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Abstract
Pancreatic cancer (PC) is the fourth leading cause of cancer death in western societies, with a 5-year survival rate of approximately 5%. There is an urgent need to develop novel therapeutic strategies. Activation of embryonic signalling pathways quiescent in the adult pancreas is a feature of PC and has been implicated in the regulation of stem cells, with components of these signalling pathways representing both novel drug targets and candidate biomarkers.
Aberrant expression of several molecules, identified by global analysis of gene expression, particularly those involved in retinoic acid (RA) signalling, were explored in PC. Their potential utility as biomarkers of prognosis and therapeutic responsiveness was assessed in a large cohort of patients and their function further investigated using in vitro and in vivo models. Bone marrow transplantation models were also developed to assess the potential of bone marrow derived cells (BMDC) as candidate pancreatic stem cells in the pancreas, since embryonic signalling pathways also regulate the stem cell niche
Several RA signalling components were aberrantly expressed in PC. The calcium-binding protein S100A2 was an independent predictor of survival following pancreatectomy.
Active RA signalling was present in rare exocrine cells of the normal adult pancreas, with marked activation during pancreatic regeneration. Loss of CRBP1, a key component of RA signalling occurred frequently in PC and was present in the earliest precursor lesions, however loss of function studies suggest that loss of CRBP1 alone was not sufficient to induce carcinogenesis.
Bone marrow transplantation experiments demonstrated contribution of BMDC to the normal exocrine pancreas, however these cells were not responsible for pancreatic acinar regeneration. BMDC contributed to the activated stellate cell population in chronic pancreatitis and PC, but not to the epithelial component.
This study identified two biomarkers predictive of response to therapy in PC with potential clinical utility, S100A2 and hENT, while also delineating the potential role of RA signalling in pancreatic regeneration and PC. Finally, a novel model of investigating tumour-host interactions was developed using bone marrow transplantation in mice.