Sedentary Lifestyle And Your RNA

Take a look at this paper from several years ago, abstract:

Pioneering epidemiological work has established strong association of sedentary lifestyle and obesity with the risk of colorectal cancer, while the detailed underlying mechanism remains unknown. Here we show that Hotair (HOX transcript antisense RNA) is a pro-adipogenic long non-coding RNA highly expressed in gluteal-femoral fat over other fat depots. Hotair knockout in adipose tissue results in gluteal-femoral fat defect. Squeeze of the gluteal-femoral fat induces intestinal proliferation in wildtype mice, while not in Hotair knockout mice. Mechanistically, squeeze of the gluteal-femoral fat induces exosomal Hotair secretion mainly by transcriptional upregulation of Hotair via NFκB. And increased exosomal Hotair in turn circulates in the blood and is partially endocytosed by the intestine, finally promoting the stemness and proliferation of intestinal stem/progenitor cells via Wnt activation. Clinically, obese subjects with sedentary lifestyle have much higher exosomal HOTAIR expression in the serum. These findings establish that sedentary lifestyle promotes exosomal Hotair release from the gluteal-femoral fat, which in turn facilitates intestinal stem and/or progenitor proliferation, raising a possible link between sedentary lifestyle with colorectal tumorigenesis.

So, there is a link between a sedentary lifestyle, and release of this HOTAIR RNA from fat, which in turn promotes the growth of intestinal stem cells and/or progenitors - cells that form the target population for mutation leading to colorectal cancer.  The importance of an active lifestyle and a lean physique is underscored by these findings, in my opinion.

Identifying And Targeting Cancer Stem Cells

Here is a paper from several years ago demonstrating further identification of (colon) cancer stem cells, with information on targeting such cells for therapy.  Abstract:

The cancer stem cell (CSC) theory highlights a self-renewing subpopulation of cancer cells that fuels tumour growth. The existence of human CSCs is mainly supported by xeno-transplantation of prospectively isolated cells, but their clonal dynamics and plasticity remain elusive. Here, we demonstrate that human LGR5+ colorectal cancer cells serve as CSCs in growing cancer tissues. Lineage-tracing experiments with a CRISPR-Cas9-mediated LGR5-CreER knock-in allele reveal self-renewal and differentiation capacity of LGR5+ tumour cells. Selective ablation of LGR5+ CSCs in LGR5-iCaspase9 knock-in organoids leads to tumour regression, followed by tumour regrowth driven by re-emerging LGR5+ CSCs. KRT20-CreER marks differentiated cancer cells that constantly diminish in tumour tissues, while reverting to LGR5+ CSCs and contributing to tumour regrowth after LGR5+ CSC ablation. We also show that combined chemotherapy potentiates LGR5+ CSCs targeting. These data provide insights into the plasticity of CSCs and their potential as a therapeutic target in human colorectal cancer.

We'll be following further developments in this field.

Vitamin D Against Colon Cancer

Roles of vitamin D in colon cancer prevention, abstract:

Colorectal cancer (CRC) is the neoplasia that is most frequently associated with vitamin D deficiency in epidemiological and observational studies in terms of incidence and mortality. Many mechanistic studies show that the active vitamin D metabolite (1α,25-dihydroxyvitamin D3 or calcitriol) inhibits proliferation and promotes epithelial differentiation of human colon carcinoma cell lines that express vitamin D receptor (VDR) via the regulation of a high number of genes. A key action underlining this effect is the multilevel inhibition of the Wnt/β-catenin signaling pathway, whose abnormal activation in colon epithelial cells initiates and promotes CRC. Recently, our group has shown that calcitriol modulates gene expression and inhibits protumoral properties of patient-derived colon cancer-associated fibroblasts (CAFs). Accordingly, high VDR expression in tumor stromal fibroblasts is associated with longer survival of CRC patients. Moreover, many types of immune cells express VDR and are regulated by calcitriol, which probably contributes to its action against CRC. Given the role attributed to the intestinal microbiota in CRC and the finding that it is altered by vitamin D deficiency, an indirect antitumoral effect of calcitriol is also plausible at this level. In summary, calcitriol has an array of potential protective effects against CRC by acting on carcinoma cells, CAFs, immune cells and probably also the gut microbiota.

