SMAD4 and neoplasm: However, once the tumor cells have become insensitive to the anti-growth signals of TGF-β [7] by a loss of downstream components of the TGF-β signaling pathway, such as p53 [8] or Smad4 [9], TGF-β promotes infiltrative growth and tumor malignancy by augmenting cellular transformation, epithelial-mesenchymal-transition driven invasion, metastasis [10], and particularly mediates suppression of the antitumor immune reaction by inhibiting cytotoxic T-cells and natural killer (NK) cells [11].