Development Of Metaplasia Research Articles

Immune-enhancing effects of endogenous glucocorticoids on gastric macrophages contribute to the development of gastric inflammation and metaplasia.

Immune-enhancing effects of endogenous glucocorticoids on gastric macrophages contribute to the development of gastric inflammation and metaplasia.

S2349 Risk Factors for Intestinal Metaplasia Development and Progression: A Systematic Review

S2349 Risk Factors for Intestinal Metaplasia Development and Progression: A Systematic Review

Endogenous glucocorticoids are required for normal macrophage activation and gastric Helicobacter pylori immunity.

Glucocorticoids are steroid hormones well known for their potent anti-inflammatory effects. However, their immunomodulatory properties are multifaceted. Increasing evidence suggests that glucocorticoid signaling promotes effective immunity and that disruption of glucocorticoid signaling impairs immune function. In this study, we conditionally deleted the glucocorticoid receptor (GR) in the myeloid lineage using the LysM-Cre driver (myGRKO). We examined the impact on macrophage activation and gastric immune responses to Helicobacter pylori, the best-known risk factor of gastric cancer. Our results indicate that, compared with wild type (WT), glucocorticoid receptor knockout (GRKO) macrophages exhibited higher expression of proinflammatory genes in steroid-free conditions. However, when challenged in vivo, GRKO macrophages exhibited aberrant chromatin landscapes and impaired proinflammatory gene expression profiles. Moreover, gastric colonization with H. pylori revealed impaired gastric immune responses and reduced T cell recruitment in myGRKO mice. As a result, myGRKO mice were protected from atrophic gastritis and pyloric metaplasia development. These results demonstrate a dual role for glucocorticoid signaling in preparing macrophages to respond to bacterial infection but limiting their pathogenic activation. In addition, our results support that macrophages are critical for gastric H. pylori immunity.NEW & NOTEWORTHY Signaling by endogenous glucocorticoids primes macrophages toward more robust responses to pathogens. Disruption of glucocorticoid signaling caused dysregulation of the chromatin landscape, blunted proinflammatory gene activation upon bacterial challenge, and impaired the gastric inflammatory response to Helicobacter pylori infection.

Chronic cigarette smoke exposure masks pathological features of Helicobacter pylori infection while promoting tumor initiation.

Gastric cancer is the fifth most common cancer and the fifth leading cause of cancer deaths worldwide. Chronic infection by the bacterium Helicobacter pylori is the most prominent gastric cancer risk factor, but only 1-3% of infected individuals will develop gastric cancer. Cigarette smoking is another independent gastric cancer risk factor, and H. pylori- infected smokers are at a 2-11-fold increased risk of gastric cancer development, but the direct impacts of cigarette smoke on H. pylori pathogenesis remain unknown. In this study, male C57BL/6 mice were infected with H. pylori and began smoking within one week of infection. The mice were exposed to cigarette smoke (CS) five days/week for 8 weeks. CS exposure had no notable impact on gross gastric morphology or inflammatory status compared to filtered-air (FA) exposed controls in mock-infected mice. However, CS exposure significantly blunted H. pylori- induced gastric inflammatory responses, reducing gastric atrophy and pyloric metaplasia development. Despite blunting these classic pathological features of H. pylori infection, CS exposures increased DNA damage within the gastric epithelial cells and accelerated H. pylori- induced dysplasia onset in the INS-GAS gastric cancer model. These data suggest that cigarette smoking may clinically silence classic clinical symptoms of H. pylori infection but enhance the accumulation of mutations and accelerate gastric cancer initiation.