Fiber And Microbiota

Dietary fiber can increase levels of certain gut microbiota bacterial species, as well as higher levels of butyrate, a short chain fatty acid with beneficial anti-cancer effects in the colon.  Abstract:

BACKGROUND:

Dysfunction of the gut microbiota is frequently reported as a manifestation of chronic diseases, and therefore presents as a modifiable risk factor in their development. Diet is a major regulator of the gut microbiota and certain types of dietary fiber may modify bacterial numbers and metabolism, including short-chain fatty acid (SCFA) generation.

OBJECTIVE:

A systematic review and meta-analysis were undertaken to assess the effect of dietary fiber interventions on gut microbiota composition in healthy adults.

DESIGN:

A systematic search was conducted across MEDLINE, EMBASE, CENTRAL, and CINAHL for randomized controlled trials using culture and/or molecular microbiological techniques evaluating the effect of fiber intervention on gut microbiota composition in healthy adults. Meta-analyses via a random-effects model were performed on alpha diversity, prespecified bacterial abundances including Bifidobacterium and Lactobacillus spp., and fecal SCFA concentrations comparing dietary fiber interventions with placebo/low-fiber comparators.

RESULTS:

A total of 64 studies involving 2099 participants were included. Dietary fiber intervention resulted in higher abundance of Bifidobacterium spp. [standardized mean difference (SMD) 0.64 (95% CI: 0.42, 0.86); P < 0.00001)] and Lactobacillus spp. [SMD: 0.22 (0.03, 0.41), P = 0.02] as well as fecal butyrate concentration [SMD: 0.24 (0.00, 0.47), P = 0.05] compared with placebo/low-fiber comparators. Subgroup analysis revealed that fructans and galacto-oligosaccharides led to significantly greater abundance of both Bifidobacterium spp. and Lactobacillus spp. compared with comparators (P < 0.00001 and P = 0.002, respectively). No differences in effect were found between fiber intervention and comparators for α-diversity, abundances of other prespecified bacteria, or other SCFA concentrations.

CONCLUSIONS:

Dietary fiber intervention, particularly involving fructans and galacto-oligosaccharides, leads to higher fecal abundance of Bifidobacterium and Lactobacillus spp. but does not affect α-diversity. Further research is required to better understand the role of individual fiber types on the growth of microbes and the overall gut microbial community. This review was registered at PROSPERO as CRD42016053101.

Prognostic Genes For Colon Cancer

Determining prognostic genes for colon cancer; abstract:

PROPOSE:

We aimed to explore the potential molecular mechanism and independent prognostic genes for colon cancer (CC).

METHODS:

Microarray datasets GSE17536 and GSE39582 were downloaded from Gene Expression Omnibus. Meanwhile, the whole CC-related dataset were downloaded from The Cancer Genome Atlas (TCGA) database. Differentially expressed mRNA (DEMs) were identified between cancer tissue samples and para-carcinoma tissue samples in TCGA dataset, followed by the KEGG pathway and GO function analyses. Furthermore, the clinical prognostic analysis including overall survival (OS) and disease-free survival (DFS) were performed in all three datasets.

RESULTS:

A total of 633 up- and 321 down-regulated mRNAs were revealed in TCGA dataset. The up-regulated mRNAs were mainly assembled in functions including extracellular matrix and pathways including Wnt signaling. The down-regulated mRNAs were mainly assembled in functions like Digestion and pathways like Drug metabolism. Furthermore, up-regulation of UL16-binding protein 2 (ULBP2) was associated with OS in CC patients. A total of 12 DEMs including Surfactant Associated 2 (SFTA2) were potential DFS prognostic genes in CC patients. Meanwhile, the GRP and Transmembrane Protein 37 (TMEM37) were two outstanding independent DFS prognostic genes in CC.

CONCLUSIONS:

ULBP2 might be a potential novel OS prognostic biomarker in CC, while GRP and TMEM37 could be served as the independent DFS prognostic genes in CC. Furthermore, functions including extracellular matrix and digestion, as well as pathways including Wnt signaling and drug metabolism might play important roles in the process of CC.

