| Summary: | Pancreatic cancer is a solid tumour with poor prognosis and ineffective therapeutic approaches. The role of the tumour microenvironment in supporting pancreatic tumour growth and metastasis has been demonstrated. In particular, a new concept of the stem cell niche as a mixed population of mesenchymal stem cells and niche cells (myofibroblast cells) involved in promoting these processes is emerging. Paracrine transmission of the Hedgehog (Hh) pathway in the pancreatic tumour microenvironment has previously been reported. This project aimed to identify the stromal pancreatic cancer cells able to respond to Hh pathway exogenous stimuli and to investigate their relationship to tumour progression, in order to define new targets for pancreatic cancer therapies. Gene and protein expression analysis in pancreatic primary tumours demonstrated overexpression of Shh ligand not only at the epithelial but also at the stromal level in advanced stages of pancreatic cancer. In vitro modelling of the mesenchymal stem cell niche (mSCN) using human bone marrow-derived mesenchymal stem cells (MSCs) co-cultured with cancer-associated fibroblasts (CAFs) or myofibroblast-like cells (MF-like, obtained by treating MSC with TGFβ) showed up-regulation of Shh gene and protein expression in comparison to single stromal cell populations (MSCs; CAFs and MF-like cells). The investigation of Hh paracrine signalling in pancreatic tumour microenvironment using different 2D in vitro assays (transwell and direct co-cultures, NShh treatments and tumour condition media cultures) demonstrated the inability of CAFs and MSCs, when grown in culture conditions that prevent their activation (increase of αSMA), to respond to Hh exogenous stimuli and suggested the mSCN as the stromal context in which paracrine induction of the Hh pathway takes place. Taken together, these results suggest a new concept: Shh expression is an indicator of the mSCN in the pancreatic cancer microenvironment and that its role as a possible target for chemotherapy should be explored.
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