Сharacterization of the immune microenvironment's cellular composition and its influence on gene expression during metaplastic changes of the gastric mucosa epithelium

Rationale. Intestinal metaplasia of gastric mucosa epithelium in chronic atrophic gastritis is considered by most authors as a precancerous condition, but it is potentially reversible. The study of the regulation mechanisms of metaplastic epithelial changes development may become the key in understanding the process of carcinogenesis and prevention of cancer development. Objective. To determine whether there is a relationship between microenvironment and development of metaplasia of gastric mucosa epithelium of patients with chronic atrophic gastritis by assessing gene expression and cellular composition of immune infiltrate. Materials and Methods. A retrospective cohort study, the alternative hypothesis of which is that the composition of the gastric mucosa immune microenvironment differs between cases with and without metaplastic changes in the epithelium. Biopsy specimens of the mucosa (n = 38) obtained during endoscopic examination from five sites (2 from the antrum, 2 from the body, 1 from the corner) of the stomach of patients with chronic atrophic gastritis of unspecified etiology, as well as the results of RNA sequencing isolated from biopsy specimens of patients with chronic gastritis obtained from the NCBI open database (n = 12) served as the material for the study. Histological, histochemical staining methods, immunohistochemical study were applied during the study. Morphometric, statistical and bioinformatic analyses were performed. Results. It was found that the proportion of macrophages, T-cytotoxic lymphocytes and plasmocytes was increased in the samples with metaplastic changes of the gastric mucosa epithelium. A correlation between T-cytotoxic lymphocytes and the chance of metaplasia development was found. It was found that changes in the number of T-helper cells, T-cytotoxic lymphocytes, T-regulatory cells and plasmocytes are associated with changes in the expression of five genes most specific for intestinal-type epithelium. Conclusion. The significant difference in the composition of the immune microenvironment between samples with and without metaplastic changes in the mucosal epithelium indicates the potential influence of immune cells on the development of metaplasia and progression of the pathological process along the Correa cascade. One of the mechanisms of regulation of metaplasia development by microenvironment may be their influence on gene expression as an epigenetic factor.

Heterogeneity of Monocarboxylate Transporter Function in Gastrointestinal Epithelium

Short-chain fatty acids and ketone bodies are important energy fuels of GI epithelial cells. Slc16a family encodes proton-coupled monocarboxylate transporters (MCTs) that mediate cellular metabolism of those energy fuels. Increasing evidence demonstrates that adenocarcinomas with overexpression of MCTs are better able to maintain microenvironmental pH and high energy metabolism to grow. However, the precise distribution and function of each MCT subtype in normal epithelial or precancerous cell lineages are mostly unknown. We investigated cell type-specific expressions of MCT subtypes MCT1, MCT2, and MCT4 by immunofluorescence in normal and gastric metaplasia model mice. As total MCT knockout leads to early lethality, we generated inducible, intestine-targeted knockout mouse models for MCT1 and MCT4, respectively. In normal GI tissues, MCT1 was strongly expressed on basolateral membranes of gastric surface cells and enterocytes, with intense staining of proliferating cells and enteroendocrine cells. No staining was observed in Brunner’s glands or Paneth cells. The low affnity subtype, MCT4 expression was localized to the first corpus glands and tuft cells in the stomach, suggesting that these cells may monitor the luminal chemical environment. Intestinal MCT4 was localized on basolateral membranes of mature enterocytes and tuft cells. In contrast, MCT2, which has the highest affnity for lactate, was localized reciprocally to MCT1. Strong MCT2 staining was identified on the basolateral membrane of secretory cells, including gastric parietal and chief cells, Brunner’s glands, and Paneth cells. The distinct MCT2 expression suggests that those secretory cells possess different energy metabolism and MCT2 may contribute to their intracellular pH homeostasis. In gastric metaplasia tissues of Mist1-Kras(G12D) mice, MCT1+ metaplastic cells were increased, and Ki67+ cells were more dependent on MCT1 than normal tissues. MCT2 expression in chief cells was disappeared during metaplasia development. MCT1ΔIEC mice lost MCT1 expression on day 8 after tamoxifen injection and decreased transcriptions of other subtypes, Mct4, Mct7, and Mct10 in intestinal mucosa. MCT1ΔIEC jejunum showed significant increase in crypt length, indicating that MCT1 loss disrupted proliferative cell function. Contrary, MCT4ΔIEC mice had no change in crypt length or Mct1 expression, but increased Mct7, and Mct10. These observations indicate that different cell types require a different MCT subtype. The increase in MCT1-dependency in proliferative metaplastic glands is consistent with the predicted effect of MCT1 inhibitors for cancer treatment. Alterations in MCT subtype expression might be a marker for early diagnosis of metaplastic cells. R37 CA244970 and R01 CA272687 to EC, VDDRC P30-058404 and VICC GI SPORE P50-CA236733 to IK. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Comparison of gastric inflammation and metaplasia induced by Helicobacter pylori or Helicobacter felis colonization in mice.

