Downregulation of GSTM2 enhances gemcitabine chemosensitivity of pancreatic cancer in vitro and in vivo.

Glutathione-S-transferases (GSTs) not only show cytoprotective role and their involvement in the development of anticancer drug resistance, but also transmit signals that control cell proliferation and apoptosis. However, the role of GST isoforms in chemotherapy resistance remains elusive in pancreatic cancer. Here, we demonstrated that gemcitabine treatment increased the GSTM2 expression in pancreatic cancer cell lines.

Suppression of stromal-derived Dickkopf-3 (DKK3) inhibits tumor progression and prolongs survival in pancreatic ductal adenocarcinoma.

Pancreatic ductal adenocarcinoma (PDAC) has a dismal prognosis, and it is unclear whether its stromal infiltrate contributes to its aggressiveness. Here, we demonstrate that Dickkopf-3 (DKK3) is produced by pancreatic stellate cells and is present in most human PDAC. DKK3 stimulates PDAC growth, metastasis, and resistance to chemotherapy with both paracrine and autocrine mechanisms through NF-κB activation.

TM4SF1 Regulates Pancreatic Cancer Migration and Invasion In Vitro and In Vivo.

Background/aims: The cell surface protein transmembrane 4 L6 family member 1 (TM4SF1) has been detected in various tumors and plays a major role in the development of cancer. We aimed to investigate the effects of TM4SF1 on the migration and invasion of pancreatic cancer in vitro and in vivo and explore its related molecular mechanisms.

Methods: qRT-PCR and immunohistochemical analyses were used to measure the expression of TM4SF1 in pancreatic cancer tissues and adjacent tissues.

TM4SF1 Promotes Gemcitabine Resistance of Pancreatic Cancer In Vitro and In Vivo.

Background: TM4SF1 is overexpressed in pancreatic ductal adenocarcinoma (PDAC) and affects the development of this cancer. Also, multidrug resistance (MDR) is generally associated with tumor chemoresistance in pancreatic cancer. However, the correlation between TM4SF1 and MDR remains unknown.

Animal Models of Gastrointestinal and Liver Diseases. The difficulty of animal modeling of pancreatic cancer for preclinical evaluation of therapeutics.

Pancreatic ductal adenocarcinoma (PDAC) is relatively rare but extremely lethal. Standard cytotoxic therapeutics provide little benefit. To date, newer targeted therapeutics have also not been highly successful.

New Blocking Antibodies against Novel AGR2-C4.4A Pathway Reduce Growth and Metastasis of Pancreatic Tumors and Increase Survival in Mice.

Anterior gradient 2 (AGR2) promotes cancer growth, metastasis, and resistance to therapy via unknown mechanisms. We investigated the effects of extracellular AGR2 signaling through the orphan glycosylphosphatidylinositol-linked receptor C4.4A in pancreatic ductal adenocarcinoma (PDAC).

Bisphosphonates inhibit stellate cell activity and enhance antitumor effects of nanoparticle albumin-bound paclitaxel in pancreatic ductal adenocarcinoma.

Pancreatic stellate cells (PSC) have been recognized as the principal cells responsible for the production of fibrosis in pancreatic ductal adenocarcinoma (PDAC). Recently, PSCs have been noted to share characteristics with cells of monocyte-macrophage lineage (MML cells). Thus, we tested whether PSCs could be targeted with the nitrogen-containing bisphosphonates (NBP; pamidronate or zoledronic acid), which are potent MML cell inhibitors.

Preliminary evaluation of 1'-[(18)F]fluoroethyl-β-D-lactose ([(18)F]FEL) for detection of pancreatic cancer in nude mouse orthotopic xenografts.

Introduction: Early detection of pancreatic cancer could save many thousands of lives. Non-invasive diagnostic imaging, including PET with [(18)F]FDG, has inadequate resolution for detection of small (2-3 mm) pancreatic tumours. We demonstrated the efficacy of PET imaging with an (18)F-labelled lactose derivative, [(18)F]FEDL, that targets HIP/PAP, a biomarker that is overexpressed in the peritumoural pancreas.

Hematogenous metastasis of ovarian cancer: rethinking mode of spread.

Ovarian cancer has a clear predilection for metastasis to the omentum, but the underlying mechanisms involved in ovarian cancer spread are not well understood. Here, we used a parabiosis model that demonstrates preferential hematogenous metastasis of ovarian cancer to the omentum. Our studies revealed that the ErbB3-neuregulin 1 (NRG1) axis is a dominant pathway responsible for hematogenous omental metastasis.

Suppression of pancreatic cancer by sulfated non-anticoagulant low molecular weight heparin.

Sulfated non-anticoagulant heparins (S-NACHs) might be preferred for potential clinical use in cancer patients without affecting hemostasis as compared to low molecular weight heparins (LMWHs). We investigated anti-tumor effects, anti-angiogenesis effects, and mechanisms of S-NACH in a mouse model of pancreatic cancer as compared to the LMWH tinzaparin. S-NACH or tinzaparin with or without gemcitabine were administered, and tumor luminescent signal intensity, tumor weight, and histopathology were assessed at the termination of the study.

Targeting pancreatic ductal adenocarcinoma acidic microenvironment.

Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer death in the USA, accounting for ~40,000 deaths annually. The dismal prognosis for PDAC is largely due to its late diagnosis. Currently, the most sensitive diagnosis of PDAC requires invasive procedures, such as endoscopic ultrasonography, which has inherent risks and accuracy that is highly operator dependent.

Designing and developing S100P inhibitor 5-methyl cromolyn for pancreatic cancer therapy.

