microbiota from patients with CRC can promote tumorigenesis in germ-free mice and mice given a carcinogen.

BRAF inhibitor treatment of melanoma causing colonic polyps: An alternative hypothesis.

Colonic polyps may arise from BRAF inhibitor treatment of melanoma, possibly due to paradoxical activation of the mitogen-activated protein (MAP)-kinase pathway. In an alternative evidence based scenario, tubular colonic adenomas with APC gene mutations have also been identified in the context of BRAF inhibitor treatment, in the absence of mutations of MAPK genes. A minority of colorectal cancers develop by an alternative "serrated polyp pathway". This article postulates a novel hypothesis, that the established phenotypic and molecular characteristics of serrated colonic polyps/CRC offer an intriguing insight into the pathobiology of BRAF inhibitor induced colonic polyps. Serrated polyps are characterized by a CpG island methylation phenotype, MLH1 silencing and cellular senescence. They also have BRAF mutations. The contention is that BRAF inhibitor induced polyps mimic the afore-described histology and molecular features of serrated polyps with the exception that instead of the presence of BRAF mutations they induce C-RAF homodimers and B-RAF: C-RAF heterodimers.

Three Pathways of Colonic Carcinogenesis in Rats.

BACKGROUND: Colorectal cancer (CRC) is one of the more intensively studied human malignancies. For many years, the general view has been that the vast majority of CRCs in humans evolve from conventional (tubular or villous) adenomas via the adenoma-carcinoma pathway. More recently, serrated colorectal polyps (hyperplastic polyps, sessile serrated polyps and traditional serrated adenomas) have emerged as an alternative pathway of colorectal carcinogenesis in humans. Archival sections from early experiments in Sprague-Dawley (SD) rats injected with dimethylhydrazine (DMH) were reviewed and the histology of colonic neoplasias was re-evaluated. Out of 215 colonic neoplasias, 9% were serrated adenomas and 6% serrated carcinomas, 11% conventional adenomas, 39% highly differentiated carcinomas, 21% gut-associated lymphoid tissue (GALT) carcinomas, 13% signet-ring cell carcinomas, and 1% villous carcinomas. In a more recent review of archived sections from DMH-treated rats with colonic GALT follicles, dysplastic crypts exhibiting asymmetrical bifurcations in GALT mucosa were found in 49% and colonic GALT carcinomas in 53% of 276 DMH-treated rats. Histology of the 146 colonic GALT-carcinomas revealed highly differentiated carcinoma in 75%, signet-ring cell carcinoma in 20%, mucinous carcinomas in 3% and mixed in the remaining 2%. Highly differentiated carcinomas were seen to evolve from dysplastic crypts with asymmetric bifurcations and from adenomas and signet-ring cell carcinomas, and from non-dysplastic crypts having goblet cells with marked anisocytosis. It is apparent that DMH treatment in SD rats induced conventional adenomas, conventional carcinomas, serrated adenomas, serrated carcinomas and GALT carcinomas. The paradigm permits to monitor in detail the early histological steps that epitomize the three alternative pathways of colonic carcinogenesis in SD rats. This model might be useful for analyzing different molecular aberrations evolving during the conventional adenoma-carcinoma pathway, the serrated carcinoma pathway, and the GALT carcinoma pathway of colonic carcinogenesis, under standard laboratory conditions.

Genetic-deletion of Cyclooxygenase-2 Downstream Prostacyclin Synthase Suppresses Inflammatory Reactions but Facilitates Carcinogenesis, unlike Deletion of Microsomal Prostaglandin E Synthase-1.

