A combination of Trastuzumab and 17-AAG induces enhanced ubiquitinylation and lysosomal pathway-dependent ErbB2 degradation and cytotoxicity in ErbB2-overexpressing breast cancer cells.

ErbB2 (or Her2/Neu) overexpression in breast cancer signifies poorer prognosis, yet it has provided an avenue for targeted therapy as demonstrated by the success of the humanized monoclonal antibody Trastuzumab (Herceptin). Resistance to Trastuzumab and eventual failure in most cases, however, necessitate alternate ErbB2-targeted therapies. HSP90 inhibitors such as 17-allylaminodemethoxygeldanamycin (17-AAG), potently downregulate the cell surface ErbB2.

Cadherin switching.

The cadherin molecules at adherens junctions have multiple isoforms. Cadherin isoform switching (cadherin switching) occurs during normal developmental processes to allow cell types to segregate from one another. Tumor cells often recapitulate this activity and the result is an aggressive tumor cell that gains the ability to leave the site of the tumor and metastasize.

Comparison of endothelial cell proliferation in normal liver and adipose tissue in B6C3F1 mice, F344 rats, and humans.

Peroxisome proliferator-activated receptor gamma (PPARgamma) and dual PPARalpha and gamma agonists have been developed for use in the treatment of diabetes and hyperlipidemias. Vascular tumors were increased in mice treated with some PPAR agonists, but not in rats. Spontaneous hemangiosarcomas are common in several strains of mice, uncommon in rats, and rarely occur in humans.

Diabetes mellitus in pancreatic cancer: is it a causal relationship?

The relationship between type 2 diabetes mellitus and pancreatic cancer (PC) is not clear. It has been reported that the increased release of islet amyloid polypeptides (IAPPs) is responsible for the impaired glucose tolerance in PC patients. However, no information exists on the patterns of IAPP expression in PC tissue in comparison with tissue from the normal pancreas and that of a patient with type 2 diabetes.

EH domain of EHD1.

EHD1 is a member of the mammalian C-terminal Eps15 homology domain (EH) containing protein family, and regulates the recycling of various receptors from the endocytic recycling compartment to the plasma membrane. The EH domain of EHD1 binds to proteins containing either an Asn-Pro-Phe or Asp-Pro-Phe motif, and plays an important role in the subcellular localization and function of EHD1. Thus far, the structures of five N-terminal EH domains from other proteins have been solved, but to date, the structure of the EH domains from the four C-terminal EHD family paralogs remains unknown.

Inhalation of tobacco smoke induces increased proliferation of urinary bladder epithelium and endothelium in female C57BL/6 mice.

Cigarette smoking is the major environmental risk factor for bladder cancer in humans. Aromatic amines, potent DNA-reactive bladder carcinogens present in cigarette smoke, contribute significantly. However, increased cell proliferation, caused by direct mitogenesis or in response to cytotoxicity, may also play a role since urothelial hyperplasia has been observed in human cigarette smokers.

Histological aggressiveness of fluorodeoxyglucose positron-emission tomogram (FDG-PET)-detected incidental thyroid carcinomas.

Background: We previously reported a high incidence of primary thyroid cancer in fluorodeoxyglucose positron-emission tomogram (FDG-PET)-detected incidental thyroid abnormalities. The aim of our study was to determine if these FDG-PET-detected thyroid malignancies represent a more-aggressive variant of primary thyroid carcinoma.

Materials And Methods: All patients that underwent operative intervention for FDG-PET-detected incidental thyroid abnormalities were identified (June 2003 to April 2006).

Collagen I promotes epithelial-to-mesenchymal transition in lung cancer cells via transforming growth factor-beta signaling.

Epithelial-to-mesenchymal transition (EMT) is a fundamental biological process whereby epithelial cells lose their polarity and undergo a transition to a mesenchymal phenotype. When cancer cells invade adjacent tissues, they use a mechanism akin to EMT, and understanding the molecular mechanisms that drive this transition will facilitate studies into new targets for prevention of metastasis. Extracellular stimuli, such as growth factors, and their cytosolic effectors cooperate to promote EMT.

EHD1 regulates cholesterol homeostasis and lipid droplet storage.

