Periostin antisense oligonucleotide suppresses bleomycin-induced formation of a lung premetastatic niche for melanoma

: Metastasis is the leading cause of cancer death. A tumor-supportive microenvironment, or premetastatic niche, at potential secondary tumor sites plays an important role in metastasis, especially in tumor cell colonization. Although a fibrotic milieu is known to promote tumorigenesis and metastasis, the underlying molecular contributors to this effect have remained unclear. Here we show that periostin, a component of the extracellular matrix that functions in tissue remodeling, has a key role in formation of a fibrotic environment that promotes tumor metastatic colonization. We found that periostin was widely expressed in fibrotic lesions of mice with bleomycin-induced lung fibrosis, and that up-regulation of periostin expression coincided with activation of myofibroblasts positive for α-smooth muscle actin. We established a lung metastasis model for B16 murine melanoma cells and showed that metastatic colonization of the lung by these cells was markedly promoted by bleomycin-induced lung fibrosis. Inhibition of periostin expression by giving an intratracheal antisense oligonucleotide targeting periostin mRNA was found to suppress bleomycin-induced lung fibrosis and thereby to attenuate metastatic colonization of the lung by melanoma cells. Our results indicate that periostin is a key player in the development of bleomycin-induced fibrosis and consequent enhancement of tumor cell colonization in the lung. Our results therefore implicate periostin as a potential target for prevention or treatment of lung metastasis.