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Steven D Leach

Publications and source records attributed to Steven D Leach.

26 records · Page 2Linked to original sources
PubMed2003

Notch mediates TGF alpha-induced changes in epithelial differentiation during pancreatic tumorigenesis.

Notch signaling regulates cell fate decisions in a wide variety of adult and embryonic tissues. Here we show that Notch pathway components and Notch target genes are upregulated in invasive pancreatic cancer, as well as in pancreatic cancer precursors from both mouse and human. In mouse pancreas, ectopic Notch activation results in accumulation of nestin-positive precursor cells and expansion of metaplastic ductal epithelium, previously identified as a precursor lesion for pancreatic cancer. Notch is also activated as a direct consequence of EGF receptor activation in exocrine pancreas and is required for TGF alpha-induced changes in epithelial differentiation. These findings suggest that Notch mediates the tumor-initiating effects of TG alpha by expanding a population of undifferentiated precursor cells.

Animals↗
PubMed2003

Overexpression of heparin-binding EGF-like growth factor in mouse pancreas results in fibrosis and epithelial metaplasia.

BACKGROUND & AIMS: Heparin-binding epidermal growth factor-like growth factor (HB-EGF) is expressed in both normal pancreatic islets and in pancreatic cancers, but its role in pancreatic physiology and disease is not known. This report examines the effects of HB-EGF overexpression in mouse pancreas. METHODS: Transgenic mice were established using a tissue-specific promoter to express an HB-EGF complementary DNA in pancreatic beta cells, effectively elevating HB-EGF protein 3-fold over endogenous levels. RESULTS: Mice overexpressing HB-EGF in pancreatic islets showed both endocrine and exocrine pancreatic defects. Initially, islets from transgenic mice failed to segregate alpha, beta, delta, and PP cells appropriately within islets, and had impaired separation from ducts and acini. Increased stroma was detected within transgenic islets, expanding with age to cause fibrosis of both endocrine and exocrine compartments. In addition to these structural abnormalities, subsets of transgenic mice developed profound hyperglycemia and/or proliferation of metaplastic ductal epithelium. Both conditions were associated with severe stromal expansion, suggesting a role for islet/stromal interaction in the onset of the pancreatic disease initiated by HB-EGF. Supporting this conclusion, primary mouse fibroblasts adhered to transgenic islets when the 2 tissues were cocultured in vitro, but did not interact with nontransgenic islets. CONCLUSIONS: An elevation in HB-EGF protein in pancreatic islets led to altered interactions among islet cells and among islets, stromal tissues, and ductal epithelium. Many of the observed phenotypes appeared to involve altered cell adhesion. These data support a role for islet factors in the development of both endocrine and exocrine disease.

Animals↗
PubMed2003

Results of pancreaticoduodenectomy for lymphoplasmacytic sclerosing pancreatitis.

OBJECTIVE: To compare the presentation and short-term results of pancreaticoduodenectomy for lymphoplasmacytic sclerosing pancreatitis (LPSP) and pancreatic adenocarcinoma (PA) and to provide long-term follow-up on patients undergoing resection for LPSP. SUMMARY BACKGROUND DATA: LPSP is a rare form of chronic pancreatitis characterized by a mixed inflammatory infiltrate centered around pancreatic ducts and ductules, combined with obliterative phlebitis. Its presentation may mimic that of PA. METHODS: Among 1,648 patients undergoing pancreaticoduodenectomy at the authors' institution from January 1992 to May 2002, 37 with LPSP were identified. The demographics, clinical features, and short- and long-term outcomes of these patients were analyzed. Where applicable, comparisons were made to a consecutive group of 45 patients who underwent pancreaticoduodenectomy for PA from July 2001 to December 2001. RESULTS: Twenty-four percent (9/37) of the LPSP patients and none of the PA patients had a history of either atopic or autoimmune disease. The LPSP patients had a similar clinical presentation to the PA patients, but the LPSP patients were less likely to have a discrete pancreatic mass on CT and more likely to have CT findings suggesting a diffusely enlarged pancreas. The LPSP patients were also less likely to have a discrete pancreatic mass at operation, more likely to have a diffusely firm or hard gland, and more likely to have a difficult portal vein/superior mesenteric vein dissection when compared to the PA patients. Transfusion requirement, operative time, postoperative length of stay, and overall complication rate were similar between groups; however, the LPSP patients had a greater operative blood loss. The median length of follow-up for LPSP patients was 33 months. No patients had recurrent jaundice. One patient with LPSP had clinically evident recurrent pancreatitis. Among LPSP patients available for current telephone interview, 68% subjectively rated their quality of life as better, 18% reported no change, and 14% reported diminished quality of life compared to before surgery. CONCLUSION: LPSP mimics PA in clinical presentation, though CT findings of a diffusely enlarged pancreas without a discrete mass may suggest a diagnosis of LPSP. Nevertheless, differentiation from pancreatic neoplasia remains difficult. Patients undergoing pancreaticoduodenectomy for LPSP have durable relief of symptoms and a subjectively improved quality of life.

