Fibroblast Proliferation and Recovery Response to the Small-molecule Inhibitor Vismodegib
Objectives: Patients with basal cell carcinoma nevoid syndrome develop multiple keratocystic odontogenic tumors (KCOTs) and numerous skin basal cell carcinomas (BCCs), which are linked to uncontrolled activation of the sonic-hedgehog (SHh) pathway. While SHh-targeted inhibitors, such as Vismodegib, reduce tumor burden, cancer recurrence in these patients upon treatment cessation suggest that other mechanisms underlie the development of these tumors, in addition to SHh. Since epithelial tumor cells are influenced by their cross-talk with dermal fibroblasts, we investigated the effect of Vismodegib on the proliferation and recovery of fibroblasts from this small-molecule inhibitor in cell cultures in vitro. Methods: Multiple human fibroblast cultures were treated for 8 days with DMSO (control), 10 nM, 10 uM, or 100 uM Vismodegib and either allowed to recover or continued treatment for an additional 8 days. Cell morphology and cell counts were determined in 6 time points during the study duration. Results were subjected to three-way, two-way and one-way ANOVA tests and Tukey’s HSD for pairwise comparisons. P-values <0.05 were considered statistically significant. Results: Under all treatment conditions, fibroblasts exhibited characteristic spindle cell morphology and no cell death. Significant inhibition of cell proliferation was continuously observed in 100 uM Vismodegib-treated cultures, but not in all other cultures (p<0.03-p<0.008). Only the cultures recovering from this drug concentration demonstrated a marked increase in cell proliferation (p=0.008) upon drug cessation at day 8. Yet, cultures that recovered from 100 uM Vismodegib demonstrated lower cell counts when compared to cell counts in recovered control cultures at the end of the study on day 16 (p=0.03). Conclusions: While the SHh inhibitor Vismodegib effectively inhibits the growth of epithelial BCC tumor cells, it may also modify the proliferation and recovery of supportive, adjacent dermal fibroblasts. In turn, altered tumor-stromal interactions likely contribute to the pathogenesis of BCC and potentially of KCOTs.
IADR/AADR/CADR General Session
2019 IADR/AADR/CADR General Session (Vancouver, BC, Canada) Vancouver, BC, Canada
2019 3279 Oral Medicine & Pathology Research
Kuna, Sunnie
( Tufts University School of Dental Medicine
, Boston
, Massachusetts
, United States
)
Mendez, Tatiana
( Tufts University School of Dental Medicine
, Boston
, Massachusetts
, United States
)
Pagni, Sarah
( Tufts University School of Dental Medicine
, Boston
, Massachusetts
, United States
)
Alt-holland, Addy
( Tufts University School of Dental Medicine
, Boston
, Massachusetts
, United States
)
Michael J. Rainen Family Foundation
NONE
Poster Session
Head and Neck Cancer and Precancer
Saturday,
06/22/2019
, 11:00AM - 12:15PM