Vascular endothelial growth factor-C and -D are involved in lymphangiogenesis in mouse unilateral ureteral obstruction.

Lymphatic remodeling in inflammation has been found in tracheal mycoplasma infection, human kidney transplant, skin inflammation, peritonitis, and corneal inflammation. Here we investigated lymphangiogenesis in fibrotic area in unilateral ureteral obstruction, a model of progressive renal fibrosis, and evaluated the roles of vascular endothelial growth factor (VEGF)-C and -D in the obstructed kidney. Compared to sham-operated mice, the number of LYVE-1-positive lymphatic vessels, the proliferation of LYVE-1-positive lymphatic endothelial cells, along with VEGF-C and -D mRNA expression were all significantly increased following ureteral obstruction. Depletion of macrophages with clodronate decreased lymphangiogenesis in the obstructed kidney. VEGF-C expression was higher in M2- than in M1-polarized macrophages from bone marrow-derived macrophages, and also increased in Raw 264.7 or renal proximal tubule cells by stimulation with TGF-ß1 or TNF-α. VEGF-D reversed the inhibitory effect of TGF-ß1 on VEGF-C-induced migration, capillary-like tube formation, and proliferation of human lymphatic endothelial cells. Additionally, the blockade of VEGF-C and VEGF-D signaling decreased obstruction-induced lymphangiogenesis. Thus, VEGF-C and VEGF-D are associated with lymphangiogenesis in the fibrotic kidney in a mouse model of ureteral obstruction.

Sclerosing hemangioma, presenting as a pneumonic pattern with mucinous adenomatous hyperplasia of the lung.

Pulmonary sclerosing hemangioma is generally considered a rare neoplasm presenting as a solitary benign nodule. During routine medical examination multiple abnormal nodular shadows were detected in the right lower lung field on chest X-ray in a 48-year-old asymptomatic woman. The patient underwent wedge resection for the pulmonary lesion. The resected lung had numerous scattered tiny nodules and small nodules congregated together, forming larger nodules. All of these lesions had typical features of sclerosing hemangioma. The authors call this unusual growth pattern of sclerosing hemangioma a 'pneumonic pattern'. Adjacent to the largest lesion, a relatively well-defined small mucinous lesion composed of mucinous tall columnar cells and basaloid squamous cells was detected. Because this lesion did not have expression of thyroid transcription factor-1, it is described as mucinous adenomatous hyperplasia.

Prostaglandins promote colon cancer cell invasion; signaling by cross-talk between two distinct growth factor receptors.

Colorectal cancer is the second most frequent cancer in the Western world, often lethal when invasion and/or metastasis occur. In addition to hepatocyte growth factor (HGF), colon cancer invasion may be driven by prostaglandins, especially the E2 series (PGE2), generated by the cyclooxygenase-2 (Cox-2) enzyme. While concentration of PGE2 as well as expression of Cox-2, HGF receptor (c-Met-R), epidermal growth factor receptor (EGFR), and beta-catenin are all dramatically increased in colon cancers and implicated in their growth and invasion, the precise role of PGE2 in the latter process remains unclear. Here we provide evidence that PGE2 transactivates c-Met-R (contingent upon functional EGFR), increases tyrosine phosphorylation and nuclear accumulation of beta-catenin, and induces urokinase-type plasminogen activator receptor (uPAR) mRNA expression. This is accompanied by increased beta-catenin association with c-Met-R and enhanced colon cancer cell invasiveness. Inactivation of EGFR and c-Met-R significantly reduced PGE2-induced cancer cell invasiveness. Clinical relevance of these findings is confirmed by our immunohistochemical studies demonstrating that cancer cells in the invasive front overexpress Cox-2, c-Met-R, and beta-catenin. Our findings explain a functional relationship between prostaglandins, EGFR, and c-Met-R in colon cancer growth and invasion.

Esophageal ulceration triggers expression of hypoxia-inducible factor-1 alpha and activates vascular endothelial growth factor gene: implications for angiogenesis and ulcer healing.

Our previous studies demonstrated that enhanced epithelial cell proliferation is important for healing of experimental esophageal ulcers. However, the roles of angiogenesis, its major mediator, vascular endothelial growth factor (VEGF), and the mechanism(s) regulating VEGF expression during esophageal ulcer healing remain unknown. Esophageal ulcers were induced in rats by focal application of acetic acid. We studied expressions of hypoxia-inducible transcription factor-1 alpha (HIF-1 alpha), an activator of the VEGF gene, and VEGF by reverse transcriptase-polymerase chain reaction, Western blotting, and immunostaining. To determine the efficacy of VEGF gene therapy in esophageal ulcer healing, we studied whether a single local injection of plasmid cDNA encoding recombinant human VEGF(165) affects ulcer healing and angiogenesis. Esophageal ulceration induced HIF-1 alpha protein expression and VEGF gene activation reflected by increased VEGF mRNA (240%) and VEGF protein (310%) levels. HIF-1 alpha protein was expressed in microvessels bordering necrosis where it co-localized with VEGF. Injection of cDNA encoding VEGF(165) significantly enhanced angiogenesis and accelerated esophageal ulcer healing. These results: 1) suggest that HIF-1 alpha may mediate esophageal ulceration-triggered VEGF gene activation, 2) indicate an essential role of VEGF and angiogenesis in esophageal ulcer healing, and 3) demonstrate the feasibility of gene therapy for the treatment of esophageal ulcers.

Selective cyclooxygenase-2 blocker delays healing of esophageal ulcers in rats and inhibits ulceration-triggered c-Met/hepatocyte growth factor receptor induction and extracellular signal-regulated kinase 2 activation.

Nonsteroidal anti-inflammatory drugs, both nonselective and cyclooxygenase-2 (COX-2) selective, delay gastric ulcer healing. Whether they affect esophageal ulcer healing remains unexplored. We studied the effects of the COX-2 selective inhibitor, celecoxib, on esophageal ulcer healing as well as on the cellular and molecular events involved in the healing process. Esophageal ulcers were induced in rats by focal application of acetic acid. Rats with esophageal ulcers were treated intragastrically with either celecoxib (10 mg/kg, once daily) or vehicle for 2 or 4 days. Esophageal ulceration triggered increases in: esophageal epithelial cell proliferation; expression of COX-2 (but not COX-1); hepatocyte growth factor (HGF) and its receptor, c-Met; and activation of extracellular signal-regulated kinase 2 (ERK2). Treatment with celecoxib significantly delayed esophageal ulcer healing and suppressed ulceration-triggered increases in esophageal epithelial cell proliferation, c-Met mRNA and protein expression, and ERK2 activity. In an ex vivo organ-culture system, exogenous HGF significantly increased ERK2 phosphorylation levels in esophageal mucosa. A structural analog of celecoxib, SC-236, completely prevented this effect. These findings indicate that celecoxib delays esophageal ulcer healing by reducing ulceration-induced esophageal epithelial cell proliferation. These actions are associated with, and likely mediated by, down-regulation of the HGF/c-Met-ERK2 signaling pathway.