Mouse infection models with Helicobacter species are widely used to study Helicobacter pathogenesis and gastric cancer initiation. However, Helicobacter pylori is not a natural mouse pathogen, and mouse-adapted H. pylori strains are poorly immunogenic. In contrast, Helicobacter felis is a natural mouse pathogen that induces robust gastric inflammation and is often used in mice to investigate gastric cancer initiation. Although both bacterial strains are widely used, their disease pathogenesis in mice differs dramatically. However, few studies have directly compared the pathogenesis of these bacterial species in mice, and the contrasting features of these two models are not clearly defined. This study directly compares the gastric inflammation, atrophy, and metaplasia development triggered by the widely used PMSS1 H. pylori and CS1 H. felis strains in mice. It serves as a useful resource for researchers to select the experimental model best suited for their studies.

Decoding spatiotemporal transcriptional dynamics and epithelial fibroblast crosstalk during gastroesophageal junction development through single cell analysis

The gastroesophageal squamocolumnar junction (GE-SCJ) is a critical tissue interface between the esophagus and stomach, with significant relevance in the pathophysiology of gastrointestinal diseases. Despite this, the molecular mechanisms underlying GE-SCJ development remain unclear. Using single-cell transcriptomics, organoids, and spatial analysis, we examine the cellular heterogeneity and spatiotemporal dynamics of GE-SCJ development from embryonic to adult mice. We identify distinct transcriptional states and signaling pathways in the epithelial and mesenchymal compartments of the esophagus and stomach during development. Fibroblast-epithelial interactions are mediated by various signaling pathways, including WNT, BMP, TGF-β, FGF, EGF, and PDGF. Our results suggest that fibroblasts predominantly send FGF and TGF-β signals to the epithelia, while epithelial cells mainly send PDGF and EGF signals to fibroblasts. We observe differences in the ligands and receptors involved in cell-cell communication between the esophagus and stomach. Our findings provide insights into the molecular mechanisms underlying GE-SCJ development and fibroblast-epithelial crosstalk involved, paving the way to elucidate mechanisms during adaptive metaplasia development and carcinogenesis.

Diagnosis of Columnar Metaplasia of the Esophageal Mucosa in Patients with Complicated Gastroesophageal Reflux Disease