Prostacyclin synthase (PGIS) and microsomal prostaglandin E synthase-1 (mPGES-1) are prostaglandin (PG) terminal synthases that function downstream of inducible cyclooxygenase (COX)-2 in the PGI2 and PGE2 biosynthetic pathways, respectively. mPGES-1 has been shown to be involved in various COX-2-related diseases such as inflammatory diseases and cancers, but it is not yet known how PGIS is involved in these COX-2-related diseases. Here, to clarify the pathophysiological role of PGIS, we investigated the phenotypes of PGIS and mPGES-1 individual knockout (KO) or double KO (DKO) mice. The results indicate that a thioglycollate-induced exudation of leukocytes into the peritoneal cavity was suppressed by the genetic-deletion of PGIS. In the PGIS KO mice, lipopolysaccharide-primed pain nociception (as assessed by the acetic acid-induced writhing reaction) was also reduced. Both of these reactions were suppressed more effectively in the PGIS/mPGES-1 DKO mice than in the PGIS KO mice. On the other hand, unlike mPGES-1 deficiency (which suppressed azoxymethane-induced colon carcinogenesis), PGIS deficiency up-regulated both aberrant crypt foci formation at the early stage of carcinogenesis and polyp formation at the late stage. These results indicate that PGIS and mPGES-1 cooperatively exacerbate inflammatory reactions but have opposing effects on carcinogenesis, and that PGIS-derived PGI2 has anti-carcinogenic effects.

A hypermorphic epithelial ß-catenin mutation facilitates intestinal tumorigenesis in mice in response to compounding WNT-pathway mutations.

Activation of the Wnt/ß-catenin pathway occurs in the vast majority of colorectal cancers. However, the outcome of the disease varies markedly from individual to individual, even within the same tumor stage. This heterogeneity is governed to a great extent by the genetic make-up of individual tumors and the combination of oncogenic mutations. In order to express throughout the intestinal epithelium a degradation-resistant ß-catenin (Ctnnb1), which lacks the first 131 amino acids, we inserted an epitope-tagged ΔN(1-131)-ß-catenin-encoding cDNA as a knock-in transgene into the endogenous gpA33 gene locus in mice. The resulting gpA33(ΔN-Bcat) mice showed an increase in the constitutive Wnt/ß-catenin pathway activation that shifts the cell fate towards the Paneth cell lineage in pre-malignant intestinal epithelium. Furthermore, 19% of all heterozygous and 37% of all homozygous gpA33(ΔN-Bcat) mice spontaneously developed aberrant crypt foci and adenomatous polyps, at frequencies and latencies akin to those observed in sporadic colon cancer in humans. Consistent with this, the Wnt target genes, MMP7 and Tenascin-C, which are most highly expressed in benign human adenomas and early tumor stages, were upregulated in pre-malignant tissue of gpA33(ΔN-Bcat) mice, but those Wnt target genes associated with excessive proliferation (i.e. Cdnn1, myc) were not. We also detected diminished expression of membrane-associated α-catenin and increased intestinal permeability in gpA33(ΔN-Bcat) mice in challenge conditions, providing a potential explanation for the observed mild chronic intestinal inflammation and increased susceptibility to azoxymethane and mutant Apc-dependent tumorigenesis. Collectively, our data indicate that epithelial expression of ΔN(1-131)-ß-catenin in the intestine creates an inflammatory microenvironment and co-operates with other mutations in the Wnt/ß-catenin pathway to facilitate and promote tumorigenesis.

Association between colorectal polyps and hypertension treatment.

OBJECTIVE: Patients who take drugs regularly are increasing, not least due to metabolic and orthopedic diseases. In the present study we aimed to investigate the association between the use of drugs, such as non-steroidal anti-inflammatory drugs (NSAIDs) and low-dose aspirin, and colorectal polyps diagnosed based on colonoscopic findings. METHODS: In total, 1318 consecutive patients who underwent total colonoscopy for the first time were cross-sectionally analyzed. Personal data including comorbidities and all medications were obtained by a questionnaire. Their blood pressure, body weight and waist circumference were measured just before the colonoscopic examination. RESULTS: Colorectal polyps were found in 577 (43.8%) patients, with a prevalence of 57.6% (296/514) in patients receiving antihypertensive treatment and 35.0% (281/804) in patients not undergoing such treatment. A multivariate analysis showed that age, waist circumference, alcohol consumption, smoking and the use of antihypertensive drugs were independent risk factors for colorectal polyps. In a secondary multivariate analysis incorporating the parameters of measured blood pressure and medication status, the number of antihypertensive drugs was strongly associated with the risk of colorectal polyps, whereas blood pressure showed no significant association. CONCLUSIONS: The use of antihypertensive drug may be a risk factor for colorectal polyps. Furthermore, this risk increases with the intensive use of antihypertensive drugs.

