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Metaplasia in the stomach is highly associated with development of intestinal-type gastric cancer. Two types of metaplasias, spasmolytic polypeptide-expressing metaplasia (SPEM) and intestinal metaplasia (IM), are considered precancerous lesions. However, it remains unclear how SPEM and IM are related. Here we investigated a new lineage-specific marker for SPEM cells, aquaporin 5 (AQP5), to assist in the identification of these 2 metaplasias.
The nature of endometrial morular metaplasia (MorM) is still unknown. The nuclear β-catenin accumulation and the not rare ghost cell keratinization suggest a similarity with hard keratin-producing odontogenic and hair matrix tumors rather than with squamous differentiation. We aimed to compare MorM to hard keratin-producing tumors. Forty-one hard keratin-producing tumors, including 26 hair matrix tumors (20 pilomatrixomas and 6 pilomatrix carcinomas) and 15 odontogenic tumors (adamantinomatous craniopharyngiomas), were compared to 15 endometrioid carcinomas with MorM with or without squamous/keratinizing features. Immunohistochemistry for β-catenin, CD10, CDX2, ki67, p63, CK5/6, CK7, CK8/18, CK19, and pan-hard keratin was performed; 10 cases of endometrioid carcinomas with conventional squamous differentiation were used as controls. In adamantinomatous craniopharyngiomas, the β-catenin-accumulating cell clusters (whorl-like structures) were morphologically similar to MorM (round syncytial aggregates of bland cells with round-to-spindled nuclei and profuse cytoplasm), with overlapping squamous/keratinizing features (clear cells with prominent membrane, rounded squamous formations, ghost cells). Both MorM and whorl-like structures consistently showed positivity for CD10 and CDX2, with low ki67; cytokeratins pattern was also overlapping, although more variable. Hard keratin was focally/multifocally positive in 8 MorM cases and focally in one conventional squamous differentiation case. Hair matrix tumors showed no morphological or immunophenotypical overlap with MorM. MorM shows wide morphological and immunophenotypical overlap with the whorl-like structures of adamantinomatous craniopharyngiomas, which are analogous to enamel knots of tooth development. This suggests that MorM might be an aberrant mimic of odontogenic differentiation.
Esophageal adenocarcinoma (EAC) is the final step of a pathway starting with esophageal reflux disease, Barrett's metaplasia and Barrett's dysplasia. Positive costimulatory ligands such as CD80 have been suggested to contribute to anti-tumor T-cell efficacy. Here we report for the first time the role of CD80 in the inflammatory esophageal carcinogenesis and characterize the immune environment of EAC. Mucosa samples from cancer were obtained during esophagectomy from patients affected by EAC. Fresh biopsies were obtained from patients who underwent endoscopy for screening or follow-up. A rodent model of reflux induced esophageal carcinogenesis was created with an esophago-gastro-jejunostomy. CD80 expression was increased in epithelial cells during metaplasia in the inflammatory esophageal carcinogenesis cascade. Cd80 null mice as well as WT mice that received antiCD80 antibodies showed a higher rate of dysplasia and KI-67+ cells. These results suggest that CD80 mediates an active immune surveillance process in early inflammation-driven esophageal carcinogenesis.
While pancreatic metaplasia has been observed in gastric mucosa of patients with chronic gastritis, it has not been described in ectopic gastric mucosa. We have identified focal clusters of cells resembling pancreatic acinar cells (CPACs) in 11 of 350 biopsies of Barrett's mucosa from 120 patients with Barrett's esophagus enrolled in a clinical efficacy trial of omeprazole versus ranitidine for treatment of gastroesophageal reflux disease. Three additional cases from our surgical files were also studied. Immunoreactivity for trypsin and chymotrypsin was present in the CPACs of all 14 cases, while stains for alpha-amylase and lipase were each positive in 12 of 13. A few cells in the CPACs were also positive for chomogranins (12 of 13 cases), serotonin (seven of 13 cases), somatostatin (three of 12), gastrin (four of 11), and pancreatic polypeptide (two of 13). No staining was seen for insulin or glucagon. Ultrastructural studies performed in one case showed features of pancreatic exocrine and endocrine (PP-type) cells in cells within CPACs. These results collectively indicate that the CPACs are aggregates of true pancreatic acinar cells admixed with a few endocrine cells. This pancreatic parenchyma in Barrett's mucosa is most likely of metaplastic origin and could be derived from the transitional zone cells or from pluripotent stem cells in the esophageal mucosa or from metaplasia of mucus cells. While the development of pancreatic metaplasia in Barrett's esophagus appears to be unrelated to drug therapy, the clinical relevance of this distinctive histological finding needs further investigation.