Aim: to improve methods of diagnostics of esophageal mucosal forms of metaplasia and dysplasia in patients with complicated forms of gastroesophageal reflux disease (GERD) using multidisciplinary approach.Material and methods. Overall, 131 patients aged 18 to 84 years (mean age — 55.8 ± 16.7 years) with confirmed diagnosis of GERD complicated by development of metaplasia of mucosa of distal esophagus were included in retroand prospective study. At the prehospital stage the patients' complaints were estimated, anamnesis was taken. At the first stage of the diagnostic program all patients underwent detailed esophagogastroduodenoscopy in high resolution with white light. The region of esophageal mucosa with signs of metaplasia and determination of its prevalence was examined and evaluated with special attention. Ultrashort segment was revealed in 26 patients, short segment — in 47 patients, long segment of mucosal metaplasia was revealed in 58 patients. Then to reveal the signs of dysplasia we used specifying endoscopic methods: the structure of pitted and microvascular pattern was estimated in narrow spectral mode using BING classification system. If an irregular type of metaplasized epithelium structure was detected in the process of BING assessment, the areas suspicious for dysplasia were marked, followed by aim forceps biopsy from them. The next stage was staining of the metaplasized segment with 1.5 % ethanic acid solution — acetowhitening. PREDICT classification system was used to evaluate the stained mucosal sections with metaplasia. Targeted forceps biopsy was performed from the altered areas that most quickly lost their coloring. The final stage of the diagnostic program in all patients was a forceps biopsy of the mucosa of the metaplasic segment according to the Seattle protocol, which requires increasing the number of fragments as the metaplasic segment lengthens in a “blind” biopsy. The biopsy material was stained with hematoxylin and eosin, and periodic acid Schiff reaction was performed in combination with alcyanine blue according to the standard technique.Results. Endoscopic examination in white light and evaluation of metaplasia extent revealed ultrashort segment (<1 cm) in 26/131 (19.9 %) patients; short segment (1–3 cm) — in 47/131 (35.9 %); long segment (> 3 cm) — in 58/131 (44.3 %) patients. Among the diagnostic techniques used, the BING and PREDICT classifications had the highest accuracy, sensitivity, and specificity (accuracy — 88.9 and 95.3 %, sensitivity — 90.5 and 91.3 %, and specificity — 86.7 and 100 %, respectively), which significantly exceeded the Seattle protocol also used in this work. The results showed a low level of specificity (31.2 %), accuracy (54.5 %), and sensitivity (76.8 %) of the Seattle protocol. The use of BING and PREDICT classifications provided marking of compromised zones, allowing targeted histological sampling.Conclusions. The original study demonstrated the greatest sensitivity, specificity, and accuracy of PREDICT and BING methods in the diagnosis of metaplasia with signs of dysplasia in patients with complicated GERD. It is also important that the use of BING and PREDICT classification systems allows to reduce the number of biopsy samples in comparison with their unreasonably large number according to the Seattle protocol, thereby reducing mucosal and submucosal trauma of the esophagus and the risk of complications.

The law of paired cases on the example of adenocystic cancer of salivary glands tissue with multicentric growth of different locations

Adenoid cystic cancer of the salivary glands is characterized by recurrent and/or metastatic course. Compared with other histological types of salivary gland cancer, it usually has a more latent clinical course with a low incidence of spread to regional lymph nodes. However, after removal of the primary tumor, local and distant relapses are quite common. In addition, the presence of prognostic factors such as metastases in the lymph nodes of the neck, low degree of tumor differentiation, perineural and lymphovascular invasion contributes to an increase in the frequency of distant metastasis with a poor prognosis.
 Cases of atypical arrangement of salivary gland tissues with extranodal heterotopia are rare. In the head and neck region, different localizations of heterotopia of salivary gland tissues have been described, but the pterygopalatine fossa was not mentioned in the available sources. The difficulty of histological diagnosis when verifying heterotopia of the salivary glands may be due to the phenomena of chronic inflammation, lymphoid infiltration, tissue fibromatosis and the development of metaplasia. The rare occurrence of heterotopia of the salivary glands, the difficulties of its diagnosis and the lack of a unified approach to surgical treatment require consideration of each individually identified case.
 The law of paired cases (also known as the law of series) is implemented in the interpretation of the presented clinical cases, when the identification of individual extraorgan foci of adenoid cystic cancer of the pterygopalatine space may be associated with a rare extranodal heterotopia of salivary gland tissue. The primary multiplicity of malignant lesions of the major salivary glands and heterotopia of salivary gland tissue can be both synchronous and metachronous. Adenoid cystic cancer of the pterygomaxillary fossa, as a component of multicentric growth of various localizations, clinically confirmed the recurrent nature of the course, the tendency to distant metastasis and generalization of the malignant process.

