While clinical outcomes from colorectal cancer (CRC) are influenced by stage at diagnosis and treatment, mounting evidence suggests that an enhanced lymphocytic reaction to a tumor may also be an ...informative prognostic indicator.
The roles of intratumoral T lymphocyte infiltration (TIL), peritumoral Crohn's-like lymphoid reaction (CLR), microsatellite instability (MSI), and clinicopathological characteristics in survival from CRC were examined using 2369 incident CRCs from a population-based case-control study in northern Israel. Cox proportional hazards regression was used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for CRC-specific and all-cause mortality in multivariable models adjusted for age, sex, ethnicity, grade, stage, and MSI. All statistical tests were two-sided.
Tumors with TIL/high-powered field (HPF) of 2 or greater were associated with a statistically significant increase in CRC-specific (P < .001) and overall survival (P < .001) compared with tumors with TIL/HPF of less than 2. Similarly, tumors with a prominent CLR experienced better CRC-specific (P < .001) and overall survival (P < .001) as compared with those with no response. High TILs (HR = 0.76, 95% CI = 0.64 to 0.89, P < .001) and a prominent CLR (HR = 0.71, 95% CI = 0.62 to 0.80, P < .001), but not MSI, were associated with a statistically significant reduction in all-cause mortality after adjustment for established prognostic factors.
TILs and CLR are both prognostic indicators for CRC after adjusting for traditional prognostic indicators.
Tropical sprue (TS) is a malabsorption syndrome of presumed infectious aetiology that affects residents of (or visitors to) the tropics. The histological changes of TS are similar to those of coeliac ...disease, with increased intraepithelial lymphocytes being central to both. Unlike in coeliac disease, however, a completely flat small bowel biopsy is uncommon in TS. TS typically involves the terminal ileum, whereas coeliac disease does not. Small intestinal bacterial overgrowth (SIBO) has been defined as an increase in number and/or a change in the type of bacteria in the upper gut. Conditions that predispose to SIBO are largely those that decrease or interfere with small bowel motility. The mucosal histology is variable, and may include modest villous blunting accompanied by increased lamina propria and epithelial inflammation. Autoimmune enteropathy (AE) is a family of rare diseases that share common themes such as immunodeficiency states and autoantibodies. AE cases typically have marked villous atrophy similar to that in fully developed coeliac disease, but they lack the intense surface epithelial lymphocytosis. Apoptosis and lymphocyte infiltration at the base of the crypts, crypt abscesses and cryptitis are also seen. Patients with anti‐goblet cell antibodies can have a lack of goblet cells, endocrine cells, and Paneth cells.
Recent studies have highlighted the existence of subclones in tumors. Lymph nodes are generally the first location of metastasis for most solid epithelial tumors, including colorectal cancer. We ...sought to understand the genetic origin of lymph node metastasis in colorectal cancer by evaluating the relationship between colorectal cancer subclones present in primary tumors and lymph nodes.
A total of 33 samples from seven colorectal cancers, including two or three spatially disparate regions from each primary tumor and one to four matched lymph nodes for each tumor, underwent next-generation whole-exome DNA sequencing, Affymetrix OncoScan SNP arrays, and targeted deep confirmatory sequencing. We performed mapping between SNPs and copy number events from the primary tumor and matched lymph node samples, allowing us to profile heterogeneity and the mutational origin of lymph node metastases. The computational method PyClone was used to define subclones within each tumor. The method Clonality Inference in Tumors Using Phylogeny (CITUP) was subsequently used to infer phylogenetic relationships among subclones.
We found that there was substantial heterogeneity in mutations and copy number changes among all samples from any given patient. For each patient, the primary tumor regions and matched lymph node metastases were each polyclonal, and the clonal populations differed from one lymph node to another. In some patients, the cancer cell populations in a given lymph node originated from multiple distinct regions of a tumor.
Our data support a model of lymph node metastatic spread in colorectal cancer whereby metastases originate from multiple waves of seeding from the primary tumor over time.
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Neutrophils are among the most prevalent immune cells in the microenvironment of colon tumors; they are believed to promote growth of colon tumors, and their numbers correlate with outcomes of ...patients with colon cancer. Trials of inhibitors of neutrophil trafficking are underway in patients with cancer, but it is not clear how neutrophils contribute to colon tumorigenesis.
Colitis-associated colon cancer was induced in mice with conditional deletion of neutrophils (LysMCre;Mcl1fl/fl) and wild-type littermates (LysMCre;Mcl1wt/wt, control mice) by administration of azoxythmethane and/or dextran sulfate sodium. Sporadic colon tumorigenesis was assessed in neutrophil-deficient and neutrophil-replete mice with conditional deletion of colon epithelial Apc (Cdx2-CreERT2;Apcfl/fl). Primary colon tumor tissues from these mice were assessed by histology, RNA sequencing, quantitative polymerase chain reaction, and fluorescence in situ hybridization analyses. Fecal and tumor-associated microbiota were assessed by 16s ribosomal RNA sequencing.
