-
Cell Feb 2019Increased levels of intestinal bile acids (BAs) are a risk factor for colorectal cancer (CRC). Here, we show that the convergence of dietary factors (high-fat diet) and...
Increased levels of intestinal bile acids (BAs) are a risk factor for colorectal cancer (CRC). Here, we show that the convergence of dietary factors (high-fat diet) and dysregulated WNT signaling (APC mutation) alters BA profiles to drive malignant transformations in Lgr5-expressing (Lgr5) cancer stem cells and promote an adenoma-to-adenocarcinoma progression. Mechanistically, we show that BAs that antagonize intestinal farnesoid X receptor (FXR) function, including tauro-β-muricholic acid (T-βMCA) and deoxycholic acid (DCA), induce proliferation and DNA damage in Lgr5 cells. Conversely, selective activation of intestinal FXR can restrict abnormal Lgr5 cell growth and curtail CRC progression. This unexpected role for FXR in coordinating intestinal self-renewal with BA levels implicates FXR as a potential therapeutic target for CRC.
Topics: Animals; Bile Acids and Salts; Cell Line; Cell Proliferation; Colorectal Neoplasms; Deoxycholic Acid; Gene Expression Regulation, Neoplastic; Humans; Intestinal Neoplasms; Intestines; Liver; Mice; Mice, Inbred C57BL; Neoplastic Stem Cells; Organoids; Receptors, Cytoplasmic and Nuclear; Risk Factors; Signal Transduction; Taurocholic Acid; Wnt Signaling Pathway
PubMed: 30794774
DOI: 10.1016/j.cell.2019.01.036 -
CA: a Cancer Journal For Clinicians Nov 2018Neuroendocrine tumors (NETs) are heterogeneous malignancies arising from the diffuse neuroendocrine system. They frequently originate in the gastroenteropancreatic (GEP)... (Review)
Review
Neuroendocrine tumors (NETs) are heterogeneous malignancies arising from the diffuse neuroendocrine system. They frequently originate in the gastroenteropancreatic (GEP) tract and the bronchopulmonary tree, and their incidence has steadily increased in the last 3 decades. Fundamental biologic and genomic differences underlie the clinical heterogeneity of NETs, and distinct molecular features characterize NETs of different grades and different primary sites. Although surgery remains the cornerstone of treatment for localized tumors, systemic treatment options for patients with metastatic NETs have expanded considerably. Somatostatin analogs have demonstrated both antisecretory and antitumor efficacy. Peptide receptor radionuclide therapy with lutetium-177 dotatate ( Lu-DOTATATE) has been approved for advanced GEP-NETs. The antitumor activity of everolimus has been demonstrated across a wide spectrum of NETs, and the antiangiogenic agent sunitinib has been approved for pancreatic NETs (pNETs). Chemotherapy with temozolomide and capecitabine has recently demonstrated an unprecedented prolongation of progression-free survival in a randomized trial of pNETs. Multiple retrospective series have reported the efficacy of liver-directed therapies both for palliating symptoms of hormone excess and for controlling tumor growth. Telotristat, an oral inhibitor of tryptophan hydroxylase, has been shown to reduce diarrhea in patients with carcinoid syndrome. Defining the therapeutic algorithm and identifying biomarkers predictive of response to treatments are among the main priorities for the next decade of research in the NET field.
Topics: Antineoplastic Agents; Biomarkers, Tumor; Cytoreduction Surgical Procedures; Humans; Incidence; Intestinal Neoplasms; Medical Oncology; Neuroendocrine Tumors; Octreotide; Organometallic Compounds; Pancreatic Neoplasms; Patient Selection; Practice Guidelines as Topic; Randomized Controlled Trials as Topic; Stomach Neoplasms; Treatment Outcome
PubMed: 30295930
DOI: 10.3322/caac.21493 -
Deutsches Arzteblatt International Mar 2018About 100 000 ostomy carriers are estimated to live in Germany today. The creation of an ostomy represents a major life event that can be associated with impaired...
BACKGROUND
About 100 000 ostomy carriers are estimated to live in Germany today. The creation of an ostomy represents a major life event that can be associated with impaired quality of life. Optimal ostomy creation and proper ostomy care are crucially important determinants of the success of treatment and of the patients' quality of life.