We have previously shown that the antiallergic drug cromolyn blocks S100P interaction with its receptor receptor for advanced glycation end product (RAGE) and improves gemcitabine effectiveness in pancreatic ductal adenocarcinoma (PDAC). However, the concentration required to achieve its effectiveness was high (100 μmol/L). In this study, we designed and synthesized analogs of cromolyn and analyzed their effectiveness compared with the parent molecule.

Prostaglandin E2 regulates pancreatic stellate cell activity via the EP4 receptor.

Objectives: Pancreatic stellate cells are source of dense fibrotic stroma, a constant pathological feature of chronic pancreatitis and pancreatic adenocarcinoma. We observed correlation between levels of cyclooxygenase 2 (COX-2) and its product prostaglandin E2 (PGE2) and the extent of pancreatic fibrosis. The aims of this study were to delineate the effects of PGE2 on immortalized human pancreatic stellate cells (HPSCs) and to identify the receptor involved.

Adrenomedullin is up-regulated in patients with pancreatic cancer and causes insulin resistance in β cells and mice.

Background & Aims: New-onset diabetes in patients with pancreatic cancer is likely to be a paraneoplastic phenomenon caused by tumor-secreted products. We aimed to identify the diabetogenic secretory product(s) of pancreatic cancer.

Methods: Using microarray analysis, we identified adrenomedullin as a potential mediator of diabetes in patients with pancreatic cancer.

Inhibition of the hedgehog pathway targets the tumor-associated stroma in pancreatic cancer.

Purpose: The Hedgehog (Hh) pathway has emerged as an important pathway in multiple tumor types and is thought to be dependent on a paracrine signaling mechanism. The purpose of this study was to determine the role of pancreatic cancer-associated fibroblasts (human pancreatic stellate cells, HPSCs) in Hh signaling. In addition, we evaluated the efficacy of a novel Hh antagonist, AZD8542, on tumor progression with an emphasis on the role of the stroma compartment.

Met receptor tyrosine kinase signaling induces secretion of the angiogenic chemokine interleukin-8/CXCL8 in pancreatic cancer.

At diagnosis, the majority of pancreatic cancer patients present with advanced disease when curative resection is no longer feasible and current therapeutic treatments are largely ineffective. An improved understanding of molecular targets for effective intervention of pancreatic cancer is thus urgent. The Met receptor tyrosine kinase is one candidate implicated in pancreatic cancer.

S100P-derived RAGE antagonistic peptide reduces tumor growth and metastasis.

Purpose: The receptor for advanced glycation end products (RAGE) contributes to multiple pathologies, including diabetes, arthritis, neurodegenerative diseases, and cancer. Despite the obvious need, no RAGE inhibitors are in common clinical use. Therefore, we developed a novel small RAGE antagonist peptide (RAP) that blocks activation by multiple ligands.

Detection of pancreatic cancer tumours and precursor lesions by cathepsin E activity in mouse models.

Background And Aims: Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer death in the USA. Surgical resection is the only effective treatment; however, only 20% of patients are candidates for surgery. The ability to detect early PDAC would increase the availability of surgery and improve patient survival.

Trefoil factor 1 stimulates both pancreatic cancer and stellate cells and increases metastasis.

Objectives: Trefoil factor 1 (TFF1) is a stable secretory protein expressed widely in the gastrointestinal mucosa that is also expressed in pancreatic ductal adenocarcinoma (PDAC). In the current study, we documented the extent and timing of TFF1 expression and investigated the effects of TFF1 on PDAC cells and stellate cells, the primary cells of the PDAC stroma.

Methods: Trefoil factor 1 expression in pancreatic cancer tissues and cell lines was analyzed using microarray, quantitative reverse transcriptase-polymerase chain reaction, and immunohistochemistry.

The induction of S100p expression by the Prostaglandin Eâ‚‚ (PGEâ‚‚)/EP4 receptor signaling pathway in colon cancer cells.

Background: Prostaglandin Eâ‚‚ (PGEâ‚‚) levels are frequently elevated in colorectal carcinomas. PGEâ‚‚ is perceived via four transmembrane G protein coupled receptors (EP1-4), among which the EP4 receptor is most relevant. PGEâ‚‚/EP4-receptor interaction activates CREB via the ERK/MEK pathway.

S100P: a novel therapeutic target for cancer.

S100P expression is described in many different cancers, and its expression is associated with drug resistance, metastasis, and poor clinical outcome. S100P is member of the S100 family of small calcium-binding proteins that have been reported to have either intracellular or extracellular functions, or both. Extracellular S100P can bind with the receptor for advanced glycation end products (RAGE) and activate cellular signaling.

The ADMR receptor mediates the effects of adrenomedullin on pancreatic cancer cells and on cells of the tumor microenvironment.

Background: Adrenomedullin (AM) is highly expressed in pancreatic cancer and stimulates pancreatic cancer cells leading to increased tumor growth and metastasis. The current study examines the role of specific AM receptors on tumor and cells resembling the tumor microenvironment (human pancreatic stellate--HPSC, human umbilical vein-- HUVEC and mouse lung endothelial cells--MLEC).

Methods And Findings: AM receptors ADMR and CRLR were present in HPSC, HUVEC and MLECs while PDAC cells possessed only ADMR receptors as assessed by RT-PCR and western blotting.

Epithelial to mesenchymal transition contributes to drug resistance in pancreatic cancer.

A better understanding of drug resistance mechanisms is required to improve outcomes in patients with pancreatic cancer. Here, we characterized patterns of sensitivity and resistance to three conventional chemotherapeutic agents with divergent mechanisms of action [gemcitabine, 5-fluorouracil (5-FU), and cisplatin] in pancreatic cancer cells. Four (L3.