In mice with inflammation-induced and sporadic colon tumors, depletion of neutrophils increased the growth, proliferation, and invasiveness of the tumors. RNA sequencing analysis identified genes that regulate antimicrobial and inflammatory processes that were dysregulated in neutrophil-deficient colon tumors compared with colon tumors from control mice. Neutrophil depletion correlated with increased numbers of bacteria in tumors and proliferation of tumor cells, tumor-cell DNA damage, and an inflammatory response mediated by interleukin 17 (IL17). The 16s ribosomal RNA sequencing identified significant differences in the composition of the microbiota between colon tumors from neutrophil-deficient vs control mice. Administration of antibiotics or a neutralizing antibody against IL17 to neutrophil-deficient mice resulted in development of less-invasive tumors compared with mice given vehicle. We found bacteria in tumors to induce production of IL17, which promotes influx of intratumor B cells that promote tumor growth and progression.
In comparisons of mice with vs without neutrophils, we found neutrophils to slow colon tumor growth and progression by restricting numbers of bacteria and tumor-associated inflammatory responses.
Recognized clinical risk factors for progression (emergency presentation, poorly differentiated tumor, depth of tumor invasion, and adjacent organ involvement) are insufficient to identify those ...patients with stage II CRC at higher risk of disease progression 4,5. ...a meta-analysis aimed to assess the predictive ability of these signatures revealed that although gene expression signatures may be associated with prognosis, their ability to accurately predict patients’ risk of progression was limited, probably due to the molecular heterogeneity of tumors 7. ...the identification of new biomarkers to inform clinical decision-making for adjuvant chemotherapy is needed 8. Methods Patients and samples The discovery dataset (named ICO/CLX) included a previously described set of 100 patients with colon cancer diagnosed at stage II and MSS paired normal-tumor samples (Colonomics study, “CLX”: www.colonomics.org; NCBI BioProject PRJNA188510). Raw sequence data were filtered based on the TCRβ V, D, and J gene definitions provided by the international ImMunoGeneTics information system (IMGT) database and binned using a modified nearest-neighbor algorithm to merge closely related sequences and remove both PCR and sequencing errors.
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Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The Crohn's-like lymphoid reaction (CLR) to colorectal cancer (CRC), a CRC-specific ectopic lymphoid reaction, is thought to play an important role in the host response to CRC. CLR is characterized ...by peritumoral lymphocytic aggregates that are found at the advancing edge of the tumor. Spatial and molecular characterization of CLR within the tumor microenvironment (TME) have uncovered a spectrum of peritumoral lymphoid aggregates with varying levels of organization and maturation. In early stages of CLR development, CD4+ T-cells cluster predominantly with mature antigen presenting dendritic cells. As CLR matures, increasing numbers of B-cells, as well as follicular dendritic cells are recruited to create lymphoid follicles. When highly organized, CLR resembles functional tertiary lymphoid structures (TLS), allowing for lymphocyte recruitment to the TME and promoting a tumor-specific adaptive immune response. CLR has been consistently associated with favorable prognostic factors and improved survival among CRC patients, often providing more prognostic information than current clinical staging systems. However, consensus is lacking regarding CLR scoring and it is not clinically assessed or reported. Differences between CLR and other cancer-associated lymphoid structures exist both in primary and metastatic disease, underscoring the need to characterize organ-specific TLS. Further research is needed to explore the role of CLR in predicting response to immunotherapy and to leverage CLR to promote immunotherapeutic strategies in CRC.
Reprogramming of cellular metabolism is a key event during tumorigenesis. Despite being known for decades (Warburg effect), the molecular mechanisms regulating this switch remained unexplored. Here, ...we identify SIRT6 as a tumor suppressor that regulates aerobic glycolysis in cancer cells. Importantly, loss of SIRT6 leads to tumor formation without activation of known oncogenes, whereas transformed SIRT6-deficient cells display increased glycolysis and tumor growth, suggesting that SIRT6 plays a role in both establishment and maintenance of cancer. By using a conditional SIRT6 allele, we show that SIRT6 deletion in vivo increases the number, size, and aggressiveness of tumors. SIRT6 also functions as a regulator of ribosome metabolism by corepressing MYC transcriptional activity. Lastly, Sirt6 is selectively downregulated in several human cancers, and expression levels of SIRT6 predict prognosis and tumor-free survival rates, highlighting SIRT6 as a critical modulator of cancer metabolism. Our studies reveal SIRT6 to be a potent tumor suppressor acting to suppress cancer metabolism.
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► SIRT6 is a tumor suppressor that regulates cancer metabolism ► SIRT6 can lead to tumor formation even in the absence of oncogene activation ► SIRT6 levels predict tumor-free survival time in human cancers ► Inhibition of glycolysis in SIRT6-deficient cells abrogates tumor formation
The loss of Sirt6 promotes the metabolic reprogramming of cancer cells by increasing aerobic glycolysis and ribosome biosynthesis.