An Anti-Cancer Antibiotic

An antibiotic, Nigericin, has anti-cancer activity, and one mechanism is through targeted suppression of Wnt signaling.  Abstract:

Nigericin, an antibiotic derived from Streptomyces hygroscopicus that works by acting as an H+, K+ and Pb2+ ionophore, has exhibited promising anticancer activity. The main purpose of this study is to investigate its inhibitory effects on Wnt/β-catenin signaling pathway in colorectal cancer (CRC) cells and clarify the underlying mechanism. We exposed two CRC lines (SW620 and KM12) to increasing concentrations of nigericin for different time periods and the 50% inhibiting concentration (IC50) values were evaluated. Our data showed that nigericin treatment significantly reduced tumor cell proliferation in dose- and time-dependent manners in CRC cells. The subsequent experiments in vitro and in vivo implied that nigericin could significantly suppress the tumor growth, migration and invasion, and induce the apoptosis of CRC cells. Our results of western blot and immunofluorescence assay showed that nigericin could suppress the Wnt/β-catenin signaling pathway in CRC cells with dose-dependent increased expressions of downstream effectors and target proteins. To further elucidate the inhibitory effects of nigericin via a β-catenin-dependent signaling mechanism, we established the stably β-catenin over-expression CRC cells. Western blot, SuperTOPflash luciferase reporter and immunoprecipitation assays all confirmed β-catenin as a critical intermediary and player in Wnt/β-catenin pathway, and nigericin exerted anti-cancer effects on CRC cells by directly targeting the β-catenin destruction complex. These results suggested that Wnt/β-catenin signaling might have an essential role in CRC progression. Nigericin targeting Wnt/β-catenin signaling might provide new insight into the molecular mechanism of nigericin towards cancer cells, and suggest possible clinical application in CRC

Another MicroRNA And Colorectal Cancer

Another microRNA has been shown to affect colorectal cancer, this time by targeting the Wnt pathway-controlling protein APC (that is typically mutated and inactivated in this form of cancer).  The microRNA may promote cancer by further decreasing APC and allowing for more deregulated Wnt signaling.  This has potential diagnostic and therapeutic applications. Abstract:

BACKGROUND:

Aberrant activation of the Wnt/β-catenin signaling pathway is frequently observed in colorectal cancer (CRC). β-catenin is the major Wnt signaling pathway effector and inactivation of adenomatous polyposis coli (APC) results in nuclear accumulation of β-catenin. It has been suggested that inactivation of APC plays an important role in activation of the Wnt/β-catenin pathway and in the progression of colorectal tumorigenesis. However, the mechanism through which APC mediates colorectal tumorigenesis is not understood. Increasing evidence suggests that the dysregulation of microRNAs (miRNAs) is involved in colorectal tumorigenesis. Although miR-494 has been reported as being an upregulated miRNA, the interplay between miR-494 and APC-mediated colorectal tumorigenesis progression remains unclear.

METHODS:

The expression of miR-494 in tissues from patients diagnosed with CRC was analyzed using a microarray and real-time PCR. The effects of miR-494 on cell proliferation and tumorigenesis in CRC cells were analyzed by flow cytometry, colony formation assays, BrdU incorporation assays, and CCK8 assays. The correlation between miR-494 expression and APC expression, as well as the mechanisms by which miR-494 regulates APC in CRC were also addressed.

RESULTS:

miR-494 was significantly upregulated in CRC tissues, and this increase was negatively associated with APC expression. APC was confirmed to be a direct target of miR-494 in CRC. Furthermore, overexpression of miR-494 induced Wnt/β-catenin signaling by targeting APC, thus promoting CRC cell growth.

CONCLUSIONS:

This study provides novel insights into the role of miR-494 in controlling CRC cell proliferation and tumorigenesis, and identifies miR-494 as a potential prognostic marker and therapeutic target.

