- Email: [email protected]
Modelling the Tumour Microenvironment in Pancreatic Ductal Adenocarcinoma
S4
Abstracts / Pancreatology 17 (2017) S1eS142
Abstract ID: 1735. Modelling the Tumour Microenvironment in Pancreatic Ductal Adenocarcinoma Sarah Brumskill 1, Lawrence Barrera 2, Fiona Campbell 3, Chris Halloran 2, John Neoptolemos 2, Robert Sutton 4, William Greenhalf 2, Peter Calcraft 5, Caroline Phillips 5, Eithne Costello 2 1 Liverpool NWCR Centre, Molecular and Clinical Cancer Medicine, University of Liverpool/ Redx Pharma, United Kingdom 2 Liverpool NWCR Centre, Molecular and Clinical Cancer Medicine, University of Liverpool, United Kingdom 3 Department of Pathology, Royal Liverpool University Hospital, United Kingdom 4 NIHR Pancreas Biomedical Research Unit, Royal Liverpool University Hospital, United Kingdom 5 Redx Pharma, United Kingdom
Introduction: Pancreatic ductal adenocarcinoma is characterised by a tumour supportive microenvironment including a dense fibrotic stroma. The tumour microenvironment has been implicated in chemo resistance which has led to a need for drug screening techniques which include elements of the tumour microenvironment. Aims: To identify the impact of cancer associated fibroblasts (CAFs) in models for testing current standard of care chemotherapy such as gemcitabine. Materials & methods: Tissues were obtained from patients undergoing surgery at Royal Liverpool University Hospital. 2D co-culture models of CAFs and pancreatic cancer cells were created and the efficacy of gemcitabine was tested using immunofluorescence, pIC50 was compared to cancer cells alone. 3D proliferation was determined using 3D Cell Titre Glo (Promega) and the expression of various markers within the spheroid was determined using immunohistochemistry. Results: In 2D, co-culture of CAFs with PANC1 cells reduced sensitivity to gemcitabine, dependant upon the number of CAFs when compared to the monoculture of the PANC1 cells. Furthermore, when SUIT2 and BXPC3 cell lines were cultured in a 3D model, the presence of CAFs caused a large rightward shift in the gemcitabine IC50 of >10,000-fold. Conclusion: The presence of CAFs within 2D and 3D co-culture models has an impact on pancreatic cancer cell resistance to gemcitabine and thus better reflects the clinical response. The difference in gemcitabine sensitivity between mono- and co-culture together with the more physiologically relevant morphology in the co-cultured spheroids, highlights a need for more sophisticated in vitro drug screening techniques to more accurately predict a compound's in vivo and subsequently clinical efficacy.
Abstract ID: 1736. The influence of erythropoetin on apoptosis and fibrosis in chronic cerulein induced pancreatitis in rats.
Materials & methods: The experiments were performed on 48 Male Wistar rats. The animals were divided into six equal groups. ( I e control, II e cerulein e induced CP, III - erythropoetin s.c. - 1 ml Epo/day, IV erythropoetin s.c. - 0,5 ml Epo/day, V e CP + 1 ml Epo, VI e CP + 0,5 ml Epo). Results: In group II the intensification of fibrosis around the pancreatic ducts was observed. A slight reduction of interstitial edema and less severe fibrosis were reported in the groups V and VI. In group II, a strong expression of a-actin was noticed in damaged acinar cells, while in groups V and VI it appeared focally. In group II there was a very weak expression of Bcl-2 in acinar cells, while in the other groups, there was no expression noted. In group II cytoplasmic expression of caspase-3 was observed in the acinar cells, while in groups V and VI it was reduced. Conclusion: Erythropoietin seems to have the effect of reducing fibrosis and apoptosis in an experimental model of CP.
Abstract ID: 1739. Operative treatment strategy for pancreatic cancer is highly region depended: A Finnish register study covering the entire nation. € 2, Samuli Kiskola 2, Pirkka Ojala 2, Aino Pirttila € 2, €lsa Reea Ahola 1, Heini Ho 1 1 Juhani Sand , Johanna Laukkarinen 1 2
Tampere University Hospital, Gastrointestinal Surgery, Finland Tampere University, Finland
Introduction: Surgical resection is the only possibility for cure in pancreatic cancer (PC). Aims: Surgical resection is the only possibility for cure in pancreatic cancer (PC). Patients & methods: All patients diagnosed with PC in 2003 and 2008 were identified from the Finnish Cancer register. The data regarding tumor, treatment and demographics were recorded from the patient archives. Patients were included in the health care region where the diagnosis was made. The health care regions were classified based on the experience in pancreas surgery into three groups (HLE¼high level of experience; n¼2, MLE¼ medium level of experience; n¼6 and LLE¼ low level of experience; n¼13). Results: 1546 patients were included (median age 72 years (range 3497), 45% men). Demographics and the ratio of stage IV disease (53%) were similar between the groups. Despite of this the proportion of radical resections was greater in HLE regions (18% vs 8-11%; p<0.01). The difference was even clearer among patients with stage I-III disease (49% vs 29-22%; p<0.05) compared to the non-HLE regions. Logistic regression analysis considering age, ASA, stage and the level of experience showed that more radical resections were performed in the HLE regions Conclusion: Accessibility to PC curative treatment is more likely if a patient is living in a health care region including a hospital with high level of experience in pancreatic surgery. This highlights the importance of centralization and education regarding the whole treatment path.
