Recent studies have suggested that in the TME, mast cells marked by KIT and CPA3 can induce the release of TGF-β, activate Smad4 signal transduction, upregulate PAR-2 and ERK1/2 expression, and activate AKT signaling, thereby inhibiting tumor cell apoptosis and inducing resistance to gemcitabine [10, 19, 38, 75]. This evidence concerns the gene SMAD4 and neoplasm.