TGIF1 In Colorectal Cancer

TGIF1 is another molecular factor discovered to promote colorectal cancer, apparently by upregulating the deregulated Wnt signaling found in most cases of that disease.  This discovery may point to novel therapeutic approaches targeting this factor.  Abstract:

Colorectal cancer (CRC) is one of the most common cancers, but the mechanisms underlying its initiation and progression are largely unknown. TGIF1 (TGFB induced factor homeobox 1) is a transcriptional corepressor that belongs to the three-amino acid loop extension (TALE) superclass of atypical homeodomains. It has been reported that TGIF1 is highly expressed in mammary cancer and non-small cell lung cancer and can enhance tumor progression. However, the role of TGIF1 in colorectal cancer remains unknown. Here, we report that TGIF1 is significantly upregulated in colorectal cancers, and its high expression predicts poor prognosis. Overexpression of TGIF1 markedly promotes the proliferation of colorectal cancer cells both in vivo and in vitro. In addition, TGIF1 activates Wnt/β-catenin signaling, and the homeodomain is indispensable for Wnt activation and β-catenin interaction. Taken together, our results suggest that TGIF1 is a novel colorectal tumor promoter and indicate that TGIF1 enhances colorectal cancer tumorigenesis through activating Wnt signaling.

HCMV And Cancer

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Human cytomegalovirus (HCMV) is common lifelong infection agent that usually remains latent after the initial infection and can become reactivated later in life. HCMV infection can promote the growth and metastatic potential of colorectal cancer cells.  Therefore, HCMV may contribute to the human cancer burden.  Abstract:

Increasing evidence suggests a link between persistent human cytomegalovirus (HCMV) infection and cancer. Although the role of HCMV in cancer is still elusive, recent studies revealed the presence of HCMV nucleic acids and proteins in different cancer types such as glioblastoma, colorectal, breast, and prostate cancers, and neuroblastoma. Although HCMV may not be directly associated with the neoplastic transformation, the presence of HCMV DNA in the tumorous tissue has been associated with altered clinical outcomes in cancer patients. However, the mechanisms involved in the association between colorectal cancer (CRC) and HCMV are unclear. In this study, we investigated the influence of HCMV infection on CRC or their derived cells. Proliferation and migration assays revealed a high infection efficiency in CRC-derived HT29 and SW480 'stem‑like' cells. After 24, 48 and 72 h of HCMV infection, both HT29 and SW480 parental and stem‑like cells showed a significant increase in cell proliferation and viability (p<0.0001). Moreover, HCMV infection promoted cell migration. These results demonstrate a significant phenotypic alteration in the CRC cell line upon HCMV infection. Using epithelial to mesenchymal transition (EMT) assays, we demonstrated that the EMT markers and driver genes were upregulated during the virus infection. The WNT signaling pathway, which is associated with the proliferation and migration of CRC cells, was upregulated (6-fold) in HCMV-infected cells as compared to the non‑infected cells at day 7 from infection.

Your Risk for Colon Cancer

50,630:
this is the projected number of colorectal cancer (CRC) -related deaths for 2018 in the U.S. Only lung cancer-related deaths exceed this number.

How does CRC start? It begins as a benign growth – polyp / adenoma. The most frequent initiating mutation is in the APC gene, and less frequently - in the proteins beta-Catenin, Axin, and KRAS. Given sufficient time - approximately 10 years - and the right mutations (i.e., mutations that allow self-sufficiency in growth signaling, resistance to apoptosis, potential for unlimited growth, etc), malignancy develops.

Once the malignancy has established itself, cure is unlikely. Therefore, the best approach is this of prevention; the words of Ben Franklin are still valid:

… an ounce of prevention is worth a pound of cure…

The power of prevention is best understood when we look at the leading causes of death for the past 100 years. NEJM has published a great review that summarizes the ten leading causes of death in the U.S. since 1900. If we compare 1900 to 2010, we will find that the three biggest killers in 1900 were the gastrointestinal infections, pneumonia, and TB.  However, these were no longer the biggest killers in 2010 (the last year in the NEJM review).

How did we achieve that? Sanitation, better nutrition, vaccination, and antibiotics. Except for the antibiotics, the rest of the measures/changes were preventive.

Since the 1960s we have also seen reduction in heart disease-associated deaths due to prevention with medications that control blood pressure and cholesterol.

The lesson is that any significant victory against a disease is achieved through preventive strategies. There is no doubt in my mind that we will claim a significant victory against cancer, when we dedicate more financial resources to prevention. Cervical cancer is the perfect example how prevention through screening and vaccines reduces cancer deaths.

However, can we prevent colorectal cancer (CRC)? Obviously, screening is one answer; although quite invasive, colonoscopy detects early lesions. What else can we do? The American Institute for Cancer Research (AICR) has estimated that approximately 45% of all CRC cases can be prevented mostly through lifestyle changes. The institute has come up with five simple recommendations … that may slash the number of CRC cases by half! The problem with all these recommendations is that they require self-discipline.