Agnieszka Madro 1, Weronika Kazmierak 1, Agnieszka Korolczuk 2, Grazyna Czechowska 1, Jacek Kurzepa 3, Anna Boguszewska-Czubara 3 1 Department of Gastroenterology with Endoscopic Unit, Medical University of Lublin, Poland 2 Department of Clinical Pathomorpfology, Medical University of Lublin, Poland 3 Department of Biochemistry and Molecular Biology, Medical University of Lublin, Poland
Introduction: Chronic pancreatitis (CP) is an inflammatory process, characterized by irreversible morphological changes. The identification of pancreatic stellate cells resulted in the development of research on the pathogenesis of CP. Erythropoietin (EPO) regulates the interaction between apoptosis and inflammation of the brain, kidney and heart muscle. Epo receptors were also found in the pancreas, in particular the islet cells. Aims: Our objective was to evaluate the influence of erythropoetin on fibrosis and apoptosis in experimental chronic pancreatitis.
Abstract ID: 1741. Lower mortality rates after pancreas surgery are achieved only when the operation is performed in a high-volume center. A nationwide study in Finland 2012-2014. Reea Ahola, Juhani Sand, Johanna Laukkarinen Tampere University Hospital, Gastrointestinal Surgery, Finland Introduction: Centralisation of pancreas surgery has been slowly proceeding in sparsely populated Finland. Aims: This study aimed to analyse the effect of hospital volume on pancreas surgery associated mortality and complications in Finland. Patients & methods: The Finnish National Register (HILMO) was searched for pancreatoduodenectomies (PD) and total pancreatectomies
Abstracts / Pancreatology 17 (2017) S1eS142
Abstract ID: 1735. Modelling the Tumour Microenvironment in Pancreatic Ductal Adenocarcinoma Sarah Brumskill 1, Lawrence Barrera 2, Fiona Campbell 3, Chris Halloran 2, John Neoptolemos 2, Robert Sutton 4, William Greenhalf 2, Peter Calcraft 5, Caroline Phillips 5, Eithne Costello 2 1 Liverpool NWCR Centre, Molecular and Clinical Cancer Medicine, University of Liverpool/ Redx Pharma, United Kingdom 2 Liverpool NWCR Centre, Molecular and Clinical Cancer Medicine, University of Liverpool, United Kingdom 3 Department of Pathology, Royal Liverpool University Hospital, United Kingdom 4 NIHR Pancreas Biomedical Research Unit, Royal Liverpool University Hospital, United Kingdom 5 Redx Pharma, United Kingdom
Introduction: Pancreatic ductal adenocarcinoma is characterised by a tumour supportive microenvironment including a dense fibrotic stroma. The tumour microenvironment has been implicated in chemo resistance which has led to a need for drug screening techniques which include elements of the tumour microenvironment. Aims: To identify the impact of cancer associated fibroblasts (CAFs) in models for testing current standard of care chemotherapy such as gemcitabine. Materials & methods: Tissues were obtained from patients undergoing surgery at Royal Liverpool University Hospital. 2D co-culture models of CAFs and pancreatic cancer cells were created and the efficacy of gemcitabine was tested using immunofluorescence, pIC50 was compared to cancer cells alone. 3D proliferation was determined using 3D Cell Titre Glo (Promega) and the expression of various markers within the spheroid was determined using immunohistochemistry. Results: In 2D, co-culture of CAFs with PANC1 cells reduced sensitivity to gemcitabine, dependant upon the number of CAFs when compared to the monoculture of the PANC1 cells. Furthermore, when SUIT2 and BXPC3 cell lines were cultured in a 3D model, the presence of CAFs caused a large rightward shift in the gemcitabine IC50 of >10,000-fold. Conclusion: The presence of CAFs within 2D and 3D co-culture models has an impact on pancreatic cancer cell resistance to gemcitabine and thus better reflects the clinical response. The difference in gemcitabine sensitivity between mono- and co-culture together with the more physiologically relevant morphology in the co-cultured spheroids, highlights a need for more sophisticated in vitro drug screening techniques to more accurately predict a compound's in vivo and subsequently clinical efficacy.