Endocytic transport is critical for the subcellular distribution of free cholesterol and the endocytic recycling compartment (ERC) is an important organelle that stores cholesterol and regulates its trafficking. The C-terminal EHD protein, EHD1, controls receptor recycling through the ERC and affects free cholesterol distribution in the cell. We utilized embryonic fibroblasts from EHD1 knockout mice (Ehd1(-/-)MEF) and SiRNA in normal MEF cells to assess the role of EHD1 in intracellular transport of cholesterol.

EHD1 and Eps15 interact with phosphatidylinositols via their Eps15 homology domains.

The C-terminal Eps15 homology domain-containing protein, EHD1, regulates the recycling of receptors from the endocytic recycling compartment to the plasma membrane. In cells, EHD1 localizes to tubular and spherical recycling endosomes. To date, the mode by which EHD1 associates with endosomal membranes remains unknown, and it has not been determined whether this interaction is direct or via interacting proteins.

A novel four-amino acid determinant defines conformational freedom within chorionic gonadotropin beta-subunits.

On the basis of apparent molecular mass heterogeneity following reducing versus nonreducing SDS-PAGE, we determined that the beta-subunit of macaque (Macaca fascicularis) chorionic gonadotropin (mCG-beta) is more conformationally constrained than the beta-subunit of human chorionic gonadotropin (hCG-beta). The amino acid sequences of these two subunits are 81% identical. To determine the conformational variance source, which was not due to glycosylation differences, we generated a series of hCG-beta-mCG-beta chimeras and identified domains that contributed to CG-beta conformational freedom.

EHD1 regulates beta1 integrin endosomal transport: effects on focal adhesions, cell spreading and migration.

beta1 integrins bind to the extracellular matrix and stimulate signaling pathways leading to crucial cellular functions, including proliferation, apoptosis, cell spreading and migration. Consequently, control of beta1 integrin function depends upon its subcellular localization, and recent studies have begun to unravel the complex regulatory mechanisms involved in integrin trafficking. We report that the C-terminal Eps15-homology (EH) domain-containing protein EHD1 plays an important role in regulating beta1 integrin transport.

NHERF links the N-cadherin/catenin complex to the platelet-derived growth factor receptor to modulate the actin cytoskeleton and regulate cell motility.

Using phage display, we identified Na+/H+ exchanger regulatory factor (NHERF)-2 as a novel binding partner for the cadherin-associated protein, beta-catenin. We showed that the second of two PSD-95/Dlg/ZO-1 (PDZ) domains of NHERF interacts with a PDZ-binding motif at the very carboxy terminus of beta-catenin. N-cadherin expression has been shown to induce motility in a number of cell types.

Distribution of pancreatic endocrine cells including IAPP-expressing cells in non-diabetic and type 2 diabetic cases.

There is a lack of agreement on the distribution of islet amyloid polypeptide (IAPP) in the pancreases of healthy and diabetic subjects. Therefore, a detailed morphometrical and immunohistochemical study was performed to obtain information on the distribution of cells expressing insulin, glucagon, somatostatin, pancreatic polypeptide (PP), and IAPP in the pancreases of non-diabetic (n=4) and diabetic individuals (n=6). In the non-diabetic cases, beta-cells contributed to approximately 64%, alpha-cells to 26%, delta-cells to 8%, PP cells to 0.

Liver transplantation for hepatocellular carcinoma: an update.

Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related death worldwide and the most common primary hepatic malignancy. It arises on a background of hepatic cirrhosis in approximately 95% of the cases in the United States. A wide variety of treatment modalities have been applied in the treatment of HCC.

Expression of Oct4, a stem cell marker, in the hamster pancreatic cancer model.

Background: Oct4 has been shown to present a stem cell marker that is expressed in embryonic cells and in germ cell tumors. Recently, its expression in a few human tissues and cancer cells has been reported. Because in the hamster pancreatic cancer model most tumors develop from within islets presumably from stem cells, we investigated the expression of Oct4 in this model.

Phosphoinositide-3 kinase-Rac1-c-Jun NH2-terminal kinase signaling mediates collagen I-induced cell scattering and up-regulation of N-cadherin expression in mouse mammary epithelial cells.

During epithelial-to-mesenchymal transitions (EMTs), cells must change their interactions with one another and with their extracellular matrix in a synchronized manner. To characterize signaling pathways cells use to coordinate these changes, we used NMuMG mammary epithelial cells. We showed that these cells become fibroblastic and scattered, with increased N-cadherin expression when cultured on collagen I.

