transforming-growth-factor-beta and Hamartoma

Peutz-Jeghers syndrome (PJS) is caused by mutations in the LKB1 gene. It is characterized by gastrointestinal polyposis and an increased cancer risk, mainly in the gastrointestinal tract. Mechanisms of PJS-associated carcinogenesis are unclear. We investigated the involvement of candidate genes and molecular pathways in PJS-associated gastrointestinal cancers and dysplastic hamartomas. Cases were selected from the Dutch PJS cohort. Available tissue was immunostained for phospho-S6, β-catenin, P53 and SMAD4. DNA was isolated from carcinoma tissue and dysplastic and non-dysplastic areas of hamartomas specifically. Mutation analyses were done for BRAF, KRAS and P53, and loss of heterozygosity (LOH) analyses for LKB1 and P53. Twenty-four of 144 patients (17%) developed 26 gastrointestinal malignancies at a median age of 49 years (interquartile range: 35-60). Eleven of 792 hamartomas (1.4%) of 9 patients were classified as dysplastic. LOH of LKB1 was detected in three of six (50%) carcinomas and in the dysplastic part of three of five (60%) hamartomas. Aberrant P53 expression was observed in 8 of 15 (53%) carcinomas. Six carcinomas with P53 overexpression harboured a P53 mutation, with loss of the remaining wild-type allele in four. Two hamartomas showing P53 overexpression in high-grade dysplastic foci harboured a P53 mutation with LOH. Loss of nuclear SMAD4 was observed in high-grade dysplastic foci of two of four (50%) hamartomas, in contrast to low-grade dysplastic foci (0/4) and non-dysplastic epithelium. Our findings suggest a role for mutant P53 in PJS-associated gastrointestinal carcinogenesis. Inactivation of transforming growth factor-β/bone morphogenetic protein signalling and complete loss of LKB1 might be involved in dysplastic transformation of gastrointestinal hamartomas specifically.

Topics: Adult; Alleles; AMP-Activated Protein Kinase Kinases; Cohort Studies; DNA Mutational Analysis; Female; Gastrointestinal Neoplasms; Gene Expression Regulation, Neoplastic; Germ-Line Mutation; Hamartoma; Humans; Immunohistochemistry; Loss of Heterozygosity; Male; Middle Aged; Netherlands; Pedigree; Peutz-Jeghers Syndrome; Protein Serine-Threonine Kinases; Smad4 Protein; Transforming Growth Factor beta; Tumor Suppressor Protein p53

Cyclo-oxygenase (COX)-2 is induced in various types of cancer tissues. Here, we demonstrate stromal expression of both COX-2 and microsomal prostaglandin E(2) synthase (mPGES)-1 in gastrointestinal hamartomas developed in Lkb1(+/-), Smad4(+/-) and Cdx2(+/-)mice. These results suggest that PGE(2) produced by COX-2 and mPGES-1 plays an important role in hamartoma development regardless of the mutated genes causing hamartomas.

Topics: Adaptor Proteins, Signal Transducing; AMP-Activated Protein Kinases; Animals; Carrier Proteins; CDX2 Transcription Factor; Cyclooxygenase 2; DNA-Binding Proteins; Genes, Tumor Suppressor; Hamartoma; Homeodomain Proteins; Immunohistochemistry; Intracellular Signaling Peptides and Proteins; Intramolecular Oxidoreductases; Isoenzymes; Mice; Peroxidases; Prostaglandin-E Synthases; Prostaglandin-Endoperoxide Synthases; Protein Serine-Threonine Kinases; Signal Transduction; Smad4 Protein; Stomach Diseases; Trans-Activators; Transforming Growth Factor beta

The aim of this study was to compare the function of lung fibroblasts obtained from surgically biopsied specimens of patients with idiopathic pulmonary fibrosis/usual interstitial pneumonia (UIP; n = 5), nonspecific interstitial pneumonia (NSIP; n = 5), and normal parts of surgically resected lungs (control; n = 5). The results showed that (1) fibroblasts obtained from UIP showed increased contractility compared with those obtained from NSIP or controls (UIP, 72.7 +/- 6.21%; NSIP, 32.8 +/- 5.46; controls, 28.5 +/- 3.51, p < 0.01 in UIP versus NSIP or control); (2) this increase in contractility was consistent with enhanced F-actin content in fibroblasts; (3) conditioned media from UIP fibroblast cultures enhanced control fibroblast contractility, whereas those obtained from NSIP or controls did not; (4) the 180 and 25 kD products representing the contractility in conditioned media were identified as fibronectin (ED-A domain) and TGF-beta1 by immunoblots, respectively; (5) the UIP-conditioned media contained higher amounts of fibronectin or TGF-beta 1 (fibronectin: UIP 289 +/- 47.1 ng/ml, NSIP 121 +/- 23.0, control 118 +/- 16.0; TGF-beta1: UIP 798 +/- 119 pg/ml, NSIP 246 +/- 69.1, control 247 +/- 53.6, p < 0.01 in UIP versus NSIP or control); () the contractility positively correlated with the amount of either fibronectin (r = 0.867, p < 0.001, n = 15) or TGF-beta 1 (r = 0.939, p < 0.001, n = 15), respectively. Thus, UIP fibroblasts showed greater contractility than did NSIP fibroblasts and up-regulated control fibroblasts.

Topics: Actins; Adenocarcinoma; Analysis of Variance; Biopsy; Cells, Cultured; Culture Media, Serum-Free; Female; Fibroblasts; Gels; Hamartoma; Humans; Lung; Lung Diseases; Lung Diseases, Interstitial; Lung Neoplasms; Male; Middle Aged; Transforming Growth Factor beta; Transforming Growth Factor beta1