Adenocarcinoma↗
PubMed2002

Transgenic overexpression of amphiregulin induces a mitogenic response selectively in pancreatic duct cells.

BACKGROUND & AIMS: The epidermal growth factor (EGF) receptor family and the corresponding ligands are frequently overexpressed in pancreatic cancer. To compare the biological effects of transforming growth factor (TGF)-alpha and amphiregulin (AR) on growth and differentiation of the exocrine pancreas, we have generated transgenic mice overexpressing AR under control of the elastase promoter. METHODS: Two independently generated transgenic mouse lines overexpress 50-, 43-, 28-, 26-, and 16-kilodalton AR forms in the pancreas. RESULTS: Morphologic and immunohistochemical examinations suggest that small intralobular duct and centro-acinar cells proliferate in response to AR in these mice. AR transgenic mice display increased Ras, Erk1/2, cyclin D/CDK4, and cyclin E/CDK2 activity and G1/S progression in pancreatic duct cells. In contrast to TGF-alpha transgenic mice, AR neither induced tubular complex formation nor elicited a strong fibrogenic response. AR induced a slight induction of ErbB2 on duct cells, whereas TGF-alpha resulted in overexpression of the EGF receptor in cells within tubular complexes. Furthermore, AR and TGF-alpha displayed different effects on differentiation of isolated acini in vitro comparable to the situation in vivo. CONCLUSIONS: These data suggest that AR induces a mitogenic response selectively in small duct cells through activation of Ras, CDK2, and CDK4, respectively. The closely related EGF receptor ligands, AR and TGF-alpha, display different biological effects when overexpressed in the exocrine pancreas in vivo.

Amphiregulin↗
PubMed2002

Matrix metalloproteinase-7 is expressed by pancreatic cancer precursors and regulates acinar-to-ductal metaplasia in exocrine pancreas.

In gastrointestinal epithelium, metaplastic conversion between predominant cell types is associated with an increased risk of neoplasia. However, the mechanisms regulating metaplastic transitions in adult epithelia are largely undefined. Here we show that matrix metalloproteinase-7 (MMP-7) is expressed not only in the majority of human pancreatic ductal adenocarcinoma specimens, but also in human pancreatic intraepithelial neoplasia and metaplastic duct lesions in human and mouse. In a mouse model of pancreatic acinar-to-ductal metaplasia, MMP-7 progressively accumulates during the metaplastic transition, resulting in a concomitant increase in solubilization of Fas ligand (FasL). Under identical conditions, mice either deficient in MMP-7 or carrying an inactive FasL gene are severely inhibited in development of progressive metaplasia and acinar cell apoptosis. Thus, MMP-7 and FasL influence the initiation and maintenance of metaplastic events in pancreatic epithelium, explaining the observed link between metaplasia and apoptosis in pancreas and other gastrointestinal tissues.

Animals↗
PubMedDate not supplied

Predicting resectability of periampullary cancer with three-dimensional computed tomography.

The radiographic assessment of extent of tumor burden and local vascular invasion appears to be enhanced with three-dimensional computed tomography (3D-CT). The purpose of this study was to evaluate the impact of preoperative 3D-CT in determining the resectability of patients with periampullary tumors. Intraoperative findings from exploratory laparotomy were gathered prospectively from 140 patients who were thought to have periampullary tumors and were deemed resectable after undergoing preoperative 3D-CT imaging. CT findings were compared to intraoperative findings, and the accuracy of 3D-CT in predicting tumor resectability and, ultimately, the likelihood of obtaining a margin-negative resection were assessed. Of the 140 patients who were thought to have resectable periampullary tumors after preoperative 3D-CT, 115 (82%) were subsequently determined to have periampullary cancer. The remaining 25 patients had benign disease. Among the patients with periampullary cancer, the extent of local tumor burden involving the pancreas and peripancreatic tissues was accurately depicted by 3D-CT in 93% of the patients. 3D-CT was 95% accurate in determining cancer invasion of the superior mesenteric vessels. Preoperative 3D-CT accurately predicted periampullary cancer resectability and a margin-negative resection in 98% and 86% of patients, respectively. For patients with pancreatic adenocarcinoma (n=85), preoperative 3D-CT resulted in a resectability rate and a margin-negative resection rate of 79% and 73%, respectively. The ability of 3D-CT to predict a margin-negative resection for periampullary cancer, including pancreatic adenocarcinoma, relies on its enhanced assessment of the extent of local tumor burden and involvement of the mesenteric vascular anatomy.

Adenocarcinoma↗
PubMedDate not supplied

Pancreatic cancer.

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Adenocarcinoma↗