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PDGFA Pathway Contributes to Acidic Microenvironment-Promoted Angiogenesis of Pancreatic Cancer
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Scientific Poster Presentations: 2016 Clinical Congress
ODP had comparable outcomes to LDP in regards to median time to chemotherapy (50 vs 48 days, p¼0.96); median nodes examined (12 vs 12, p¼0.61); 30-day mortality (1.6% vs 1.1%, p¼0.43); 90-day mortality (3.5% vs 2.4%, p¼0.28); 30-day readmission rate (8.6% vs 9.4%, p¼0.67). However, the median length of stay was shorter in the LDP group (6 vs 7 days, p¼0.0001). CONCLUSIONS: In the absence of randomized trials, this is the largest comparative study demonstrating LDP as an acceptable alternative to ODP, associated with a lower margin positive rate, shorter length of stay, and without detriment in long-term survival. Aberrant miR-186/PDGFA Pathway Contributes to Acidic MicroenvironmentPromoted Angiogenesis of Pancreatic Cancer Gang Zhao, PhD, Cheng Xiang, Shuai Zhu, Shijiang Deng, Chi He, Chunyou Wang, MD Pancreatic Disease Institute, Union Hospital, HUST, Wuhan, China INTRODUCTION: Acidic microenvironment is a hallmark of malignant tumors including pancreatic cancer, but its role on angiogenesis is far from elucidated. The present study aims to investigate the potential role and mechanism of acidic microenvironment on the angiogenesis of pancreatic cancer. METHODS: The acidic conditional medium of pancreatic cancer cell lines PANC-1 and BxPC-3 was collected for the culture of human umbilical vein endothelial cells (HUVEC). The angiogenesis of HUVEC were tested by tube formation and sprouting assay. Furthermore, the microRNA array was applied to analyze the alteration of microRNAs in pancreatic cancer cells under acidic medium. The regulation of miR-186 on its potential target platelet derived growth factor A (PDGFA) was revealed by dual-luciferase assay. Expression of miR-186 and PDGFA was manipulated for biological function investigation. The correlation of miR-186 with PDGFA, micro vascular density and clinical characteristic was analyzed in pancreatic cancer specimen. RESULTS: The acidic conditional medium significantly stimulated angiogenetic ability of HUVEC compared to normal conditional medium. MicroRNA array data showed that miRNA186 was significantly decreased in the acidity treated pancreatic cancer cell, accompanied with PDGFA upregulation. The dual luciferase assay revealed that PDGFA was the direct target of miR-186. Overexpression of miR-186 obviously decreased PDGFA expression and angiogenesis of HUVEC which was promoted by acidic conditional medium. In vivo, overexpression of miR-186 or knockdown of PDGFA obviously inhibited tumourigenicity and angiogenesis of xenograft tumor model. In clinical analysis, miR-186 expression was downregulated in pancreatic cancer and negatively correlated with PDGFA expression and prognosis.
J Am Coll Surg
CONCLUSIONS: Acidic microenvironment is involved in the angiogenesis of pancreatic cancer which is partially attributed to aberrant miR-186/PDGFA pathway. Activated Stroma Differences at Metastatic Sites in Pancreatic Cancer Robert Torphy, MD, Naim Rashid, PhD, Richard Moffitt, PhD, Michael A Hollingsworth, PhD, Jen Jen Yeh, MD, FACS University of Colorado, Denver, CO, University of North Carolina, Chapel Hill, NC, University of Nebraska, Omaha, NE INTRODUCTION: Gene expression analysis of stroma in primary pancreatic ductal adenocarcinoma (PDAC) identified ‘normal’ and ‘activated’ stroma subtypes (SS). The presence of ‘activated’ SS imparted a worse prognosis. The role of activated stroma in metastasis remains unclear. Our aim was to investigate SS in primary and metastatic sites and its association with tumor stroma density (TSD). METHODS: Tissue microarrays were constructed from 6 patients with metastatic PDAC using 98 triplicate cores from primary and metastatic sites. Dual immunofluorescence (IF) was performed with collagen I, a-SMA (alpha-smooth muscle actin) and FAP (fibroblast activation protein). SS predictions were made based on gene expression data. TSD was calculated from digitally annotating H&E stained cores. RESULTS: TSD was significantly different between primary tumors (0.60), peritoneal (0.74), solid organ (0.19), and lymph node (0.22) metastasis (p¼0.0008). Strong stroma expression of a-SMA, but not FAP, differed between primary tumors (60%), peritoneal (65%), solid organ (42%), and lymph node metastasis (63%) (p¼0.012) and a-SMA expression had a positive correlation with TSD (rs¼0.39, p¼0.01). ‘Activated’ SS was significantly enriched in primary compared to metastatic sites (odds ratio 6.67, p¼0.04). CONCLUSIONS: The differences in SS, TSD, and a-SMA staining between primary and metastatic tumors suggests that tumor stroma is both histologically and molecularly different depending on tumor location or route of spread. Traditional immunohistochemical markers of activated pancreatic stellate cells (a-SMA and FAP) do not adequately explain these differences. The development and use of stroma targeting therapies may need to account for the variability of tumor stroma in primary vs metastatic disease. AMPKa1 Promotes Low Glucose Microenvironment-Induced EpithelialMesenchymal Transition of Pancreatic Cancer Cells by Targeting ZEB1 Gang Zhao, PhD, Shichang Deng, PhD, Xiang Li, PhD, Shufeng Zhao, Shuai Zhu, Chi He, Shijiang Deng, Yang Liu, Chunyou Wang, MD Pancreatic Disease Institute, Union Hospital, HUST, Wuhan, China