Activating mutations and amplification of Kras and, more frequently, signatures for Kras activation are noted in stomach cancer. Expression of mutant KrasG12D in the mouse gastric mucosa has been shown to induce hyperplasia and metaplasia. However, the mechanisms by which Kras activation leads to gastric metaplasia are not fully understood. Here we report that KrasLSL-G12D/+;Pdx1-cre, a mouse model known for pancreatic cancer, also mediates KrasG12D expression in the stomach, causing gastric hyperplasia and metaplasia prior to the pathologic changes in the pancreas. These mice exhibit ectopic cell proliferation at the base of gastric glands, whereas wild-type mice contain proliferating cells primarily at the isthmus/neck of the gastric glands. Notch signaling is decreased in the KrasLSL-G12D/+;Pdx1-cre gastric mucosa, as shown by lower levels of cleaved Notch intracellular domains and downregulation of Notch downstream target genes. Expression of a Notch ligand Jagged1 is downregulated at the base of the mutant gland, accompanied by loss of chief cell marker Mist1. We demonstrate that exogenous Jagged1 or overexpression of Notch intracellular domain stimulates Mist1 expression in gastric cancer cell lines, suggesting positive regulation of Mist1 by Notch signaling. Finally, deletion of Jagged1 or Notch3 in KrasLSL-G12D/+;Pdx1-cre mice promoted development of squamous cell carcinoma in the forestomach, albeit short of invasive adenocarcinoma in the glandular stomach. Taken together, these results reveal downregulation of Notch signaling and Mist1 expression during the initiation of Kras-driven gastric tumorigenesis and suggest a tumor-suppressive role for Notch in this context.
Goblet cell metaplasia that causes mucus hypersecretion and obstruction in the airway lumen could be life threatening in asthma and chronic obstructive pulmonary disease patients. Inflammatory cytokines such as IL-13 mediate the transformation of airway ciliary epithelial cells to mucin-secreting goblet cells in acute as well as chronic airway inflammatory diseases. However, no effective and specific pharmacologic treatment is currently available. Here, we investigated the mechanisms by which aldose reductase (AR) regulates the mucus cell metaplasia in vitro and in vivo.
Metaplasia can result when injury reactivates latent developmental signaling pathways that determine cell phenotype. Barrett's esophagus is a squamous-to-columnar epithelial metaplasia caused by reflux esophagitis. Hedgehog (Hh) signaling is active in columnar-lined, embryonic esophagus and inactive in squamous-lined, adult esophagus. We showed previously that Hh signaling is reactivated in Barrett's metaplasia and overexpression of Sonic hedgehog (SHH) in mouse esophageal squamous epithelium leads to a columnar phenotype. Here, our objective was to identify Hh target genes involved in Barrett's pathogenesis. By microarray analysis, we found that the transcription factor Foxa2 is more highly expressed in murine embryonic esophagus compared with postnatal esophagus. Conditional activation of Shh in mouse esophageal epithelium induced FOXA2, while FOXA2 expression was reduced in Shh knockout embryos, establishing Foxa2 as an esophageal Hh target gene. Evaluation of patient samples revealed FOXA2 expression in Barrett's metaplasia, dysplasia, and adenocarcinoma but not in esophageal squamous epithelium or squamous cell carcinoma. In esophageal squamous cell lines, Hh signaling upregulated FOXA2, which induced expression of MUC2, an intestinal mucin found in Barrett's esophagus, and the MUC2-processing protein AGR2. Together, these data indicate that Hh signaling induces expression of genes that determine an intestinal phenotype in esophageal squamous epithelial cells and may contribute to the development of Barrett's metaplasia.