The increased intake of fiber is one of the recommendations. Although the topic has been controversial for the past few decades, in 2003, two massive prospective epidemiological studies (one from Europe and one from the U.S.) concluded that fiber does protect against colon cancer: increasing the intake of fiber from 15 g to 35 g results in 40% decrease in risk.

Here is the summary of one of the studies:

Lancet 2003 May 3;361(9368):1496-501.Bingham SA:  
We prospectively examined the association between dietary fibre intake and incidence of colorectal cancer in 519978 individuals aged 25-70 years in ten European countries. Participants completed a dietary questionnaire in 1992-98 and were followed up for cancer incidence. …data for 1065 reported cases of colorectal cancer were included in the analysis. Dietary fibre in foods was inversely related to incidence of large bowel cancer (adjusted relative risk 0.75 [95% CI 0.59-0.95] for the highest versus lowest quintile of intake), the protective effect being greatest for the left side of the colon, and least for the rectum. After calibration with more detailed dietary data, the adjusted relative risk for the highest versus lowest quintile of fibre from food intake was 0.58 (0.41-0.85). No food source of fibre was significantly more protective than others, and non-food supplement sources of fibre were not investigated. In populations with low average intake of dietary fibre, an approximate doubling of total fibre intake from foods could reduce the risk of colorectal cancer by 40%.

In 2011, AICR and the continuous update project announced that the protective effect of fiber against colon cancer is upgraded from probable to convincing.

Colorectal Cancer And Bacterial Colonization

Colonization by a specific bacterial species is “strongly associated” with colorectal cancer; whether this is cause or effect – or both – remains to fully determined.  This study suggests that it is at least effect – conditions leading to cancer development, including deregulation of Wnt signaling, favor the colonization at the expense of other bacterial species.  It is of course also possible that these “bad” (?) bacteria, once established, then affect the further progression of the cancer.  At the very least, their presence is a sign something is not right.  Abstract:

Colonization by Streptococcus gallolyticus subsp. gallolyticus (SGG) is strongly associated with the occurrence of colorectal cancer (CRC). However, the factors leading to its successful colonization are unknown, and whether SGG influences the oncogenic process or benefits from the tumor-prone environment to prevail remains an open question. Here, we elucidate crucial steps that explain how CRC favors SGG colonization. By using mice genetically prone to CRC, we show that SGG colonization is 1,000-fold higher in tumor-bearing mice than in normal mice. This selective advantage occurs at the expense of resident intestinal enterococci. An SGG-specific locus encoding a bacteriocin ("gallocin") is shown to kill enterococci in vitro. Importantly, bile acids strongly enhance this bacteriocin activity in vivo, leading to greater SGG colonization. Constitutive activation of the Wnt pathway, one of the earliest signaling alterations in CRC, and the decreased expression of the bile acid apical transporter gene Slc10A2, as an effect of the Apc founding mutation, may thereby sustain intestinal colonization by SGG. We conclude that CRC-specific conditions promote SGG colonization of the gut by replacing commensal enterococci in their niche.

Cannabinoids For Metastatic Colon Cancer?

Rimonabant, which interacts with cannabinoid receptors, inhibits canonical Wnt signaling in colorectal cancer cells; this form of Wnt signaling is often deregulated in cancer.  An opposing signaling pathway, non-canonical Wnt signaling, is upregulated in some, but not all, colorectal cancer cells.  This reagent also reduced tumor growth in a mouse model of colon cancer.  Thus, the authors conclude that: “Obtained data heavily supported the rationale for the use of cannabinoids in combined therapies for metastatic CRC harbouring activating mutations of β-Catenin” – although of course more research is needed.  Abstract:

