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

The Potential for Circulating Tumor Cells in Pancreatic Cancer Management.

Pancreatic cancer is one the most lethal malignancies. Only a small proportion of patients with this disease benefit from surgery. Chemotherapy provides only a transient benefit. Though much effort has gone into finding new ways for early diagnosis and treatment, average patient survival has only been improved in the order of months. Circulating tumor cells (CTCs) are shed from primary tumors, including pre-malignant phases. These cells possess information about the genomic characteristics of their tumor source in situ, and their detection and characterization holds potential in early cancer diagnosis, prognosis, and treatment. Liquid Biopsies present an alternative to tumor biopsy that are hard to sample. Below we summarize current methods of CTC detection, the current literature on CTCs in pancreatic cancer, and future perspectives

Molecular basis for the interplay of apoptosis and proliferation mediated by Bcl-xL:Bim interactions in pancreatic cancer cells

A major mechanism through which cancer cells avoid apoptosis is by promoting the association of anti-apoptotic members of the pro-survival Bcl-2 protein family (like Bcl-2 and Bcl-xL) with BH3 domain-only proteins (like Bim and Bid). Apoptosis and cell proliferation have been shown to be linked for many cancers but the molecular basis for this link is far from understood. We have identified the Bcl-xL:Bim protein–protein interface as a direct regulator of proliferation and apoptosis in pancreatic cancer cells. We were able to predict and subsequently verify experimentally the effect of various Bcl-xL single-point mutants (at the position A142) on binding to Bim by structural analysis and computational modeling of the inter-residue interactions at the Bcl-xL:Bim protein–protein interface. The mutants A142N, A142Q, and A142Y decreased binding of Bim to Bcl-xL and A142S increased this binding. The Bcl-xL mutants, with decreased affinity for Bim, caused an increase in apoptosis and a corresponding decrease in cell proliferation. However, we could prevent these effects by introducing a small interfering RNA (siRNA) targeted at Bim. These results show a novel role played by the Bcl-xL:Bim interaction in regulating proliferation of pancreatic cancer cells at the expense of apoptosis. This study presents a physiologically relevant model of the Bcl-xL:Bim interface that can be used for rational therapeutic design for the inhibition of proliferation and cancer cell resistance to apoptosis

Determination of Rottlerin, a Natural Protein Kinases C Inhibitor, in Pancreatic Cancer Cells and Mouse Xenografts by RP-HPLC Method.

Rottlerin is a natural polyphenolic ketone isolated from the pericarps of Mallotus phillippinensis. In previous studies we showed that parenteral administration of rottlerin reduced tumor growth in murine xenograft models of pancreatic cancer. The aim of this study was to develop a simple and validated method for the quantitative determination of rottlerin in plasma and tumor tissues of mice fed a rottlerin diet. A xenograft model of pancreatic cancer was prepared by injection of 2×106 HPAF-II cells subcutaneously into nude mice. One week before tumor implantation, mice were randomly allocated to standard diet (AIN76A) and standard diet supplement with 0.012% rottlerin (n=6 per group). Mice were sacrificed after 6 weeks on diets. Rottlerin was extracted from the plasma and tissues using protein precipitation-extraction and analyzed by reverse-phase HPLC-DAD method. The same HPLC method was also applied to determine rottlerin levels in conditioned culture media and in cell lysates from HPAF-II cells exposed to 25 µM concentration of rottlerin. A substantial amount of rottlerin was detected in tumor (2.11 ± 0.25 nmol/g tissue) and plasma (2.88 ± 0.41 µM) in mice fed rottlerin diet. In addition, significant levels of rottlerin (57.4 ± 5.4 nmol/mg protein) were detected in cell lysates from rottlerin-treated HPAF-II cells. These data indicate that rottlerin is efficiently absorbed in cells and tissues both in vivo and in vitro and suggest a strong potential for rottlerin as a preventive or adjuvant supplement for pancreatic cancer

Tobacco and alcohol as risk factors for pancreatic cancer

Pancreatic cancer is projected to become the leading cause of cancer deaths by 2050. The risk for pancreatic cancer may be reduced by up to 27% by modifying lifestyle risk factors, most notably tobacco smoking. Based on analysis of more than 2 million unselected individuals from general population, this article quantified the risk of pancreatic cancer in relation to lifelong tobacco smoking and alcohol consumption status, both alone and in combination. It also provided a state-of-the-art review of animal studies on the effect of tobacco smoke and alcohol on genetically engineered mouse models of pancreatic precursor lesions, as well as the role of immune microenvironment in pancreatic carcinogenesis activated by tobacco and alcohol