Abstract ID: 1736. The influence of erythropoetin on apoptosis and fibrosis in chronic cerulein induced pancreatitis in rats.
Materials & methods: The experiments were performed on 48 Male Wistar rats. The animals were divided into six equal groups. ( I e control, II e cerulein e induced CP, III - erythropoetin s.c. - 1 ml Epo/day, IV erythropoetin s.c. - 0,5 ml Epo/day, V e CP + 1 ml Epo, VI e CP + 0,5 ml Epo). Results: In group II the intensification of fibrosis around the pancreatic ducts was observed. A slight reduction of interstitial edema and less severe fibrosis were reported in the groups V and VI. In group II, a strong expression of a-actin was noticed in damaged acinar cells, while in groups V and VI it appeared focally. In group II there was a very weak expression of Bcl-2 in acinar cells, while in the other groups, there was no expression noted. In group II cytoplasmic expression of caspase-3 was observed in the acinar cells, while in groups V and VI it was reduced. Conclusion: Erythropoietin seems to have the effect of reducing fibrosis and apoptosis in an experimental model of CP.
Abstract ID: 1739. Operative treatment strategy for pancreatic cancer is highly region depended: A Finnish register study covering the entire nation. € 2, Samuli Kiskola 2, Pirkka Ojala 2, Aino Pirttila € 2, €lsa Reea Ahola 1, Heini Ho 1 1 Juhani Sand , Johanna Laukkarinen 1 2
Tampere University Hospital, Gastrointestinal Surgery, Finland Tampere University, Finland
Introduction: Surgical resection is the only possibility for cure in pancreatic cancer (PC). Aims: Surgical resection is the only possibility for cure in pancreatic cancer (PC). Patients & methods: All patients diagnosed with PC in 2003 and 2008 were identified from the Finnish Cancer register. The data regarding tumor, treatment and demographics were recorded from the patient archives. Patients were included in the health care region where the diagnosis was made. The health care regions were classified based on the experience in pancreas surgery into three groups (HLE¼high level of experience; n¼2, MLE¼ medium level of experience; n¼6 and LLE¼ low level of experience; n¼13). Results: 1546 patients were included (median age 72 years (range 3497), 45% men). Demographics and the ratio of stage IV disease (53%) were similar between the groups. Despite of this the proportion of radical resections was greater in HLE regions (18% vs 8-11%; p<0.01). The difference was even clearer among patients with stage I-III disease (49% vs 29-22%; p<0.05) compared to the non-HLE regions. Logistic regression analysis considering age, ASA, stage and the level of experience showed that more radical resections were performed in the HLE regions Conclusion: Accessibility to PC curative treatment is more likely if a patient is living in a health care region including a hospital with high level of experience in pancreatic surgery. This highlights the importance of centralization and education regarding the whole treatment path.
Agnieszka Madro 1, Weronika Kazmierak 1, Agnieszka Korolczuk 2, Grazyna Czechowska 1, Jacek Kurzepa 3, Anna Boguszewska-Czubara 3 1 Department of Gastroenterology with Endoscopic Unit, Medical University of Lublin, Poland 2 Department of Clinical Pathomorpfology, Medical University of Lublin, Poland 3 Department of Biochemistry and Molecular Biology, Medical University of Lublin, Poland
Introduction: Chronic pancreatitis (CP) is an inflammatory process, characterized by irreversible morphological changes. The identification of pancreatic stellate cells resulted in the development of research on the pathogenesis of CP. Erythropoietin (EPO) regulates the interaction between apoptosis and inflammation of the brain, kidney and heart muscle. Epo receptors were also found in the pancreas, in particular the islet cells. Aims: Our objective was to evaluate the influence of erythropoetin on fibrosis and apoptosis in experimental chronic pancreatitis.
Abstract ID: 1741. Lower mortality rates after pancreas surgery are achieved only when the operation is performed in a high-volume center. A nationwide study in Finland 2012-2014. Reea Ahola, Juhani Sand, Johanna Laukkarinen Tampere University Hospital, Gastrointestinal Surgery, Finland Introduction: Centralisation of pancreas surgery has been slowly proceeding in sparsely populated Finland. Aims: This study aimed to analyse the effect of hospital volume on pancreas surgery associated mortality and complications in Finland. Patients & methods: The Finnish National Register (HILMO) was searched for pancreatoduodenectomies (PD) and total pancreatectomies