CDKN2A-p16 Deletion and Activated KRASG12D Drive Barrett’s-Like Gland Hyperplasia-Metaplasia and Synergize in the Development of Dysplasia Precancer Lesions

Background & AimsBarrett’s esophagus (BE) is the precursor of esophageal dysplasia and adenocarcinoma (EAC). CDKN2A-p16 deletions were reported in 34-74% of BE patients who progressed to dysplasia and EAC, suggesting that p16 loss may drive neoplastic progression. KRAS activation frequently occurs in EAC and pre-cancer lesions. LGR5+ stem cells in the squamocolumnar-junction (SCJ) of mouse stomach, contribute as BE progenitors. We aimed to determine the functional effects of p16 loss and KRAS activation in Barrett’s-like metaplasia and dysplasia development. MethodsWe established mouse models with conditional knockout of CDKN2A-p16 (p16KO) and/or activated KRASG12D expression in interleukin-1b transgenic mice targeting SCJ LGR5+ cells and characterized histologic alterations (mucous-gland hyperplasia/metaplasia, inflammation, and dysplasia) in mouse SCJ. Gene expression was determined by microarray, RNAseq, and immunohistochemistry of SCJ tissues and cultured 3D organoids. Resultsp16KO mice exhibited increased mucous-gland hyperplasia/metaplasia vs. controls (p=.0051). Combined p16KO+KRASG12D resulted in more frequent dysplasia and higher dysplasia scores with 82% of p16KO+KRASG12D mice developing high-grade dysplasia (p=0.0036). SCJ transcriptome analysis showed several activated pathways in p16KO vs. control mice (apoptosis, TNF-alpha/NFkB, proteasome degradation, p53 signaling, MAPK, KRAS, and G1-to-S transition). Conclusionsp16 deletion in LGR5+ cell precursors triggers increased SCJ mucous-gland hyperplasia/metaplasia. KRASG12D synergizes with p16 deletion resulting in higher grades of SCJ glandular dysplasia, mimicking Barrett’s high-grade dysplasia. These genetically modified mouse models establish a functional role of p16 and activated KRAS in the progression of Barrett’s like lesions to dysplasia in mice, representing an in vivo model of esophageal pre-cancer. Derived 3D organoid models further provide in vitro modeling opportunities of esophageal pre-cancer stages.

Increased expression of neutrophil CD15 correlates with the severity of anterior ocular surface damage in type II diabetes mellitus.

Diabetes mellitus is associated with increased risk of ocular surface diseases in elderly. We consider neutrophil CD15 as a potential marker of ocular surface damage in type II diabetes mellitus patients. We aimed to evaluate expression of neutrophil CD15 and correlate it with results of conjunctival impression cytology and routine objective anterior ocular surface tests (TMH, NIBUT, LLT, MGD) in T2DM patients. We prospectively enrolled sixty type II diabetes mellitus patients (120 eyes) into a study group. The control group included forty (80 eyes) age- and sex-matched healthy individuals. All patients underwent comprehensive ophthalmological examination, and tear meniscus height test (TMH), noninvasive tear break-up time (NIBUT), lipid layer thickness measurement (LLT), Meibomian gland dysfunction evaluation (MGD), conjunctival impression cytology (CIC) and expression of CD15. Abnormal Nelson's grades of squamous metaplasia (grades 2 and 3) were observed in 50% (60 eyes) of the study group, and 13.8 (11 eyes) of the control group. Fifteen patients with type II diabetes mellitus suffered from grade 3 squamous metaplasia. Nelson's grades of squamous metaplasia have shown a positive correlation with the level of CD15 expression either in the study and control groups (rs = 0.628, p = <0.0001; rs = 0.746, p < 0.0001; respectively). The research shows significantly reduced values of routine objective ocular tests in type II diabetes mellitus patients in comparison to healthy participants older than 60 y.o. Increased CD15 in the peripheral blood is associated with the development of squamous metaplasia and may be used to evaluate the severity of ocular surface damage in type II diabetes mellitus patients.