Chemopreventive effects of Strobilanthes crispus leaf extract on azoxymethane-induced aberrant crypt foci in rat colon.

In this work, microscopic and histological studies suggest that Strobilanthes crispus ethanol extract reduce azoxymethane (AOM)-induced colonic aberrant crypt foci (ACF) in rats. S. crispus is considered a traditional medicine and used as an antioxidant. Its leaf contains a large amount of phenolic compounds to which its radical scavenging role is attributed and enhance its ability to eradicate oxidative stress reactions. The study was designed to determine the chemopreventive effect of S. crispus ethanol extract in vivo and in vitro by elucidating the effect of the extract on intermediate biomarkers which can be used as effective predictors of colon cancer. S. crispus was analyzed for DPPH free radical scavenging, nitric oxide (NO) and ferric acid reduction. The results indicated that S. crispus oral administration significantly inhibited colorectal carcinogenesis induced by AOM as revealed by the reduction in the number of ACF. S. crispus down-regulated the expression of PCNA, Bcl2 and ß-catenin. Additionally, it exerted a pronounced inhibitory effect on MDA and NO levels and stimulatory effect on CAT and GPx activities. These results demonstrate that S. crispus is a chemopreventive agent for colorectal cancer through the suppression of early and intermediate carcinogenic phases that may be related to its flavonoid content.

Systematic Review with Meta-Analysis: Alcohol Consumption and Risk of Colorectal Serrated Polyp.

BACKGROUND: Alcohol intake is closely related to colorectal cancer, which remains inconsistent with studies on the relation between alcohol consumption and risk of colorectal serrated polyp (SP) which was proven to have potential of developing into malignant serrated neoplasm. AIM: A meta-analysis investigating the association between alcohol intake and colorectal SP with the dose-response of alcohol intake was conducted. METHODS: The literature search was performed on PubMed to identify pertinent articles presenting results for at least three categories of alcohol consumption dated up to October 2014. Summarized relative risks (RRs) with 95 % confidence intervals (CIs) were estimated using random or fixed effects models based on statistical heterogeneity. RESULTS: A total of ten observational studies were identified in this meta-analysis. All drinkers were associated with 24 % increased risk of colorectal SP compared with non-/occasional drinkers. In particular, the light alcohol intake was not related to an increased risk of colorectal SP (RR 1.05, 95 % CI 0.93-1.18), whereas the RRs were 1.19 (95 % CI 1.02-1.40) for moderate alcohol intake and 1.60 (95 % CI 1.35-1.91) for heavy alcohol intake. The risks were consistent in further dose-response analysis. Meanwhile, subgroup analyses demonstrated that patients in America had more increased risk of SP with respect to those in Europe and Asia. In terms of subtype of colorectal SP, alcohol consumption had a greater influence on SSA than HP. CONCLUSIONS: This is the first meta-analysis that demonstrated the relationship between moderate and heavy alcohol consumption and increasing risks of colorectal SP.

Combinational chemoprevention effect of celecoxib and an oral antiangiogenic LHD4 on colorectal carcinogenesis in mice.

