Recruitment and Activation of Pancreatic Stellate Cells from the Bone Marrow in Pancreatic Cancer: A Model of Tumor-Host Interaction
Open Access
- 14 October 2011
- journal article
- research article
- Published by Public Library of Science (PLoS) in PLOS ONE
- Vol. 6 (10), e26088
- https://doi.org/10.1371/journal.pone.0026088
Abstract
Chronic pancreatitis and pancreatic cancer are characterised by extensive stellate cell mediated fibrosis, and current therapeutic development includes targeting pancreatic cancer stroma and tumor-host interactions. Recent evidence has suggested that circulating bone marrow derived stem cells (BMDC) contribute to solid organs. We aimed to define the role of circulating haematopoietic cells in the normal and diseased pancreas. Whole bone marrow was harvested from male β-actin-EGFP donor mice and transplanted into irradiated female recipient C57/BL6 mice. Chronic pancreatitis was induced with repeat injections of caerulein, while carcinogenesis was induced with an intrapancreatic injection of dimethylbenzanthracene (DMBA). Phenotype of engrafted donor-derived cells within the pancreas was assessed by immunohistochemistry, immunofluorescence and in situ hybridisation. GFP positive cells were visible in the exocrine pancreatic epithelia from 3 months post transplantation. These exhibited acinar morphology and were positive for amylase and peanut agglutinin. Mice administered caerulein developed chronic pancreatitis while DMBA mice exhibited precursor lesions and pancreatic cancer. No acinar cells were identified to be donor-derived upon cessation of cerulein treatment, however rare occurrences of bone marrow-derived acinar cells were observed during pancreatic regeneration. Increased recruitment of BMDC was observed within the desmoplastic stroma, contributing to the activated pancreatic stellate cell (PaSC) population in both diseases. Expression of stellate cell markers CELSR3, PBX1 and GFAP was observed in BMD cancer-associated PaSCs, however cancer-associated, but not pancreatitis-associated BMD PaSCs, expressed the cancer PaSC specific marker CELSR3. This study demonstrates that BMDC can incorporate into the pancreas and adopt the differentiated state of the exocrine compartment. BMDC that contribute to the activated PaSC population in chronic pancreatitis and pancreatic cancer have different phenotypes, and may play important roles in these diseases. Further, bone marrow transplantation may provide a useful model for the study of tumor-host interactions in cancer and pancreatitis.This publication has 51 references indexed in Scilit:
- Organ-, inflammation- and cancer specific transcriptional fingerprints of pancreatic and hepatic stellate cellsMolecular Cancer, 2010
- Inhibition of Hedgehog Signaling Enhances Delivery of Chemotherapy in a Mouse Model of Pancreatic CancerScience, 2009
- Chimeric mice reveal clonal development of pancreatic acini, but not isletsBiochemical and Biophysical Research Communications, 2009
- Transplantation of bone marrow derived cells promotes pancreatic islet repair in diabetic miceBiochemical and Biophysical Research Communications, 2008
- In Vivo Lineage Tracing Defines the Role of Acinar-to-Ductal Transdifferentiation in Inflammatory Ductal MetaplasiaGastroenterology, 2007
- Sensitive detection of GFP utilizing tyramide signal amplification to overcome gene silencingExperimental Cell Research, 2007
- Preexisting pancreatic acinar cells contribute to acinar cell, but not islet β cell, regenerationJCI Insight, 2007
- The pancreatic stellate cell: a star on the rise in pancreatic diseasesJCI Insight, 2007
- One Thousand Consecutive PancreaticoduodenectomiesAnnals of Surgery, 2006
- Stem cell plasticity and tumour formationEuropean Journal of Cancer, 2006