Myofibroblasts in the stroma of oral cancer promote tumorigenesis via secretion of activin A.

Myofibroblasts are essential during wound healing and are often found in the stroma of oral squamous cell carcinomas (OSCC). Although the molecular mechanisms by which myofibroblasts influence OSCC remain largely unknown, previous studies demonstrated that presence of myofibroblast in OSCC stroma is an important risk factor of patient's shortened survival. Here we showed that some growth factors are produced in higher levels by tumor-associated myofibroblasts compared to tumor-associated fibroblasts, including activin A. Myofibroblast-conditioned media containing activin A significantly increased OSCC cell proliferation and tumor volume, whereas down-regulation of activin A in the conditioned media decreased proliferation. In addition, myofibroblasts induced in vitro invasion of OSCC cells, which was accompanied by an increased production of matrix metalloproteinases (MMP). In vivo, a significant correlation between presence of myofibroblasts and activities of MMP-2 and MMP-9 was observed in OSCC samples. However, blockage of activin A synthesis by myofibroblasts did not affect invasion and MMP production by OSCC cells. Together, our data demonstrate that activin A is required for the proliferative effects of myofibroblasts on OSCC cells. We conclude that myofibroblasts in the stroma of OSCC may influence proliferation and invasion, resulting in more aggressive tumor.