Resection of the olfactory mucosa (OM) is sometimes unavoidable during surgery; however, it is not known whether the OM can completely recover thereafter. The aim of this study was to uncover whether the OM fully recovers after mucosal resection and describe the process of OM regeneration. 8-week-old male Sprague-Dawley rats (n = 18) were subjected to OM resection at the nasal septum; six rats were euthanized for histological examination 0, 30, and 90 days after surgery. Immunohistochemistry was performed to identify olfactory receptor neuron (ORN) lineage cells [mature and immature ORNs and ORN progenitors, and olfactory ensheathing cells (OECs)], as well as dividing and apoptotic cells. Squamous and respiratory metaplasia and inflammatory cell infiltration were also assessed. On day 30 after resection, the mucosa had regenerated, and mainly contained thin nerve bundles, basal cells, and immature ORNs, with a few mature ORNs and OECs. On day 90, the repaired nasal mucosa had degenerated into stratified squamous or ciliated pseudostratified columnar epithelia, with reducing ORNs. The lamina propria contained numerous macrophages. Partial regeneration was observed within 1 month after OM resection, whereas subsequent degeneration into squamous and respiratory epithelia occurred within 3 months. Given the poor persistence of ORNs and OECs, OM resection is likely to result in olfactory impairment. Overall, surgeons should be cautious not to injure the OM during surgery.
Barrett's esophagus (BE) is a precancerous lesion of esophageal adenocarcinoma (EAC). It is a pathological change in which the squamous epithelium distal esophagus is replaced by columnar epithelium. Loss of P53 is involved in the development of BE and is taken as a risk factor for the progression. We established a HET1A cell line with P53 stably knockdown by adenovirus vector infection, followed by 30 days of successive acidic bile salt treatment. MTT, transwell assay, and wound closure assay were applied to assess cell proliferation and migration ability. The expression of key factors was analyzed by RT-qPCR, western blotting and immunohistochemical staining. Our data show that the protein expression level of P53 reduced after exposure to acidic bile salt treatment, and the P53 deficiency favors the survival of esophageal epithelial cells to accommodate the stimulation of acidic bile salts. Furthermore, exposure to acidic bile salt decreases cell adhesions by repressing the JAK/STAT signaling pathway and activating VEGFR/AKT in P53-deficient esophageal cells. In EAC clinical samples, P53 protein expression is positively correlated with that of ICAM1 and STAT3 and negatively correlated with VEGFR protein expression levels. These findings elucidate the role of P53 in the formation of BE, explain the mechanism of P53 deficiency as a higher risk of progression for BE formation, and provide potential therapeutic targets for EAC.
Tissue metaplasia is uncommon in adults because established cis-element programs resist rewiring. In Barrett's esophagus, the distal esophageal mucosa acquires a predominantly intestinal character, with notable gastric features, and is predisposed to developing invasive cancers. We sought to understand the chromatin underpinnings of Barrett's metaplasia and why it commonly displays simultaneous gastric and intestinal properties.
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.