In a high percentage (≥85%) of both sporadic and familial adenomatous polyposis forms of colorectal cancer (CRC), the inactivation of the APC tumor suppressor gene initiates tumor formation and modulates the Wnt/β-Catenin transduction pathways involved in the control of cell proliferation, adhesion and metastasis. Increasing evidence showed that the endocannabinoids control tumor growth and progression, both in vitro and in vivo. We evaluated the effect of Rimonabant, a Cannabinoid Receptor 1 (CB1) inverse agonist, on the Wnt/β-Catenin pathway in HCT116 and SW48 cell lines carrying the genetic profile of metastatic CRC poorly responsive to chemotherapies. In these models, Rimonabant inhibited the Wnt/β-Catenin canonical pathway and increased β-Catenin phosphorylation; in HCT116 cells, but not in SW48, the compound also triggered the Wnt/β-Catenin non canonical pathway activation through induction of Wnt5A and activation of CaMKII. The Rimonabant-induced downregulation of Wnt/β-Catenin target genes was partially ascribable to a direct inhibition of p300/KAT3B histone acetyltransferase, a coactivator of β-Catenin dependent gene regulation. Finally, in HCT116 xenografts, Rimonabant significantly reduced tumor growth and destabilized the nuclear localization of β-Catenin. Obtained data heavily supported the rationale for the use of cannabinoids in combined therapies for metastatic CRC harbouring activating mutations of β-Catenin.

Colon Cancer Mutations Associated With The Gut Microbiota

An extremely important study on colon cancer concludes: “We found statistically significant associations between loss-of-function mutations in tumor genes and shifts in the abundances of specific sets of bacterial taxa, suggestive of potential functional interaction.”  Further, the correlation between bacterial types and tumor mutations allowed for predictions about interactions between the mutations and the downstream signaling pathways affected by these mutations.  One can expect future work to more clearly delineate the molecular mechanisms of interaction between the microbiota and cancer mutations.  In the meantime, once again – for the thousandth time it seems – the importance of the gut microbiota is emphasized.  Abstract:

Variation in the gut microbiome has been linked to colorectal cancer (CRC), as well as to host genetic variation. However, we do not know whether, in addition to baseline host genetics, somatic mutational profiles in CRC tumors interact with the surrounding tumor microbiome, and if so, whether these changes can be used to understand microbe-host interactions with potential functional biological relevance. Here, we characterized the association between CRC microbial communities and tumor mutations using microbiome profiling and whole-exome sequencing in 44 pairs of tumors and matched normal tissues. We found statistically significant associations between loss-of-function mutations in tumor genes and shifts in the abundances of specific sets of bacterial taxa, suggestive of potential functional interaction. This correlation allows us to statistically predict interactions between loss-of-function tumor mutations in cancer-related genes and pathways, including MAPK and Wnt signaling, solely based on the composition of the microbiome. In conclusion, our study shows that CRC microbiomes are correlated with tumor mutational profiles, pointing towards possible mechanisms of molecular interaction.

More On Gut Microbiota And Colorectal Cancer

Another paper about gut microbiota and colorectal cancer is of interest.  Abstract:

Pre-clinical and clinical data produce mounting evidence that the microbiota is strongly associated with colorectal carcinogenesis. Dysbiosis may change the course of carcinogenesis as microbial actions seem to impact genetic and epigenetic alterations leading to dysplasia, clonal expansion and malignant transformation. Initiation and promotion of colorectal cancer may result from direct bacterial actions, bacterial metabolites and inflammatory pathways. Newer aspects of microbiota and colorectal cancer include quorum sensing, biofilm formation, sidedness and effects/countereffects of microbiota and probiotics on chemotherapy. In the future, targeting the microbiota will probably be a powerful weapon in the battle against CRC as gut microbiology, genomics and metabolomics promise to uncover important linkages between microbiota and intestinal health.

Again we see the paradigm that targeting the gut microbiota, to yield a more healthy bacterial profile,c can be a future anti-cancer approach.

Legumes And Colorectal Adenoma Risk

An unsurprising finding is that legume consumption is associated with deceased risk for colorectal adenoma.  More investigations are required because such “meta-analysis” can have confounding variables.  Still, the conclusion is consistent with all else we know about dietary recommendations regarding colorectal cancer prevention. Prevent the adenoma (poly), prevent the carcinoma (cancer). Fiber helps.  Abstract:

Background

The anticancer effects of legumes have been explored extensively, but evidence from epidemiologic studies on colorectal adenoma is controversial. We performed a meta-analysis to assess these issues.

Methods

A systemic search of several databases was conducted for relevant studies evaluating the relationship between legume intake and adenoma risk, with no language restriction, from January 1, 1966, to April 1, 2013.

