Fibroblast Growth and Senescence Response to the Sonic-Hedgehog Inhibitor Vismodegib

Objectives: Development of multiple keratocystic odontigenic tumors (KCOTs) and hundreds of basal cell carcinomas (BCCs) are a few of the hallmark manifestations of Basal cell carcinoma nevoid syndrome (BCCNS). As abnormal activation of the sonic-hedgehog (SHh) pathway in neoplastic basal cells is the major driver of BCC development, SHh inhibitors, such as Vismodegib, have emerged as effective, systemic BCC treatment modalities. However, appearance of drug-resistant tumors and cancer recurrence in BCCNS patients indicates that additional molecular events underlie BCC development. Since epithelial tumors may not only modify their microenvironment but also be influenced by it, we investigated the response of dermal fibroblasts to Vismodegib.
Methods: Human fibroblasts were treated with 10 nM, 10 uM or 100 uM Vismodegib or DMSO for seven days, imaged and counted. Immunostaining and beta-galactosidase production were used to determine the cellular localization of the SHh transcription factor Gli1 and induction of cell senescence.
Results: While fibroblasts retained their characteristic, elongated shape under the different treatments, significant inhibition of cell growth was demonstrated in 100 uM Vismodegib-treated cultures. In control, 10 nM or 10 uM Vismodegib-treated cultures Gli1 was localized to the cell nuclei, and similar level of cell senescence was detected in these cultures. However, whereas under 100 uM Vismodegib conditions Gli1 was restricted to the cell cytoplasm, the inhibition of cell growth was coupled with marked decreased in cell senescence.
Conclusions: Although aberrant activation of the SHh pathway in BCC cells can be effectively blocked by Vismodegib, this systemic treatment modality is not limited to these cells only. The growth and senescence of fibroblasts within the tumor microenvironment could also be affected by this inhibitor. These cells, in turn, may influence the growth and fate of neoplastic BCC cells and contribute to drug-resistance and cancer recurrence of BCCs and potentially KCOTs in BCCNS patients.