Sponges are known to possess remarkable reconstitutive and regenerative abilities ranging from common wounding or body part regeneration to more impressive re-building of a functional body from dissociated cells. Among the four sponge classes, Homoscleromorpha is notably the only sponge group to possess morphologically distinct basement membrane and specialized cell-junctions, and is therefore considered to possess true epithelia. The consequence of this peculiar organization is the predominance of epithelial morphogenesis during ontogenesis of these sponges. In this work we reveal the underlying cellular mechanisms used during morphogenesis accompanying ectosome regeneration in the homoscleromorph sponge model: Oscarella lobularis. We identified three main sources of novel exopinacoderm during the processes of its regeneration and the restoration of functional peripheral parts of the aquiferous system in O. lobularis: (1) intact exopinacoderm surrounding the wound surface, (2) the endopinacoderm from peripheral exhalant and inhalant canals, and (3) the intact choanoderm found on the wound surface. The basic morphogenetic processes during regeneration are the spreading and fusion of epithelial sheets that merge into one continuous epithelium. Transdifferentiation of choanocytes into exopinacocytes is also present. Epithelial-mesenchymal transition is absent during regeneration. Moreover, we cannot reveal any other morphologically distinct pluripotent cells. In Oscarella, neither blastema formation nor local dedifferentiation and proliferation have been detected, which is probably due to the high morphogenetic plasticity of the tissue. Regeneration in O. lobularis goes through cell transdifferentiation and through the processes, when lost body parts are replaced by the remodeling of the remaining tissue. Morphogenesis during ectosome regeneration in O. lobularis is correlated with its true epithelial organization. Knowledge of the morphological basis of morphogenesis during Oscarella regeneration could have important implications for our understanding of the diversity and evolution of regeneration mechanisms in metazoans, and is a strong basis for future investigations with molecular-biological approaches.
Targeting airway goblet cell metaplasia is a novel strategy that can potentially reduce the chronic obstructive pulmonary disease (COPD) symptoms. Tumor suppressor liver kinase B1 (LKB1) is an important regulator of the proliferation and differentiation of stem/progenitor cells. In this study, we report that LKB1 expression was downregulated in the lungs of patients with COPD and in those of cigarette smoke-exposed mice. Nkx2.1Cre; Lkb1f/f mice with conditional loss of Lkb1 in mouse lung epithelium displayed airway mucus hypersecretion and pulmonary macrophage infiltration. Single-cell transcriptomic analysis of the lung tissues from Nkx2.1Cre; Lkb1f/f mice further revealed that airway goblet cell differentiation was altered in the absence of LKB1. An organoid culture study demonstrated that Lkb1 deficiency in mouse airway (club) progenitor cells promoted the expression of FIZZ1/RELM-α, which drove airway goblet cell differentiation and pulmonary macrophage recruitment. Additionally, monocyte-derived macrophages in the lungs of Nkx2.1Cre; Lkb1f/f mice exhibited an alternatively activated M2 phenotype, while expressing RELM-α, which subsequently aggravated airway goblet cell metaplasia. Our findings suggest that the LKB1-mediated crosstalk between airway progenitor cells and macrophages regulates airway goblet cell metaplasia. Moreover, our data suggest that LKB1 agonists might serve as a potential therapeutic option to treat respiratory disorders associated with goblet cell metaplasia.
The contribution of the microenvironment to pancreatic acinar-to-ductal metaplasia (ADM), a preneoplastic transition in oncogenic Kras-driven pancreatic cancer progression, is currently unclear. Here we show that disruption of paracrine Hedgehog signaling via genetic ablation of Smoothened (Smo) in stromal fibroblasts in a Kras(G12D) mouse model increased ADM. Smo-deleted fibroblasts had higher expression of transforming growth factor-α (Tgfa) mRNA and secreted higher levels of TGFα, leading to activation of EGFR signaling in acinar cells and increased ADM. The mechanism involved activation of AKT and noncanonical activation of the GLI family transcription factor GLI2. GLI2 was phosphorylated at Ser230 in an AKT-dependent fashion and directly regulated Tgfa expression in fibroblasts lacking Smo Additionally, Smo-deleted fibroblasts stimulated the growth of Kras(G12D)/Tp53(R172H) pancreatic tumor cells in vivo and in vitro. These results define a non-cell-autonomous mechanism modulating Kras(G12D)-driven ADM that is balanced by cross-talk between Hedgehog/SMO and AKT/GLI2 pathways in stromal fibroblasts.
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