The Potential for Circulating Tumor Cells in Pancreatic Cancer Management

Pancreatic cancer is one the most lethal malignancies. Only a small proportion of patients with this disease benefit from surgery. Chemotherapy provides only a transient benefit. Though much effort has gone into finding new ways for early diagnosis and treatment, average patient survival has only been improved in the order of months. Circulating tumor cells (CTCs) are shed from primary tumors, including pre-malignant phases. These cells possess information about the genomic characteristics of their tumor source in situ, and their detection and characterization holds potential in early cancer diagnosis, prognosis, and treatment. Liquid Biopsies present an alternative to tumor biopsy that are hard to sample. Below we summarize current methods of CTC detection, the current literature on CTCs in pancreatic cancer, and future perspectives

MSP-RON Signaling Is Activated in the Transition From Pancreatic Intraepithelial Neoplasia (PanIN) to Pancreatic Ductal Adenocarcinoma (PDAC)

Pancreatic ductal adenocarcinoma (PDAC) is among the deadliest epithelial malignancies and remains difficult to treat. Pancreatic intraepithelial neoplasias (PanINs) represent the majority of the pre-cancer lesions in the pancreas. The PDAC microenvironment consists of activated pancreatic stellate cells (PSCs) and immune cells, which are thought to contribute to neoplastic transformation. However, the signaling events involved in driving the transition from the neoplastic precursor to the more advanced and aggressive forms in the pancreas are not well understood. Recepteur d’Origine Nantais (RON) is a c-MET family receptor tyrosine kinase that is implicated in playing a role in cell proliferation, migration and other aspects of tumorigenesis. Macrophage stimulating protein (MSP) is the ligand for RON and becomes activated upon proteolytic cleavage by matriptase (also known as ST14), a type II transmembrane serine protease. In the current study, by immunohistochemistry (IHC) analysis of human pancreatic tissues, we found that the expression levels MSP and matriptase are drastically increased during the transition from the preneoplastic PanIN stages to the more advanced and aggressive PDAC. Moreover, RON is highly expressed in both PDAC and in cancer-associated stellate cells. In contrast, MSP, RON, and matriptase are expressed at low levels, if any, in normal pancreas. Our study underscores an emerging role of MSP-RON autocrine and paracrine signaling events in driving malignant progression in the pancreas

Rottlerin stimulates apoptosis in pancreatic cancer cells through interactions with proteins of the Bcl-2 family

Rottlerin is a polyphenolic compound derived from Mallotus philipinensis. In the present study, we show that rottlerin decreased tumor size and stimulated apoptosis in an orthotopic model of pancreatic cancer with no effect on normal tissues in vivo. Rottlerin also induced apoptosis in pancreatic cancer (PaCa) cell lines by interacting with mitochondria and stimulating cytochrome c release. Immunoprecipitation results indicated that rottlerin disrupts complexes of prosurvival Bcl-xL with Bim and Puma. Furthermore, siRNA knockdown showed that Bim and Puma are necessary for rottlerin to stimulate apoptosis. We also showed that rottlerin and Bcl-2 and Bcl-xL inhibitor BH3I-2' stimulate apoptosis through a common mechanism. They both directly interact with mitochondria, causing increased cytochrome c release and mitochondrial depolarization, and both decrease sequestration of BH3-only proteins by Bcl-xL. However, the effects of rottlerin and BH3I-2' on the complex formation between Bcl-xL and BH3-only proteins are different. BH3I-2' disrupts complexes of Bcl-xL with Bad but not with Bim or Puma, whereas rottlerin had no effect on the Bcl-xL interaction with Bad. Also BH3I-2', but not rottlerin, required Bad to stimulate apoptosis. In conclusion, our results demonstrate that rottlerin has a potent proapoptotic and antitumor activity in pancreatic cancer, which is mediated by disrupting the interaction between prosurvival Bcl-2 proteins and proapoptotic BH3-only proteins. Thus rottlerin represents a promising novel agent for pancreatic cancer treatment