The present “in vitro” study was made in order to assess whether the exposure of cancer cells to EGF in the tumor microenvironment modifies pancreatic cancer cell signalling, proliferation and invasion in response to EGF itself, TGFβ1 and S100A8/A9 singly or combined and whether SMAD4 has a part in this scenario. Here, S100A8 is linked to familial pancreatic carcinoma.