Recruitment and activation of pancreatic stellate cells from the bone marrow in pancreatic cancer: a model of tumor-host interaction.
OBJECTIVE
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.


METHODS
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.


RESULTS
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.


CONCLUSIONS
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.
Cancer Research Program, Garvan Institute of Medical Research, Darlinghurst, Sydney, Australia.
Christopher J
CJ
Scarlett
Emily K
EK
Colvin
Mark
M
Pinese
David K
DK
Chang
Adrienne L
AL
Morey
Elizabeth A
EA
Musgrove
Marina
M
Pajic
Minoti
M
Apte
Susan M
SM
Henshall
Robert L
RL
Sutherland
James G
JG
Kench
Andrew V
AV
Biankin
D015127:9,10-Dimethyl-1,2-benzanthracene; D000818:Animals; D001853:Bone Marrow / Q000473:pathology*; D016026:Bone Marrow Transplantation; D002465:Cell Movement; D005260:Female; D049452:Green Fluorescent Proteins / Q000378:metabolism; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008954:Models, Biological; D010179:Pancreas / Q000293:injuries / Q000473:pathology; D010190:Pancreatic Neoplasms / Q000473:pathology*; D058954:Pancreatic Stellate Cells / Q000473:pathology*; D012038:Regeneration
D049452:Green Fluorescent Proteins; D015127:9,10-Dimethyl-1,2-benzanthracene