Scientific Poster Presentations: 2016 Clinical Congress
ODP had comparable outcomes to LDP in regards to median time to chemotherapy (50 vs 48 days, p¼0.96); median nodes examined (12 vs 12, p¼0.61); 30-day mortality (1.6% vs 1.1%, p¼0.43); 90-day mortality (3.5% vs 2.4%, p¼0.28); 30-day readmission rate (8.6% vs 9.4%, p¼0.67). However, the median length of stay was shorter in the LDP group (6 vs 7 days, p¼0.0001). CONCLUSIONS: In the absence of randomized trials, this is the largest comparative study demonstrating LDP as an acceptable alternative to ODP, associated with a lower margin positive rate, shorter length of stay, and without detriment in long-term survival. Aberrant miR-186/PDGFA Pathway Contributes to Acidic MicroenvironmentPromoted Angiogenesis of Pancreatic Cancer Gang Zhao, PhD, Cheng Xiang, Shuai Zhu, Shijiang Deng, Chi He, Chunyou Wang, MD Pancreatic Disease Institute, Union Hospital, HUST, Wuhan, China INTRODUCTION: Acidic microenvironment is a hallmark of malignant tumors including pancreatic cancer, but its role on angiogenesis is far from elucidated. The present study aims to investigate the potential role and mechanism of acidic microenvironment on the angiogenesis of pancreatic cancer. METHODS: The acidic conditional medium of pancreatic cancer cell lines PANC-1 and BxPC-3 was collected for the culture of human umbilical vein endothelial cells (HUVEC). The angiogenesis of HUVEC were tested by tube formation and sprouting assay. Furthermore, the microRNA array was applied to analyze the alteration of microRNAs in pancreatic cancer cells under acidic medium. The regulation of miR-186 on its potential target platelet derived growth factor A (PDGFA) was revealed by dual-luciferase assay. Expression of miR-186 and PDGFA was manipulated for biological function investigation. The correlation of miR-186 with PDGFA, micro vascular density and clinical characteristic was analyzed in pancreatic cancer specimen. RESULTS: The acidic conditional medium significantly stimulated angiogenetic ability of HUVEC compared to normal conditional medium. MicroRNA array data showed that miRNA186 was significantly decreased in the acidity treated pancreatic cancer cell, accompanied with PDGFA upregulation. The dual luciferase assay revealed that PDGFA was the direct target of miR-186. Overexpression of miR-186 obviously decreased PDGFA expression and angiogenesis of HUVEC which was promoted by acidic conditional medium. In vivo, overexpression of miR-186 or knockdown of PDGFA obviously inhibited tumourigenicity and angiogenesis of xenograft tumor model. In clinical analysis, miR-186 expression was downregulated in pancreatic cancer and negatively correlated with PDGFA expression and prognosis.
J Am Coll Surg
CONCLUSIONS: Acidic microenvironment is involved in the angiogenesis of pancreatic cancer which is partially attributed to aberrant miR-186/PDGFA pathway. Activated Stroma Differences at Metastatic Sites in Pancreatic Cancer Robert Torphy, MD, Naim Rashid, PhD, Richard Moffitt, PhD, Michael A Hollingsworth, PhD, Jen Jen Yeh, MD, FACS University of Colorado, Denver, CO, University of North Carolina, Chapel Hill, NC, University of Nebraska, Omaha, NE INTRODUCTION: Gene expression analysis of stroma in primary pancreatic ductal adenocarcinoma (PDAC) identified ‘normal’ and ‘activated’ stroma subtypes (SS). The presence of ‘activated’ SS imparted a worse prognosis. The role of activated stroma in metastasis remains unclear. Our aim was to investigate SS in primary and metastatic sites and its association with tumor stroma density (TSD). METHODS: Tissue microarrays were constructed from 6 patients with metastatic PDAC using 98 triplicate cores from primary and metastatic sites. Dual immunofluorescence (IF) was performed with collagen I, a-SMA (alpha-smooth muscle actin) and FAP (fibroblast activation protein). SS predictions were made based on gene expression data. TSD was calculated from digitally annotating H&E stained cores. RESULTS: TSD was significantly different between primary tumors (0.60), peritoneal (0.74), solid organ (0.19), and lymph node (0.22) metastasis (p¼0.0008). Strong stroma expression of a-SMA, but not FAP, differed between primary tumors (60%), peritoneal (65%), solid organ (42%), and lymph node metastasis (63%) (p¼0.012) and a-SMA expression had a positive correlation with TSD (rs¼0.39, p¼0.01). ‘Activated’ SS was significantly enriched in primary compared to metastatic sites (odds ratio 6.67, p¼0.04). CONCLUSIONS: The differences in SS, TSD, and a-SMA staining between primary and metastatic tumors suggests that tumor stroma is both histologically and molecularly different depending on tumor location or route of spread. Traditional immunohistochemical markers of activated pancreatic stellate cells (a-SMA and FAP) do not adequately explain these differences. The development and use of stroma targeting therapies may need to account for the variability of tumor stroma in primary vs metastatic disease. AMPKa1 Promotes Low Glucose Microenvironment-Induced EpithelialMesenchymal Transition of Pancreatic Cancer Cells by Targeting ZEB1 Gang Zhao, PhD, Shichang Deng, PhD, Xiang Li, PhD, Shufeng Zhao, Shuai Zhu, Chi He, Shijiang Deng, Yang Liu, Chunyou Wang, MD Pancreatic Disease Institute, Union Hospital, HUST, Wuhan, China