To achieve a clinically rational regimen for cancer chemoprevention with improved efficacy and safety, the combination effect of celecoxib and newly developed oral angiogenesis inhibitor, LHD4, on chemoprevention was evaluated. The chemopreventive effects of celecoxib, LHD4, and the combination of celecoxib and LHD4 were evaluated in a murine colorectal carcinogenesis model. After 17 experimental weeks, mouse colon tissues were collected and examined in terms of polyp volume and degree of carcinogenesis, inflammation, and angiogenesis. Mice in the celecoxib-treated or LHD4-treated groups had total polyp volumes of 47.0±9.7 and 120.1±45.2 mm, respectively, which represented decreases of 65.6 and 22.3% from the control (154.5±33.5 mm). However, the polyp volume in the combination group was 22.8±9.3 mm, a decrease of 85.2% from the control. In the comparison of carcinogenesis, the percentage of normal tissue (i.e. excluding proliferative tissue) was found to be 40.6% in the control, 51.7% in the celecoxib, 56.9% in the LHD4, and 81.7% in the combination group. In accordance with attenuated carcinogenesis, both inflammation and angiogenesis were also well controlled. Together, these results suggest that the combinatory use of celecoxib and a newly developed oral heparin conjugate could be a promising regimen for chemoprevention by intervening in both inflammation and angiogenesis.

Role of microRNAs in resveratrol-mediated mitigation of colitis-associated tumorigenesis in Apc(Min/+) mice.

The pleiotropic effects of resveratrol include anti-inflammatory, antioxidant, and anticancer activities, and thus unique possibilities exist to explore mechanistic pathways of chemoprevention. The aim of this study was to investigate the role of microRNA (miRNA) alterations induced by resveratrol in the context of chemopreventive mechanisms against dextran sodium sulfate (DSS)-induced colitis-associated tumorigenesis in the Apc(Min/+) mouse. To that end, Apc(Min/+) mice were exposed to 2% DSS to enhance intestinal inflammation and polyp development. Concurrently, mice received either vehicle or resveratrol treatment via oral gavage for 5 weeks. Interestingly, treatment of DSS-exposed mice with resveratrol resulted in decreased number and size of polyps, fewer histologic signs of cell damage, and decreased proliferating epithelial cells in intestinal mucosa compared with vehicle. Resveratrol treatment dramatically reversed the effects of DSS on the numbers of specific inflammatory CD4(+) T cells, CD8(+) T cells, B cells, natural killer T cells, and myeloid-derived suppressor cells in mesenteric lymph nodes. Resveratrol treatment also decreased interleukin-6 (IL-6) and tumor necrosis factor-α protein levels and reduced IL-6 and cyclooxygenase-2 mRNA expression. Microarray analysis revealed 104 miRNAs exhibiting >1.5-fold differences in expression in the intestinal tissue of resveratrol-treated mice. Among them, two miRNAs with anti-inflammatory properties, miRNA-101b and miRNA-455, were validated to be upregulated with resveratrol treatment by reverse-transcription polymerase chain reaction. Pathway analysis revealed that numerous differentially regulated miRNAs targeted mRNAs associated with inflammatory processes with known roles in intestinal tumorigenesis. These results suggest that resveratrol mediates anti-inflammatory properties and suppresses intestinal tumorigenesis through miRNA modulation.

Discovery of potential targets of selenomethionine-mediated chemoprevention in colorectal carcinoma mouse model using proteomics analysis.

Despite some controversy, selenomethionine (SeMet)-mediated protection against colorectal cancer (CRC) might be a very promising non-cytotoxic option. However, responsive molecular targets and underlying mechanisms of SeMet-mediated chemoprevention are still unclear. Our aim was to discover new targets of SeMet-mediated chemoprevention in CRC using proteomics analysis. We found dietary SeMet supplementation before carcinoma initiation effectively suppressed polyp incidence and dysplastic lesions without any adverse effects. To determine chemopreventive targets of SeMet, we employed two-dimensional gel electrophoresis-based proteomics analysis in CRC mouse model. Pretreatment with SeMet apparently modulated the expression of 30 proteins with functions in major processes like chronic inflammation, oxidative stress and apoptosis as discovered through pathway analysis with Pathway Studio software. We validated four proteins selected from pathway analysis including prohibitin, purine nucleoside phosphorylase, annexin 2 and c-reactive protein by immunohistochemistry. 8-Hydroxy-2'-deoxyguanosine (8-OHdG), a known oxidative stress marker, was decreased by SeMet treatment in CRC mice as seen by immunohistochemistry. Further network analysis was done among these new four validated proteins, 8-OHdG and colorectal cancer. These four proteins found by proteomics analysis might be considered as potential chemopreventive biomarkers of SeMet against colon cancer and can help develop and improve approaches in preventive, therapeutic and prognostic aspects.