Results

Three cohort and eleven case control studies with 8,380 cases and a total of 101,856 participants were included in the analysis; the pooled odds ratio (95% confidence interval) for the highest vs. lowest consumption categories was 0.83 (0.75–0.93), with moderate level of heterogeneity (I2 = 25.9% and P = 0.146) based on a random effects model. A decreased risk of adenoma was also observed in most of our subgroup meta-analyses.

Conclusions

Higher intake of legumes significantly reduced the risk of colorectal adenoma in our meta-analysis. Nevertheless, due to possible confounders and bias, further investigations are warranted to confirm this relationship.

Against Colitis And Cancer

Chronic inflammation of the colon can increase risk for cancer; an antibody to a pro-inflammatory mediator can reduce inflammation in a mouse model, reducing cancer risk through the modulation of important cancer- related signaling pathways that can be affected by inflammation.  This is a promising therapeutic approach.  Abstract:

The association between chronic inflammation and cancer has long been recognized. The inflammatory bowel disease ulcerative colitis frequently progresses to colon cancer; however, the underlying mechanism is still unclear. S100a9 has been emerged as an important pro-inflammatory mediator in acute and chronic inflammation, and the aberrant expression of S100a9 also contributes to tumorigenic processes such as cell proliferation, angiogenesis, metastasis, and immune evasion. We previously revealed that S100a8 and S100a9 are highly activated and play an important role in the process of colitis-associated carcinogenesis, which suggests an attractive therapeutic target for ulcerative colitis and related colon cancer. Here, we report that administration of a neutralizing anti-S100a9 antibody significantly ameliorated dextran sulfate sodium (DSS)-induced colitis and accompanied by diminished cellular infiltrate of innate immunity cells (macrophages, neutrophils, and dendritic cells) and production of pro-inflammatory cytokines (Tnfα, Il1β, Ifnγ, Il6, Il17a, Il23a, Il4, and Il12a). The protective effect of anti-S100a9 antibody treatment was also observed in azoxymethane (AOM)/DSS-induced colitis-associated cancer (CAC) mouse model. The inflammatory response, tumor cell proliferation, and immune cells infiltration in the colon tissues were suppressed by anti-S100a9 antibody. Gene expression profiling showed that key pathways known to be involved in CAC development, such as Wnt signaling pathway, PI3K-Akt signaling pathway, cytokine-cytokine receptor interaction, and ECM-receptor interaction pathway, were suppressed after treatment with anti-S100a9 antibody in CAC mice. In view of the protective effect of neutralizing anti-S100a9 antibody against DSS-induced colitis and AOM/DSS-induced CAC in mouse model, this study suggests that anti-S100a9 antibody may provide a novel therapeutic approach to treat ulcerative colitis and may decrease the risk for developing CAC.

Three Is Enough

Colorectal cancer is a prime example of the multiple hit hypothesis, a cancer that is driven by the accumulation of sequential mutations in key genes.  Here is a study in mice asserting that only three mutations in key pathways were sufficient to drive a metastatic form of this cancer in the animal model.  Abstract:

Colorectal cancer (CRC) is driven by the accumulation of driver mutations, but the contributions of specific mutations to different steps in malignant progression is not fully understood. In this study, we generated mouse models harboring different combinations of key CRC driver mutations (Apc, Kras, Tgfbr2, Trp53, Fbxw7) in intestinal epithelial cells to comprehensively investigate their roles in the development of primary tumors and metastases. Apc∆716 mutation caused intestinal adenomas and combination with Trp53R270H mutation or Tgfbr2 deletion induced submucosal invasion. The addition of KrasG12D mutation yielded EMT-like morphology and lymph vessel intravasation of the invasive tumors. In contrast, combinations of Apc∆716 with KrasG12D and Fbxw7 mutation was insufficient for submucosal invasion but still induced EMT-like histology. Studies using tumor-derived organoids showed that KrasG12D was critical for liver metastasis following splenic transplantation, when this mutation was combined with either Apc∆716 plus Trp53R270H or Tgfbr2 deletion, with the highest incidence of metastasis displayed by tumors with a Apc∆716 KrasG12D Tgfbr2-/- genotype. RNAseq analysis of tumor organoids defined distinct gene expression profiles characteristic for the respective combinations of driver mutations, with upregulated genes in Apc∆716 KrasG12D Tgfbr2-/- tumors found to be similarly upregulated in specimens of human metastatic CRC. Our results show how activation of Wnt and Kras with suppression of TGF-β signaling in intestinal epithelial cells is sufficient for CRC metastasis, with possible implications for the development of metastasis prevention strategies.

