Abstract
205 Background: Exocrine pancreatic cancer is the fifth cause of cancer-related death in Europe and has a very poor prognosis for all disease stages. To date no medical treatment has significantly increased patients' survival. One of the reasons for pancreatic cancer's chemoresistance is the complex tumor architecture: cancer cells are surrounded by a dense desmoplastic stroma that blocks drugs delivery. Moreover, pancreatic cancer is characterized by a marked heterogeneity of cells, including cancer stem cells (CSCs) that act as tumor-initiating cells and hierarchically control the differentiated cancer cells. Recent studies in multiple pancreatic cancer model systems have implicated the Hedgehog signaling pathway in these tumor-stromal interactions. The Hedgehog signaling pathway, a crucial regulator of proliferation and differentiation during embryonic development, has been reported to be aberrant and SMO overexpression seems to be a mechanism of activation of this pathway in human pancreatic cancer fibroblasts. Several studies are ongoing to evaluate the potential role of Hedgehog inhibitors, we investigated the contribution of Hedgehog to pancreatic progression and aggressiveness, evaluating the associated of stemness and desmoplastic reaction. Methods: In 110 histological samples of pancreatic ductal adenocarcinoma were performed molecular biology assessment of SPARC, CD133, CD44, CD24, OCT3/4, SHH, IHH, DHH, SMO, PTCH1, PTCH2. Results: Our analysis showed a strictly correlation between overexpression of SMO and high levels of SPARC (p=0.0005) and stemness markers CD133 (p=0.04) and OCT3/4 (p=0.0023) Conclusions: Our data demonstrate a critical and conserved role of Hedgehog signaling in the regulation of stem cell lineages and in the determination of a pronounced desmoplastic reaction determining chemoresistance and disease progression. We can speculate that patients with an aggressive profile defined by SMO overexpression would be the best candidates for treatment with Hedgehog inhibitors. This evidence suggests that this pathway may hold promise for new therapeutic approaches.
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