Background & Aims Hypoxic inflammation (decreased oxygen tension at sites of inflammation) is a feature of inflammatory bowel disease (IBD). The hypoxia response is mediated by the transcription ...factors hypoxia-inducible factor (HIF) 1α and endothelial PAS domain protein 1 (EPAS1 or HIF2α), which are induced in intestinal tissues of patients with IBD. HIF1α limits intestinal barrier dysfunction, but the role of EPAS1 has not been assessed under conditions of hypoxic inflammation or in models of IBD. Methods Acute colitis was induced by administration of Citrobacter rodentium or dextran sulfate sodium (DSS) to transgenic hypoxia reporter mice (oxygen-dependent degradation−luciferase), mice with conditional overexpression of Epas1 ( Epas1LSL/LSL ), mice with intestinal epithelium-specific deletion of Epas1 ( Epas1ΔIE ), or wild-type littermates (controls). Colon tissues from these mice and from patients with ulcerative colitis or Crohn's disease were assessed by histologic and immunoblot analyses, immunohistochemistry, and quantitative polymerase chain reaction. Results Levels of hypoxia and EPAS1 were increased in colon tissues of mice after induction of colitis and patients with ulcerative colitis or Crohn's disease compared with controls. Epas1ΔIE mice had attenuated colonic inflammation and were protected from DSS-induced colitis. Intestine-specific overexpression of EPAS1, but not HIF-1α, led to spontaneous colitis, increased susceptibility to induction of colitis by C rodentium or DSS, and reduced survival times compared with controls. Disruption of intestinal epithelial EPAS1 attenuated the inflammatory response after administration of DSS or C rodentium , and intestine-specific overexpression of EPAS1 increased this response. We found EPAS1 to be a positive regulator of tumor necrosis factor−α production by the intestinal epithelium. Blocking tumor necrosis factor−α completely reduced hypoxia-induced intestinal inflammation. Conclusions EPAS1 is a transcription factor that activates mediators of inflammation, such as tumor necrosis factor−α, in the intestinal epithelium and promotes development of colitis in mice.
Inflammatory bowel disease (IBD) is a chronic inflammatory disorder and is a major risk factor for colorectal cancer (CRC). Hypoxia is a feature of IBD and modulates cellular and mitochondrial ...metabolism. However, the role of hypoxic metabolism in IBD is unclear. Because mitochondrial dysfunction is an early hallmark of hypoxia and inflammation, an unbiased proteomics approach was used to assess the mitochondria in a mouse model of colitis. Through this analysis, we identified a ferrireductase: six-transmembrane epithelial antigen of prostate 4 (STEAP4) was highly induced in mouse models of colitis and in IBD patients. STEAP4 was regulated in a hypoxia-dependent manner that led to a dysregulation in mitochondrial iron balance, enhanced reactive oxygen species production, and increased susceptibility to mouse models of colitis. Mitochondrial iron chelation therapy improved colitis and demonstrated an essential role of mitochondrial iron dysregulation in the pathogenesis of IBD. To address if mitochondrial iron dysregulation is a key mechanism by which inflammation impacts colon tumorigenesis, STEAP4 expression, function, and mitochondrial iron chelation were assessed in a colitis-associated colon cancer model (CAC). STEAP4 was increased in human CRC and predicted poor prognosis. STEAP4 and mitochondrial iron increased tumor number and burden in a CAC model. These studies demonstrate the importance of mitochondrial iron homeostasis in IBD and CRC.
Background & Aims
Non‐alcoholic fatty liver disease (NAFLD) is defined based on recent alcohol consumption; however, remote or lifetime alcohol consumption is not taken into account. It is not known ...whether lifetime alcohol consumption contributes to the severity of disease in patients with NAFLD. To determine the effect of lifetime alcohol consumption on the histological severity in patients with NAFLD.
Patients & Methods
Adults >18 years of age with presumed NAFLD and alcohol consumption <40 g/week were enrolled. Lifetime alcohol consumption was determined using a questionnaire. Patients with a history of long‐term alcohol abuse or dependence were excluded. A liver biopsy was reviewed by a single pathologist in a blinded fashion. Demographic, clinical and histological findings were compared in those who had regular alcohol consumption and those who did not.
Results
A total of 77 patients had fatty liver on biopsy. Fifty‐two patients had a history of regular alcohol consumption. The median lifetime cumulative alcohol intake was 24 gram‐years. On multivariable analysis, increasing age (OR 1.07, 95% CI 1.01–1.14) was associated with severe liver disease, whereas alcohol consumption of ≥24 gram‐years was associated with less severe disease (OR 0.26, 95% CI 0.07–0.97, P = 0.04). Patients who continued to consume alcohol or had been abstinent for ≤1 year had less severe disease.
Conclusion
Some degree of regular alcohol consumption over the course of a lifetime compared to minimal intake appears to have a protective effect on the histological severity of liver disease among patients with strictly defined NAFLD.
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