Chemoprevention of benzo(a)pyrene-induced colon polyps in ApcMin mice by resveratrol.

Human dietary exposure to benzo(a)pyrene (BaP) has generated interest with regard to the association of BaP with gastrointestinal carcinogenesis. Since colon cancer ranks third among cancer-related mortalities, it is necessary to evaluate the effect of phytochemicals on colon cancer initiation and progression. In this study, we investigated the preventive effects of resveratrol (RVT) on BaP-induced colon carcinogenesis in Apc(Min) mouse model. For the first group of mice, 100 µg BaP/kg body weight was administered to mice in peanut oil via oral gavage over a 60-day period. For the second group, RVT was coadministered with BaP at a dose of 45 µg/kg. For the third group, RVT was administered for 1 week prior to BaP exposure for 60 days. Jejunum, colon and liver were collected at 60 days post BaP and RVT exposure; adenomas in jejunum and colon were counted and subjected to histopathology. RVT reduced the number of colon adenomas in BaP+RVT-treated mice significantly compared to that in mice that received BaP alone. While dysplasia of varying degrees was noted in colon of BaP-treated mice, the dysplasias were of limited occurrence in RVT-treated mice. To ascertain whether the tumor inhibition is a result of altered BaP-induced toxicity of tumor cells, growth, apoptosis and proliferation of adenocarcinoma cells were assessed posttreatment with RVT and BaP. Cotreatment with RVT increased apoptosis and decreased cell proliferation to a greater extent than with BaP alone. Overall, our observations reveal that RVT inhibits colon tumorigenesis when given together with BaP and holds promise as a therapeutic agent.

Rapidly progressive colonic dysplasia/neoplasia in a series of treated lung cancer patients: Is paclitaxel involved?

Incidence of second malignancies in patients with advanced lung cancer is not well-studied, in part because of a short survival in this patient population. Apart from a genetic predisposition, various environmental hazards may also be at play in their pathogenesis. Chronic smoking exposure decreases T-cell responsiveness and stimulates production of a variety of inhibitory cytokines. Paclitaxel has been associated with several immunosuppressive effects such as decreased numbers and activity of dendritic cells, NK-cells, and monocytes. We herein describe the first series of lung cancer patients who developed colonic polyps/colon cancer either during or immediately following chemotherapy with paclitaxel, suggesting a possible role of this agent in their pathogenesis.

Microsomal prostaglandin E synthase-1 is involved in multiple steps of colon carcinogenesis.

Accumulating evidence indicates that cyclooxygenase (COX)-2-derived prostaglandin (PG) E(2) is involved in the development of various tumors, including colorectal cancer. However, the precise contribution of microsomal PGE synthase (mPGES)-1, a terminal enzyme that acts downstream of COX-2 in the PGE(2)-biosynthetic pathway, to multiple processes of tumor development is not yet fully understood. Here, we show the pro-tumorigenic role of mPGES-1 in chemical carcinogen-induced colon carcinogenesis and intrasplenic tumor transplantation models. Genetic deletion of mPGES-1 significantly reduced both the total number and size of colorectal polyps at 18 weeks after azoxymethane administration with reduced nuclear translocation of ß-catenin, altered expression profiles of chemokines/cytokines and increased production of antitumorigenic PGs, prostaglandin D(2) and prostacyclin in tumor tissues. At an early stage (6 weeks), mPGES-1 deficiency significantly reduced the number of aberrant crypt foci, while its transgenic overexpression increased the number. Furthermore, the growth of intrasplenically transplanted tumor cells was suppressed in mPGES-1 knockout (KO) mice. Co-culture of tumor cells with bone marrow-derived macrophages (BM-MΦs) isolated from wild-type (WT) mice resulted in the induction of mPGES-1 in BM-MΦs and increased the growth of tumor cells in vitro, whereas mPGES-1-null BM-MΦs failed to facilitate tumor growth. The adoptive transfer of WT BM-MΦs into mPGES-1 KO mice restored the growth of transplanted tumor cells, indicating that mPGES-1 in MΦs is important for the growth of adjacent tumor cells. Taken together, our findings suggest that the inhibition of mPGES-1 is an alternative therapeutic target for colorectal and possibly other cancers.

