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9 recordsLinked to original sources
PubMed1978

Possible regulatory mechanisms of the cornea. I. Epithelial-stromal interaction in vitro.

Electron microscopic studies of pure epithelial and stromal cultures and of combined cultures demonstrated that keratocytes activity was inhibited by the presence of epithelial cells in culture. The degradation of collagen and the formation of clear zones around the keratocytes within the explants of pure stroma is interpreted as an indication for the production of a collagenolytic substance by the active keratocytes. The collagenolytic activity of the keratocytes was not observed within the stroma of combined cultures and was probably inhibited by the activity of epithelial cells in these cultures. Furthermore, using a microculture method for the assessment of the metabolic activity of corneal cells in vitro, supernatants of epithelial cell cultures were shown to have a marked inhibitory effect on the capacity of keratocytes to synthesize DNA. No effect of stromal cell supernatant on epithelial cell activity could be detected by the same methods. It is suggested that this "one way" influence as observed in vitro might, in certain conditions, play a role as a regulatory mechanism in vivo.

Animals↗
PubMed1978

Regulation of corneal collagenase production: epithelial-stromal cell interactions.

Mixtures of epithelial and stromal cells isolated from normal adult rabbit cornea, when cocultured in the presence of cytochalasin B, produced latent collagenase, whereas neither cell type alone, nor the mixture in the absence of this agent, did so. The enzyme, a characteristic animal collagenase, required proteolytic activation. The relative concentrations of epithelial and stromal cells had a profound effect on on collagenase production, the enzyme activity bieng directly proportional to the number of stromal cells but inversely proportional to the number of epithelial cells. The amount of enzyme released into the medium was also directly proportional to cytochalasin B concentration. Media conditioned by cytochalasin B-treated epithelial or stromal cells did not stimulate collagenase secretion by the other cell type. The data suggest direct cell contact or close proximity as the mode of productive interaction and tentatively identify the stromal cell as the source of enzyme and the epithelial cell as a stimulator.

Animals↗
PubMed2026

Stromal Hedgehog Signaling Drives Segment-Specific Malignant Transformation of Gastrointestinal Stem Cells by Producing Bone Morphogenetic Protein Antagonists.

BACKGROUND & AIMS: Hedgehog signaling plays a complex role in epithelial-stromal interactions, but its effects on gastrointestinal stem cells mediated by heterogeneous stromal cell populations remain incompletely defined. Here, we investigate how stromal Hedgehog signaling regulates gastric stem cells and tumorigenesis in a segment-specific manner. METHODS: We genetically activated Hedgehog signaling in distinct stromal cell lineages using Col1a2-, Pdgfra-, Gli1-, Acta2-, and Prrx1-CreERT mouse lines, combined with lineage tracing, RNA sequencing, chromatin immunoprecipitation-quantitative polymerase chain reaction, and pharmacologic interventions. Human gastric cancer data from The Cancer Genome Atlas were also analyzed. RESULTS: We show that genetic activation of Hedgehog signaling in stromal cells marked by Col1a2, Pdgfra, or Gli1, but not by Acta2, induces tumorigenesis in the stomach and gastroesophageal junction, but not in the small or large intestine. Hedgehog signaling increases the expression of multiple bone morphogenetic protein antagonists in gastric but not colonic stromal cells, via Gli1-mediated transcription. These bone morphogenetic protein antagonists, in turn, activate Wnt/β-catenin signaling in gastric stem cells, driving their proliferation and initiating gastric cancer expressing CD44 and Sox9, but not Lgr5. Activating bone morphogenetic protein or inhibiting Wnt signaling blocks tumor initiation. Analysis of patient data from The Cancer Genome Atlas reveals elevated Hedgehog signaling in gastric cancers, which correlates with suppressed bone morphogenetic protein signaling. CONCLUSIONS: These findings uncover a gastrointestinal segment-specific oncogenic role for Hedgehog signaling in Col1a2+Acta2- stromal cells, mediated through the bone morphogenetic protein-Wnt-β-catenin axis.

BMP Antagonists↗
PubMed1977

Quantitation and immunocytochemical localization of human skin collagenase in basal cell carcinoma.

Human skin collagenase was quantitated by radioimmunoassay in 21 basal cell carcinomas. Immunoreactive collagenase protein was found to be approximately 2-fold greater in extracts of these tumors than in extracts of normal skin, suggesting that this enzyme may be important in the pathogenesis of soft tissue destruction in vivo. To further define the role of collagenase in such destruction, immunofluorescent staining with specific antiserum to human skin collagenase was used to localize collagenase in the basal cell carcinomas. The enzyme was found only in the stromal elements surrounding the tumor islands. No staining of the epithelial components of the basal cell carcinomas was found. These findings suggest that the normal connective tissue elements may have been stimulated to produce an increased amount of collagenase and emphasize the importance of epithelial-stromal interaction in soft tissue invasiveness.

Basal Cell Carcinoma↗
PubMed2026

Profibrogenic Gremlin-1 expression in prostate cancer and the clinicopathologic association.

BACKGROUND: Gremlin-1 (GREM1) is a profibrogenic molecule involved in TGF-&#x3b2; signaling. Recent studies have implicated GREM1 in androgen receptor (AR)-independent signaling and castration resistance in advanced prostate cancer. However, its compartment expression patterns and clinicopathologic significance in primary prostate cancer remain unclear. METHODS: GREM1 mRNA expression and clinicopathologic associations were analyzed in the Cancer Genome Atlas (TCGA) prostate adenocarcinoma (TCGA-PRAD), the Memorial Sloan Kettering Cancer Center (MSKCC), and the German Cancer Research Center (DKFZ) primary prostate cancer cohorts. Correlations between GREM1 and genes related to TGF-&#x3b2; signaling, extracellular matrix organization, fibroblast activation, and AR signaling were evaluated by Spearman analysis. GREM1 protein expression was examined by immunohistochemistry in commercial human prostate cancer tissue microarrays (TMAs) using compartment-specific QuPath-based H-scores. RESULTS: GREM1 expression was relatively elevated in prostate and bladder cancers. Across the three prostate cancer cohorts, higher GREM1 expression was associated with adverse pathologic features and was most consistently correlated with FAP. Inverse correlations were observed with selected AR-related genes, whereas no significant correlation was found with AR itself. Higher GREM1 expression was associated with shorter disease-free survival only in MSKCC but was not an independent prognostic factor after clinicopathologic adjustment. Quantitative immunohistochemistry in 43 patients showed higher epithelial than stromal GREM1 H-scores (median, 3.10 vs 1.41; P < 0.0001), with heterogeneous staining in both compartments. Neither epithelial nor stromal H-scores were associated with Gleason score or pathologic T stage. CONCLUSIONS: GREM1 mRNA expression in primary prostate cancer was associated with adverse clinicopathologic features, and a fibroblast-associated transcriptional context but did not demonstrate independent prognostic value. At the protein-level, GREM1 expression was heterogeneous in both epithelial and stromal compartments, with higher epithelial H-scores on average. These findings support further investigation of the biological significance of GREM1 expression in primary prostate cancer.

TCGA↗