METHODS
This article is based on pertinent publications retrieved by a selective search in PubMed, GoogleScholar, and Scopus, and on the authors' experience.
RESULTS
Intestinal stomata can be created using either the small or the large bowel. More than 75% of all stomata are placed as part of the treatment of colorectal cancer. The incidence of stoma-related complications is reported to be 10-70%. Skin irritation, erosion, and ulceration are the most common early complications, with a combined incidence of 25-34%, while stoma prolapse is the most common late complication, with an incidence of 8-75%. Most early complications can be managed conservatively, while most late complications require surgical revision. In 19% of cases, an ostomy that was initially planned to be temporary becomes permanent. Inappropriate stoma location and inadequate ostomy care are the most common causes of early complications. Both surgical and patient-related factors influence late complications.
CONCLUSION
Every step from the planning of a stoma to its postoperative care should be discussed with the patient in detail. Preoperative marking is essential for an optimal stoma site. Optimal patient management with the involvement of an ostomy nurse increases ostomy acceptance, reduces ostomy-related complications, and improves the quality of life of ostomy carriers.
Topics: Adult; Aged; Female; Germany; Humans; Intestinal Neoplasms; Male; Middle Aged; Ostomy; Quality of Life; Risk Factors; Self-Management; Surgical Stomas
PubMed: 29607805
DOI: 10.3238/arztebl.2018.0182 -
Neuroendocrinology 2020The traditionally promulgated perspectives of neuroendocrine neoplasms (NEN) as rare, indolent tumours are blunt and have been outdated for the last 2 decades. Clear... (Review)
Review
The traditionally promulgated perspectives of neuroendocrine neoplasms (NEN) as rare, indolent tumours are blunt and have been outdated for the last 2 decades. Clear increments in their incidence over the past decades render them increasingly clinically relevant, and at initial diagnosis many present with nodal and/or distant metastases (notably hepatic). The molecular pathogenesis of these tumours is increasingly yet incompletely understood. Those arising from the small bowel (SB) or pancreas typically occur sporadically; the latter may occur within the context of hereditary tumour predisposition syndromes. NENs can also be associated with endocrinopathy of hormonal hypersecretion. Tangible advances in the development of novel biomarkers, functional imaging modalities and therapy are especially applicable to this sub-set of tumours. The management of SB and pancreatic neuroendocrine tumours (NET) may be challenging, and often comprises a multidisciplinary approach wherein surgical, medical, interventional radiological and radiotherapeutic modalities are implemented. This review provides a comprehensive overview of the epidemiology, pathophysiology, diagnosis and treatment of SB and pancreatic NETs. Moreover, we provide an outlook of the future in these tumour types which will include the development of precision oncology frameworks for individualised therapy, multi-analyte predictive biomarkers, artificial intelligence-derived clinical decision support tools and elucidation of the role of the microbiome in NEN development and clinical behaviour.
Topics: Humans; Intestinal Neoplasms; Neuroendocrine Tumors; Pancreatic Neoplasms
PubMed: 31557758
DOI: 10.1159/000503721 -
Circulation Aug 2018Heart failure (HF) survival has improved, and nowadays, many patients with HF die of noncardiac causes, including cancer. Our aim was to investigate whether a causal...
BACKGROUND
Heart failure (HF) survival has improved, and nowadays, many patients with HF die of noncardiac causes, including cancer. Our aim was to investigate whether a causal relationship exists between HF and the development of cancer.
METHODS
HF was induced by inflicting large anterior myocardial infarction in APC mice, which are prone to developing precancerous intestinal tumors, and tumor growth was measured. In addition, to rule out hemodynamic impairment, a heterotopic heart transplantation model was used in which an infarcted or sham-operated heart was transplanted into a recipient mouse while the native heart was left in situ. After 6 weeks, tumor number, volume, and proliferation were quantified. Candidate secreted proteins were selected because they were previously associated both with (colon) tumor growth and with myocardial production in post-myocardial infarction proteomic studies. Myocardial gene expression levels of these selected candidates were analyzed, as well as their proliferative effects on HT-29 (colon cancer) cells. We validated these candidates by measuring them in plasma of healthy subjects and patients with HF. Finally, we associated the relation between cardiac specific and inflammatory biomarkers and new-onset cancer in a large, prospective general population cohort.
