Mechanical loading is known to trigger proliferation of tumor cells. Periostin is a new molecule found to increase in many cancers. To determine how mechanical strain modulates tumor growth and its possible mediation by periostin through TGF-beta1, Lewis lung cancer cells were cultured on flexible-bottomed culture plates and cyclically strained using Flexercell Strain Unit. Real-time RT-PCR was used to quantify periostin and TGF-beta1 mRNA levels at 6, 12, 18, and 24 h of loading. In addition, periostin and TGF-beta1 neutralizing antibodies were added to the medium. We showed that the proliferative ability of Lewis cancer cells was significantly increased by cyclical strain. This change can be blocked by 5 microg/ml of periostin neutralizing antibody. Periostin mRNA increased by 1.1-, 3.2-, 4.7-, and 9.2-fold while TGF-beta1 mRNA increased by 5.3-, 10.3-, 7.1-, and 6.5-fold at 6, 12, 18, and 24 h, respectively. Periostin protein in medium increased after cyclical strain. Expression of periostin mRNA in response to mechanical loading was completely blocked by 2.5 microg/ml of TGF-beta1 neutralizing antibody. In addition, overexpression of periostin in Lewis cells can promote cell proliferation. Our results suggest that periostin is a potent positive regulator of tumor growth in response to mechanical loading and is possibly a downstream factor of TGF-beta1.