Interactions between EHD proteins and Rab11-FIP2: a role for EHD3 in early endosomal transport.

Eps15 homology domain (EHD) 1 enables membrane recycling by controlling the exit of internalized molecules from the endocytic recycling compartment (ERC) en route to the plasma membrane, similar to the role described for Rab11. However, no physical or functional connection between Rab11 and EHD-family proteins has been demonstrated yet, and the mode by which they coordinate their regulatory activity remains unknown. Here, we demonstrate that EHD1 and EHD3 (the closest EHD1 paralog), bind to the Rab11-effector Rab11-FIP2 via EH-NPF interactions.

Are there any stem cells in the pancreas?

A vast number of studies indicate the presence of stem/progenitor cells virtually in all tissues in adult organs, particularly in bone marrow. Recent studies, however, cast doubt about the existence of true stem cells in adult tissue. The complex integrity of several cells with distinct morphologic and functional properties in the mature pancreas confers an appropriate status for stem cell research.

Pancreatic hepatocellular tumor.

Background: Hepatocellular differentiation of pancreatic cells has been observed under certain conditions in several species, including humans. Their cell of origin and biology has remained controversial. Generally, these lesions have been considered a degenerative process.

Intratumoral molecular or genetic markers as predictors of clinical outcome with chemotherapy in colorectal cancer.

Identification of molecular markers at either the intragenic, chromosomal, mRNA, or protein level that might predict whether colorectal cancer patients are likely to benefit from adjuvant or palliative therapy is a high priority. The majority of clinical studies addressing this issue, particularly those done in the adjuvant setting, analyzed tumor samples from patients treated in the era when 5-fluorouracil (5-FU) alone or combined with leucovorin or levamisole were the mainstay of therapy. This review highlights some of the intratumoral molecular markers that may have importance as predictors of benefit with 5-FU-based therapy.

ErbB2 oncogene antibodies differentiate between the normal and diseased pancreas, and between chronic pancreatitis and pancreatic cancer.

Histological differentiation between chronic pancreatitis and pancreatic cancer, especially in biopsy material, remains challenging and the frequent association of 'secondary' chronic pancreatitis (due to ductal obstruction) with pancreatic cancer causes additional diagnostic problems. Our study, using anti-ErbB2 antibodies from Santa Cruz and Dako in tissues from the normal pancreas, chronic pancreatitis and pancreatic cancer showed that these antibodies discriminate between primary chronic pancreatitis and 'secondary' chronic pancreatitis due to pancreatic cancer. Tissues from 28 pancreatic cancer patients, 15 chronic pancreatitis patients and 12 organ donors or early autopsy cases were subjected to immunohistochemical studies using polyclonal ErbB2 antibodies from Santa Cruz and Dako.

New advances on the functions of epidermal growth factor receptor and ceramides in skin cell differentiation, disorders and cancers.

Recent advances in understanding of the biological functions of the epidermal growth factor and epidermal growth factor receptor (EGF-EGFR) system and ceramide production for the maintenance of skin integrity and barrier function are reported. In particular, the opposite roles of EGFR and ceramide cascades in epithelial keratinocyte proliferation, migration and terminal differentiation are described. Moreover, the functions of ceramides in the epidermal permeability barrier are reviewed.

The combination of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL/Apo2L) and Genistein is effective in inhibiting pancreatic cancer growth.

Objectives: Our previous studies have shown that, contrary to many other human pancreatic adenocarcinoma cell lines, AsPC1 cells are resistant to the apoptotic effect of the tumor necrosis factor-related apoptosis-inducing ligand, also called Apo2L (TRAIL/Apo2L). In our in vitro studies, the combination of TRAIL/Apo2L and protein synthesis inhibitor, genistein, but not genistein alone, was, however, effective in inducing apoptosis in AsPC1 cells. In the present study, we examined the effect of TRAIL/Apo2L with genistein on the growth of AsPC1 cells in vitro and in vivo.

R-cadherin influences cell motility via Rho family GTPases.

Classical cadherins are the transmembrane proteins of the adherens junction and mediate cell-cell adhesion via homotypic interactions in the extracellular space. In addition, they mediate connections to the cytoskeleton by means of their association with catenins. Decreased cadherin-mediated adhesion has been implicated as an important component of tumorigenesis.