Dynamic tuft cell expansion during gastric metaplasia and dysplasia.

Tuft cells are chemosensory cells associated with luminal homeostasis, immune response, and tumorigenesis in the gastrointestinal tract. We aimed to elucidate alterations in tuft cell populations during gastric atrophy and tumorigenesis in humans with correlative comparison to relevant mouse models. Tuft cell distribution was determined in human stomachs from organ donors and in gastric pathologies including Ménétrier's disease, Helicobacter pylori gastritis, intestinal metaplasia (IM), and gastric tumors. Tuft cell populations were examined in Lrig1-KrasG12D , Mist1-KrasG12D , and MT-TGFα mice. Tuft cells were evenly distributed throughout the entire normal human stomach, primarily concentrated in the isthmal region in the fundus. Ménétrier's disease stomach showed increased tuft cells. Similarly, Lrig1-Kras mice and mice overexpressing TGFα showed marked foveolar hyperplasia and expanded tuft cell populations. Human stomach with IM or dysplasia also showed increased tuft cell numbers. Similarly, Mist1-Kras mice had increased numbers of tuft cells during metaplasia and dysplasia development. In human gastric cancers, tuft cells were rarely observed, but showed positive associations with well-differentiated lesions. In mouse gastric cancer xenografts, tuft cells were restricted to dysplastic well-differentiated mucinous cysts and were lost in less differentiated cancers. Taken together, tuft cell populations increased in atrophic human gastric pathologies, metaplasia, and dysplasia, but were decreased in gastric cancers. Similar findings were observed in mouse models, suggesting that, while tuft cells are associated with precancerous pathologies, their loss is most associated with the progression to invasive cancer.

Kyoto International Consensus Report on Anatomy, Pathophysiology and Clinical Significance of the Gastroesophageal Junction

Aim: to present the main statements of Kyoto International Consensus report on anatomy, pathophysiology, and clinical significance of the gastroesophageal junction.Key points. The experts reviewed and adopted 28 statements concerning (1) the definition of the gastroesophageal junction (GEJ); (2) the definition of the GEJ zone, covering the area located 1 cm proximal and 1 cm distal in relation to gastroesophageal junction; (3) the assessment of chemical and bacterial (Helicobacter pylori) factors leading to the development of inflammation, metaplasia and neoplasia of the mucosa of the GEJ; and (4) a new definition of Barrett’s esophagus.Conclusion. The new definitions of GEJ, GEJ zone and Barrett’s esophagus adopted by the International Consensus will be used in subsequent studies, which will contribute to improving the results of treatment of diseases of this area.

Correlation of Clinical and Histopathological Features of Salivary Pleomorphic Adenoma.

Salivary gland tumors represent about 3% of the head and neck tumors. Pleomorphic adenoma (PA) is the most common benign salivary gland tumor. This study was conducted to investigate and describe some clinical and histopathological aspects of salivary pleomorphic adenomas with special reference to the epithelial and mesenchymal components. In this retrospective study, one hundred tissue samples diagnosed as PA were sourced from archival tissue blocks between 2009 and 2019 in this retrospective study. Some clinical and demographic features, including age, sex, tumor size, and tumor location were recorded. This study included only samples taken by excisional biopsy. Then, the samples were histologically classified into three subtypes according to the proportion of epithelial and stromal components. The demographic and clinicopathological variables were statistically analyzed using Chi-square test or Fisher's exact test, considering a significance level of 5% (p< .05). In the present study, most cases (61%) were found in females, representing a female-male ratio of 1.6:1. The peak incidence was seen in the 4th and 5th decades of life. In 87% of cases, PA occurred in major salivary glands. There was a significant difference between the age of the patient and squamous metaplasia (p= 0.036). There was also a significant difference between the size of tumor and the amount of myxoid stroma (p= 0.021). Extensive myxoid stromawas mostly seen in tumors larger than 3.37cm (p= 0.001). In addition, there was a statistically significant difference between capsular invasion and the development of squamous metaplasia (p= 0.001). In this study, there was a significant correlation between the gland type and capsular features and between the size of tumor and rate of squamous metaplasia. A detailed clinical and histopathological analysis of PAs may provide a better insight to the pathophysiology of the lesion, tumor cell differentiation, and prognostic factors.

