Abstract
Background and AimsChronic 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.MethodsWhole 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.ResultsGFP 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.ConclusionsThis 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.
Highlights
Pancreatic cancer (PC) remains one of the most devastating cancers, and is the fourth leading cause of cancer death in western societies with a survival rate of less than 5% [1]
Chronic pancreatitis is a significant risk factor for the development of pancreatic cancer and both are characterised by extensive stellate cell mediated fibrosis, which in the case of pancreatic cancer facilitates cancer progression and metastasis [3,4]
Successful reconstitution of bone marrow in transplanted mice was demonstrable in peripheral blood at 1 month post transplant using Fluorescence Activated Cell Sorting (FACS) analysis for green fluorescent protein (GFP) expression
Summary
Pancreatic cancer (PC) remains one of the most devastating cancers, and is the fourth leading cause of cancer death in western societies with a survival rate of less than 5% [1]. Observations made in recent years have demonstrated that adult stem cells have remarkable flexibility in their differentiation repertoires This plasticity allows adult stem cells, those of bone marrow origin, to engraft alternative nonhaematopoietic locations and transdifferentiate into cell types appropriate to their new niche. Bone marrow derived cells (BMDC) can either engraft or fuse to adopt, or be reprogrammed, to the differentiated state of the particular epithelia [9] (reviewed in [10]) This suggests that the endogenous stem cell of an organ, and its role in growth and regeneration, is not confined to each specific organ but may be a dynamic system involving circulating BMDC with stem cell niche environments regulating recruitment, proliferation and differentiation [7,11]. We aimed to define the role of circulating haematopoietic cells in the normal and diseased pancreas
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