Association of meat intake and meat-derived mutagen exposure with the risk of colorectal polyps by histologic type.

The association of meat intake and meat-derived mutagens with colorectal tumor risk remains unclear. We evaluated this hypothesis in a large colonoscopy-based case-control study. Included in the study were 2,543 patients with polyp [(1,881 with adenomas and 622 with hyperplastic polyp (HPP)] and 3,764 polyp-free controls. Surveys obtained information about meat intake by cooking methods and doneness levels plus other suspected or known risk factors for colorectal tumors. Unconditional logistic regression was used to derive ORs after adjusting for potential confounders. High intake of red meat and processed meat (P(trend) < 0.05), particularly red meat cooked using high-temperature cooking methods (P(trend) ≤ 0.01), was associated with an elevated risk for colorectal polyps. A significant positive association between exposures to meat-derived heterocyclic amines (HCA) and risk of polyps was found for both adenomas and HPPs. Furthermore, the positive association with red meat intake and HCA exposure was stronger for multiple adenomas than for single adenoma as well as for serrated than for nonserrated adenomas. This study supports a role for red meat and meat-derived mutagen exposure in the development of colorectal tumor.

Loss of adiponectin promotes intestinal carcinogenesis in Min and wild-type mice.

BACKGROUND & AIMS: Metabolic syndrome- and obesity-associated cancers, including colon cancer, are common in Western countries. Visceral fat accumulation and decreased levels of plasma adiponectin (APN) have been associated with development of human colorectal adenoma. We investigated the function of APN in intestinal carcinogenesis. METHODS: APN+/+, APN+/-, or APN-/- mice (C57BL/6J) were given injections of azoxymethane (AOM), which led to development of intestinal tumors; these strains of mice were also crossed with Min mice to assess polyp formation. Adipocytokine levels and phosphorylation/activation of AMP-activated protein kinase (AMPK) were evaluated to investigate the mechanisms of APN in tumor growth. RESULTS: The total number of polyps in the intestines of male APN+/-Min and APN-/-Min mice increased 2.4- and 3.2-fold, respectively, by the age of 9 weeks and 3.2- and 3.4-fold, respectively, by 12 weeks, compared with those of APN+/+Min mice. Similar results were obtained from female mice. AOM induced colon tumor formation in 40% of APN+/+, 50% of APN+/-, and 71% of APN-/- (P<.05) mice, respectively; mean values for tumor multiplicity of each genotype were 0.5, 0.6, and 1.1 (P<.05), respectively. Phosphorylation of AMPK decreased in intestinal epithelial cells of APN-/- mice compared with APN+/+ mice. Among serum adipocytokines, plasminogen activator inhibitor-1 levels increased in APN-/-Min mice and APN-/- mice that received injections of AOM. Activation of AMPK suppressed expression of plasminogen activator inhibitor-1 in Min mice. CONCLUSIONS: Mice with disruptions in APN develop more intestinal tumors and have decreased activation (phosphorylation) of AMPK and increased levels of plasminogen activator inhibitor-1, compared with wild-type mice. APN and its receptor might be developed as targets for cancer chemopreventive agents.