A tuft cell - ILC2 signaling circuit provides therapeutic targets to inhibit gastric metaplasia and tumor development

Although gastric cancer is a leading cause of cancer-related deaths, systemic treatment strategies remain scarce. Here, we report the pro-tumorigenic properties of the crosstalk between intestinal tuft cells and type 2 innate lymphoid cells (ILC2) that is evolutionarily optimized for epithelial remodeling in response to helminth infection. We demonstrate that tuft cell-derived interleukin 25 (IL25) drives ILC2 activation, inducing the release of IL13 and promoting epithelial tuft cell hyperplasia. While the resulting tuft cell - ILC2 feed-forward circuit promotes gastric metaplasia and tumor formation, genetic depletion of tuft cells or ILC2s, or therapeutic targeting of IL13 or IL25 alleviates these pathologies in mice. In gastric cancer patients, tuft cell and ILC2 gene signatures predict worsening survival in intestinal-type gastric cancer where ~40% of the corresponding cancers show enriched co-existence of tuft cells and ILC2s. Our findings suggest a role for ILC2 and tuft cells, along with their associated cytokine IL13 and IL25 as gatekeepers and enablers of metaplastic transformation and gastric tumorigenesis, thereby providing an opportunity to therapeutically inhibit early-stage gastric cancer through repurposing antibody-mediated therapies.

Cholesterol Metabolism in Pancreatic Cancer.

Pancreatic cancer's substantial impact on cancer-related mortality, responsible for 8% of cancer deaths and ranking fourth in the US, persists despite advancements, with a five-year relative survival rate of only 11%. Forecasts predict a 70% surge in new cases and a 72% increase in global pancreatic cancer-related deaths by 2040. This review explores the intrinsic metabolic reprogramming of pancreatic cancer, focusing on the mevalonate pathway, including cholesterol biosynthesis, transportation, targeting strategies, and clinical studies. The mevalonate pathway, central to cellular metabolism, significantly shapes pancreatic cancer progression. Acetyl coenzyme A (Acetyl-CoA) serves a dual role in fatty acid and cholesterol biosynthesis, fueling acinar-to-ductal metaplasia (ADM) and pancreatic intraepithelial neoplasia (PanIN) development. Enzymes, including acetoacetyl-CoA thiolase, 3-hydroxy-3methylglutaryl-CoA (HMG-CoA) synthase, and HMG-CoA reductase, are key enzymes in pancreatic cancer. Inhibiting HMG-CoA reductase, e.g., by using statins, shows promise in delaying PanIN progression and impeding pancreatic cancer. Dysregulation of cholesterol modification, uptake, and transport significantly impacts tumor progression, with Sterol O-acyltransferase 1 (SOAT1) driving cholesterol ester (CE) accumulation and disrupted low-density lipoprotein receptor (LDLR) expression contributing to cancer recurrence. Apolipoprotein E (ApoE) expression in tumor stroma influences immune suppression. Clinical trials targeting cholesterol metabolism, including statins and SOAT1 inhibitors, exhibit potential anti-tumor effects, and combination therapies enhance efficacy. This review provides insights into cholesterol metabolism's convergence with pancreatic cancer, shedding light on therapeutic avenues and ongoing clinical investigations.

Кистозно-железистая метаплазия мочевого пузыря.

