Src as the link between inflammation and cancer.

Although a causal link between chronic inflammation and cancer has been established, the exact molecular mechanism linking inflammation to cancer remains largely unknown. It was previously postulated that molecular switches responsible for cancer cell development, and for infiltration of inflammatory cells into cancer, were divided into a distinct set of intracellular proteins and signaling pathways. However, recent evidence suggests that both tumor cells and tumor-infiltrating immune cells utilize the same kinases, mostly that of Src family, to facilitate cancer development and progression. In the past few years several groups have found that Src activation both in cancer and inflammatory cells is mainly driven by pro-inflammatory cytokines within the tumor microenvironment. Here we evaluate the cross talks between Src kinase pathways in immune cells and cancer cells. We conclude that Src might serve as a critical mechanistic link between inflammation and cancer, mediating and propagating a cycle between immune and tissue cells that can ultimately lead to the development and progression of cancer

Environmental and Genetic Stressors and the Unfolded Protein Response in Exocrine Pancreatic Function – A Hypothesis

The exocrine pancreas has the greatest protein synthetic capacity of any mammalian organ and is challenged with the synthesis, processing and transporting a large load of digestive enzymes. Based on recent findings we present a hypothesis proposing that mutations in the digestive enzymes and environmental risks impacting the pancreas (i.e., alcohol abuse, smoking, metabolic disorders, and drugs) cause endoplasmic reticulum (ER) stress. We review recent findings showing that in normal pancreas the ER stress resulting from alcohol abuse leads to an adaptive unfolded protein response (UPR) allowing for maintenance of protein synthesis, processing, and transport. However, when key pathways necessary for the adaptive UPR are altered, the exocrine cell of the pancreas is unable to maintain these processes and cellular pathology results. These findings may explain why some individuals with alcohol abuse disorders develop organ injury and disease while most do not. Further, the findings allow us to hypothesize that the UPR in the exocrine pancreas adapts the protein synthetic machinery of the ER stress resulting from mutational and environmental stressors. When the ability of the UPR to adapt to the stressors is exceeded, pathologic pathways and disease develop

Pancreatic adaptive responses in alcohol abuse: Role of the unfolded protein response.

The majority of those who drink excessive amounts of alcohol do not develop pancreatic disease. One overarching hypothesis is that alcohol abuse requires additional risk factors, either environmental or genetic, for disease to occur. However, another reason be a result of alcohol-induced activation of adaptive systems that protect the pancreas from the toxic effects of alcohol. We show that mechanisms within the unfolded protein response (UPR) of the endoplasmic reticulum (ER) that can lead to protection of the pancreas from pancreatic diseases with alcohol abuse. The remarkable ability of the pancreas to adapt its machinery to alcohol abuse using UPR systems and continue functioning is the likely reason that pancreatitis from alcohol abuse does not occur in the majority of heavy drinkers. These findings indicate that methods to enhance the protective responses of the UPR can provide opportunities for prevention and treatment of pancreatic diseases

What are the macrophages and stellate cells doing in pancreatic adenocarcinoma?

Pancreatic ductal adenocarcinoma is a devastating disease characterized by a dense desmoplastic stroma. Chemo- and radio-therapeutic strategies based on targeting cancer cells have failed in improving the outcome of this cancer suggesting important roles for stroma in therapy resistance. Cells in the tumor stroma have been shown to regulate proliferation, resistance to apoptosis and treatments, epithelial to mesenchymal transition (EMT) and stemness of cancer cells. Stellate cells in their activated state have been thought over the past decade to only have tumor promoting roles. However, recent findings suggest that stellate cells may have protective roles as well. The present review highlights the latest findings on the role of two major components of tumor stroma, pancreatic stellate cells and macrophages, in promoting or inhibiting pancreatic cancer, focused on their effects on EMT and cancer stemness

Role of YAP and TAZ in pancreatic ductal adenocarcinoma and in stellate cells associated with cancer and chronic pancreatitis.

Pancreatic ductal adenocarcinoma (PDAC) is characterized by a fibrotic and inflammatory microenvironment that is formed primarily by activated, myofibroblast-like, stellate cells. Although the stellate cells are thought to contribute to tumorigenesis, metastasis and drug resistance of PDAC, the signaling events involved in activation of the stellate cells are not well defined. Functioning as transcription co-factors, Yes-associated protein (YAP) and its homolog transcriptional co-activator with PDZ-binding motif (TAZ) modulate the expression of genes involved in various aspects of cellular functions, such as proliferation and mobility. Using human tissues we show that YAP and TAZ expression is restricted to the centroacinar and ductal cells of normal pancreas, but is elevated in cancer cells. In particular, YAP and TAZ are expressed at high levels in the activated stellate cells of both chronic pancreatitis and PDAC patients as well as in the islets of Langerhans in chronic pancreatitis tissues. Of note, YAP is up regulated in both acinar and ductal cells following induction of acute and chronic pancreatitis in mice. These findings indicate that YAP and TAZ may play a critical role in modulating pancreatic tissue regeneration, neoplastic transformation, and stellate cell functions in both PDAC and pancreatitis

Protective effects of urocortin 2 against caerulein-induced acute pancreatitis.

Because little is known about the role of corticotropin-releasing factor (CRF) agonists in regulating responses in pancreatitis, we evaluated the effects of urocortin 2 (UCN2) and stressin1 in caerulein-induced acute pancreatitis (AP) model in rats. Male rats were pretreated with UCN2 or stressin1 for 30 min followed by induction of AP with supraphysiologic doses of caerulein. Serum amylase and lipase activity, pancreatic tissue necrosis, immune cell infiltrate, nuclear factor (NF)-κB activity, trypsin levels, and intracellular Ca2+ ([Ca2+]i) were ascertained. UCN2, but not stressin1 attenuated the severity of AP in rats. UCN2, but not stressin1, reduced serum amylase and lipase activity, cell necrosis and inflammatory cell infiltration in AP. NF-κB activity in pancreatic nuclear extracts increased in AP and UCN2 treatment reduced caerulein-induced increases in NF-κB activity by 42%. UCN2 treatment prevented caerulein-induced degradation of IκB-α in the cytosolic fraction as well as increased levels of p65 subunit of NF-κB in the cytosolic fraction. Pancreatic UCN2 levels decreased in AP compared with saline. UCN2 evoked [Ca2+]i responses in primary acinar cells and abolished caerulein-evoked [Ca2+]i responses at 0.1nM, and decreased by ~50% at 1.0nM caerulein. UCN2 stimulation resulted in redistribution of a portion of F-actin from the apical to the basolateral pole. UCN2 prevented the massive redistribution of F-actin observed with supraphysiologic doses of caerulein. UCN2, but not stressin1 attenuated severity of an experimental pancreatitis model. The protective effects of UCN2, including anti-inflammatory and anti-necrotic effects involve activation of the CRF2 receptor, [Ca2+]i signaling, and inhibition of NF-κB activity