RESULTS
The presence of failing hearts, both native and heterotopically transplanted, resulted in significantly increased intestinal tumor load of 2.4-fold in APC mice (all P<0.0001). The severity of left ventricular dysfunction and fibrotic scar strongly correlated with tumor growth ( P=0.002 and P=0.016, respectively). We identified several proteins (including serpinA3 and A1, fibronectin, ceruloplasmin, and paraoxonase 1) that were elevated in human patients with chronic HF (n=101) compared with healthy subjects (n=180; P<0.001). Functionally, serpinA3 resulted in marked proliferation effects in human colon cancer (HT-29) cells, associated with Akt-S6 phosphorylation. Finally, elevated cardiac and inflammation biomarkers in apparently healthy humans (n=8319) were predictive of new-onset cancer (n=1124) independently of risk factors for cancer (age, smoking status, and body mass index).
CONCLUSIONS
We demonstrate that the presence of HF is associated with enhanced tumor growth and that this is independent of hemodynamic impairment and could be caused by cardiac excreted factors. A diagnosis of HF may therefore be considered a risk factor for incident cancer.
Topics: Adenomatous Polyps; Adult; Aged; Animals; Anterior Wall Myocardial Infarction; Case-Control Studies; Cell Proliferation; Disease Models, Animal; Female; Genes, APC; HT29 Cells; Heart Failure; Humans; Inflammation Mediators; Intercellular Signaling Peptides and Proteins; Intestinal Neoplasms; Intestinal Polyps; Male; Mice, Inbred C57BL; Mice, Transgenic; Middle Aged; Prognosis; Risk Assessment; Risk Factors; Signal Transduction; Time Factors; Tumor Burden; Ventricular Remodeling
PubMed: 29459363
DOI: 10.1161/CIRCULATIONAHA.117.030816 -
Nature Apr 2017The non-essential amino acids serine and glycine are used in multiple anabolic processes that support cancer cell growth and proliferation (reviewed in ref. 1). While...
The non-essential amino acids serine and glycine are used in multiple anabolic processes that support cancer cell growth and proliferation (reviewed in ref. 1). While some cancer cells upregulate de novo serine synthesis, many others rely on exogenous serine for optimal growth. Restriction of dietary serine and glycine can reduce tumour growth in xenograft and allograft models. Here we show that this observation translates into more clinically relevant autochthonous tumours in genetically engineered mouse models of intestinal cancer (driven by Apc inactivation) or lymphoma (driven by Myc activation). The increased survival following dietary restriction of serine and glycine in these models was further improved by antagonizing the anti-oxidant response. Disruption of mitochondrial oxidative phosphorylation (using biguanides) led to a complex response that could improve or impede the anti-tumour effect of serine and glycine starvation. Notably, Kras-driven mouse models of pancreatic and intestinal cancers were less responsive to depletion of serine and glycine, reflecting an ability of activated Kras to increase the expression of enzymes that are part of the serine synthesis pathway and thus promote de novo serine synthesis.
Topics: Animals; Antioxidants; Biguanides; Cell Line, Tumor; Diet; Disease Models, Animal; Female; Food Deprivation; Glycine; Humans; Intestinal Neoplasms; Lymphoma; Male; Mice; Mitochondria; Nutritional Status; Oxidative Phosphorylation; Pancreatic Neoplasms; Proto-Oncogene Proteins p21(ras); Serine; Survival Rate
PubMed: 28425994
DOI: 10.1038/nature22056 -
Journal of the National Comprehensive... Sep 2019Small bowel adenocarcinoma (SBA) is a rare malignancy of the gastrointestinal tract that has increased in incidence across recent years. Often diagnosed at an advanced...
Small bowel adenocarcinoma (SBA) is a rare malignancy of the gastrointestinal tract that has increased in incidence across recent years. Often diagnosed at an advanced stage, outcomes for SBA are worse on average than for other related malignancies, including colorectal cancer. Due to the rarity of this disease, few studies have been done to direct optimal treatment, although recent data have shown that SBA responds to treatment differently than colorectal cancer, necessitating a separate approach to treatment. The NCCN Guidelines for Small Bowel Adenocarcinoma were created to establish an evidence-based standard of care for patients with SBA. These guidelines provide recommendations on the workup of suspected SBA, primary treatment options, adjuvant treatment, surveillance, and systemic therapy for metastatic disease. Additionally, principles of imaging and endoscopy, pathologic review, surgery, radiation therapy, and survivorship are described.