Introduction. Cystic-glandular cystitis is one of the varieties of metaplasia of the bladder wall, which, in rare cases, can manifest itself in the form of voluminous polypoid growths. Clinical study. This article presents a case of polypoid changes in the bladder wall due to cystic glandular cystitis in a 74-year-old man against the background of a chronic inflammatory process and achalasia of the upper urinary tract. This observation confirms the theory of the etiological significance for the development of urothelial metaplasia of a long-term persistent urinary tract infection. The only reliable method for diagnosing cystic glandular cystitis and differential diagnosis of pseudotumor changes from urothelial carcinoma is morphological, after transurethral resection. Conclusion. The observation presented in this article showed that the clinical manifestations of cystic glandular cystitis can be variable and require an integrated approach to diagnosis and treatment.

Identifying Adult Stomach Tissue Stem/Progenitor Cells Using the Iqgap3-2A-CreERT2 Mouse.

Identification of unique gene markers of normal and cancer stem cells is an effective strategy to study cells of origin and understand tumor behavior. Lineage tracing experiments using the Cre recombinase driven by a stem cell-specific promoter in the CreERT2 reporter mouse model enables identification of adult stem cells and delineation of stem cell activities in vivo. In our recent research on the mouse stomach, Iqgap3 was identified as a homeostatic stem cell marker located in the isthmus of the stomach epithelium. Lineage tracing with the Iqgap3-2A-CreERT2;Rosa26-LSL-tdTomato mouse model demonstrated stem cell activity in Iqgap3-expressing cells. Using the Iqgap3-2A-CreERT2 mouse model to target oncogenic KrasG12D expression to Iqgap3-expressing cells, we observed the rapid development of precancerous metaplasia in the stomach and proposed that aberrant Iqgap3-expressing cells may be critical determinants of early carcinogenesis. In this chapter, we detail a lineage tracing protocol to assess stem cell activity in the murine stomach. We also describe the procedure of inducing KrasG12D expression in Iqgap3-expressing homeostatic stem cells to explore their role as cells of origin and to trace the early cellular changes that precede neoplastic transformation.

Regulation of Parietal Cell Homeostasis by Bone Morphogenetic Protein Signaling.

Loss of bone morphogenetic protein (BMP) signaling in the stomach, achieved by transgenic expression of the BMP inhibitor noggin (H + /K + -Nog mice), causes parietal cell (PC) loss, spasmolytic polypeptide-expressing metaplasia, a marker of preneoplasia, and activation of cell proliferation. We examined if specific inhibition of BMP signaling in PCs leads to aberrations in epithelial homeostasis. Mice with floxed alleles of BMP receptor 1a (Bmpr1a flox/flox mice) were crossed to H + /K + -Cre mice to generate H + /K + -Cre;Bmpr1a flox/flox mice. Morphology of the mucosa was analyzed by hematoxylin and eosin staining. Distribution of H+/K+-ATPase-, IF-, and Ki-67-positive cells was analyzed by immunostaining. Expression of pit and neck cell mucins was determined by staining with the lectins Ulex Europaeus Agglutinin 1 and Griffonia (Bandeiraea) simplicifolia lectin II, respectively. Isolation of PCs from control and Nog-expressing mice was achieved by crossing H + /K + -Nog mice to Rosa26-tdTomato (Tom) mice to generate H + /K + -Nog;Rosa26-tdTom mice. H + /K + -Cre mice were then crossed to H + /K + -Nog;Rosa26-tdTom mice to generate H + /K + -Cre;H + /K + -Nog;Rosa26-tdTom mice. Tom-labeled PCs were purified by flow cytometry. Changes in PC transcripts were measured by RNA-Seq. Six-month-old H + /K + -Cre;Bmpr1a flox/flox mice exhibited increased epithelial cell proliferation, presence of transitional cells showing colocalization of IF with both Griffonia (Bandeiraea) simplicifolia lectin II-binding mucins and the H+/K+-ATPase, and expansion of Ulex Europaeus Agglutinin 1-positive cells. PC transcripts from Nog-expressing mice demonstrated induction of markers of Spasmolytic Polypeptide-Expressing Metaplasia. PC-specific loss of BMP signaling alters the homeostasis of the gastric epithelium leading to the development of metaplasia.