Salmonella And Colon Cancer

Public Domain, https://commons.wikimedia.org/w/index.php?curid=450281 

Salmonella, at least in mouse models, can promote colon cancer, at least in part by affecting Wnt signaling factors.  The microbial population in your body is one of the major determinants of healyh, in one form or another.  Abstract:

Salmonella infection is a major public health concern, and colonization in humans can be chronic and increases the risk of cancers. Wnt signaling is a key pathway for intestinal renewal and development, inflammation, and tumorigenesis. In the current study, we report a novel role of Wnt1 in infection and colon cancer using cell culture models, a Salmonella-colitis colon cancer model, and human samples. In contrast to the bacteria-induced increases in Wnt2 and Wnt11, Salmonella colonization significantly reduced the level of Wnt1 in intestinal epithelial cells in vivo and in vitro. The bacterial AvrA protein is known to activate the canonical Wnt pathway. Wnt1 expression level was downregulated by AvrA-expressing Salmonella but stabilized by AvrA-deficient Salmonella in the intestine of Salmonella-colitis mice. In a chronic Salmonella-infected cancer model, the Wnt1 protein level was decreased in the AvrA+ infected group. Thus, we further assessed the functional role of Wnt1 downregulation in the inflammatory response and colorectal cancer (CRC) progression. Moreover, downregulation of Wnt1 by the Crispr-Cas9 method promoted cancer cell invasion and migration. Interestingly, we found that Wnt1 was downregulated in human CRC tissue, and Wnt1 downregulation may be correlated with cancer progression. Our study provides insights into mechanisms by which enteric bacteria regulate Wnt1 expression and potentially contribute to infection-associated colon cancer.

Leaf Extract Against Colorectal cancer

Here is a study suggesting that Ginkgo biloba L. leaf extract may be beneficial against colorectal cancer by affecting important cell signaling pathways that mediate that disease. The authors state: “The outcomes of the present investigation encourage the use of Ginkgo biloba L. leaf extract as a complementary and alternative therapeutic approach to abate CRC.”  As always consult your own physician; in my opinion, “complementary” may be useful, but “alternative” (as in use this but do not use traditional medical treatments) is a mistake. I have heard of too many horror stories of patients eschewing regular treatment for alternatives and then dying if a curable cancer because they realized, too late, that the alternative was really no alternative at all.  But, again, I am not a medical doctor and I am only giving my own opinion based on scientific background as well as personal experience and anecdote.  I would urge all cancer patients to follow the advice of their oncologists and, of course, ask whether other things can complement treatment.

Gut Microbiome In FAP

The gut microbiome is known to typically be abnormal in patients with sporadic colorectal cancer (CRC).  A study has now shown that individuals with a form of hereditary CRC have bacterial biofilms containing tumorigenic, cancer-promoting bacterial strains, and exhibit cancer-promoting gene expression due to this bacterial colonization.  Mouse models of CRC exhibit accelerated tumor development when colonized by these strains.  These important findings underscore the importance of the gut bacteria and suggests targets for therapeutic intervention. Abstract:

Individuals with sporadic colorectal cancer (CRC) frequently harbor abnormalities in the composition of the gut microbiome; however, the microbiota associated with precancerous lesions in hereditary CRC remains largely unknown. We studied colonic mucosa of patients with familial adenomatous polyposis (FAP), who develop benign precursor lesions (polyps) early in life. We identified patchy bacterial biofilms composed predominately of Escherichia coli and Bacteroides fragilis Genes for colibactin (clbB) and Bacteroides fragilis toxin (bft), encoding secreted oncotoxins, were highly enriched in FAP patients' colonic mucosa compared to healthy individuals. Tumor-prone mice cocolonized with E. coli (expressing colibactin), and enterotoxigenic B. fragilis showed increased interleukin-17 in the colon and DNA damage in colonic epithelium with faster tumor onset and greater mortality, compared to mice with either bacterial strain alone. These data suggest an unexpected link between early neoplasia of the colon and tumorigenic bacteria.