Topics: Adenocarcinoma; Combined Modality Therapy; Diagnosis, Differential; Humans; Intestinal Neoplasms; Intestine, Small; Neoplasm Staging; Practice Guidelines as Topic; Risk Factors; Survivorship; Treatment Outcome; Watchful Waiting
PubMed: 31487687
DOI: 10.6004/jnccn.2019.0043 -
Gastroenterology Sep 2023Small intestinal cancer is a rare cancer, with limited studies exploring its epidemiology. To our knowledge, this study is the first effort to comprehensively analyze...
BACKGROUND & AIMS
Small intestinal cancer is a rare cancer, with limited studies exploring its epidemiology. To our knowledge, this study is the first effort to comprehensively analyze the incidence, risk factors, and trends for small intestinal cancer by sex, age, and country.
METHODS
Global Cancer Observatory, Cancer Incidence in Five Continents Plus, and Global Burden of Disease were accessed to estimate the age-standardized rates of small intestinal cancer incidence (International Classification of Diseases, 10th Revision, Clinical Modification: C17) and prevalence of lifestyle risk factors, metabolic risk factors, and inflammatory bowel disease (IBD). Risk factor associations were assessed by linear and logistic regressions. Average annual percent change was calculated using joinpoint regression.
RESULTS
A total of 64,477 small intestinal cancer cases (age-standardized rate, 0.60 per 100,000) were estimated globally in 2020, with a higher disease burden found in North America (1.4). Higher small intestinal cancer incidence was associated with higher human development index; gross domestic product; and prevalence of smoking, alcohol drinking, physical inactivity, obesity, diabetes, lipid disorder, and IBD (β = 0.008-0.198; odds ratios, 1.07-10.01). There was an overall increasing trend of small intestinal cancer incidence (average annual percent change, 2.20-21.67), and the increasing trend was comparable among the 2 sexes but more evident in the older population aged 50-74 years than in the younger population aged 15-49 years.
CONCLUSION
There was a substantial geographic disparity in the burden of small intestinal cancer, with higher incidence observed in countries with higher human development index; gross domestic product; and prevalence of unhealthy lifestyle habits, metabolic disorders, and IBD. There was an overall increasing trend in small intestinal cancer incidence, calling for the development of preventive strategies.
Topics: Humans; Male; Female; Adolescent; Young Adult; Adult; Middle Aged; Aged; Intestinal Neoplasms; Incidence; Risk Factors
PubMed: 37277079
DOI: 10.1053/j.gastro.2023.05.043 -
Biomolecules Oct 2020Necroptosis is a caspases-independent programmed cell death displaying intermediate features between necrosis and apoptosis. Albeit some physiological roles during... (Review)
Review
Necroptosis is a caspases-independent programmed cell death displaying intermediate features between necrosis and apoptosis. Albeit some physiological roles during embryonic development such tissue homeostasis and innate immune response are documented, necroptosis is mainly considered a pro-inflammatory cell death. Key actors of necroptosis are the receptor-interacting-protein-kinases, RIPK1 and RIPK3, and their target, the mixed-lineage-kinase-domain-like protein, MLKL. The intestinal epithelium has one of the highest rates of cellular turnover in a process that is tightly regulated. Altered necroptosis at the intestinal epithelium leads to uncontrolled microbial translocation and deleterious inflammation. Indeed, necroptosis plays a role in many disease conditions and inhibiting necroptosis is currently considered a promising therapeutic strategy. In this review, we focus on the molecular mechanisms of necroptosis as well as its involvement in human diseases. We also discuss the present developing therapies that target necroptosis machinery.
Topics: Animals; Gastroenteritis; Humans; Inflammation; Intestinal Neoplasms; Intestines; Medical Oncology; Molecular Targeted Therapy; Necroptosis
PubMed: 33050394
DOI: 10.3390/biom10101431 -
Gastroenterology Jan 2022
Topics: Catenins; Humans; Intestinal Neoplasms; Wnt Signaling Pathway; beta Catenin
PubMed: 34678214
DOI: 10.1053/j.gastro.2021.09.074