(WHS-P2.04) Cancer and lymphatic marker FOXC2 drives wound healing and fibrotic tissue formation
Friday, May 17, 2024
10:30 AM – 11:30 AM East Coast USA Time
Background Wound repair is a complex process that engages many different physiological systems as the tissue progresses through a series of interdependent phases, including inflammation and remodeling. The FOXC2 transcription factor has been tied to tissue development during embryogenesis, and has been clinically associated with aggressive basal-like human breast cancers. Systemic dysregulation of FOXC2 expression has also been found to promote defects in lymphatic remodeling and hyperplastic lymphedema-distichiasis (LD). Since chronic lymphedema is a forerunner of several malignancies and cancers have been known to arise from poorly healing chronic wounds, we examined the effect of Foxc2 dysfunction on skin wound healing. Methods We used our splinted excisional wounding model that mimics human-like wound healing on wildtype and Foxc2 +/- mice, which demonstrate incomplete lymphatic vasculature, lymphatic dysfunction, and enhanced cancer metastasis. Wound size was measured over the course of 18 days. Tissue was explanted from both groups at post-operative day (POD) 14 and 18 and stained with Masson’s Trichrome to assess scar formation, Picrosirius Red for dermal integrity, or immunofluorescence to assess macrophage (F4/80) cell populations. Results Wildtype mice had completely healed wounds by POD 14, while Foxc2+/- mice did not heal until POD18 (p=0.0104). On PODs 8 (p < 0.0001), 10 (p < 0.0001), 12 (p < 0.0001), and 14 (p=0.0002), the wound size of Foxc2+/- mice was significantly larger than that of wildtype mice. Scar area of healed Foxc2+/- mice (POD 18) was significantly larger than that of healing Foxc2+/- mice (POD14; p=0.0098) and that of healed wildtype mice (POD 14; p=0.0294). Collagen fibers in the healing scar of Foxc2+/- mice were narrower (p=0.0117) and more highly aligned (p=0.0110), indicating significantly more fibrosis in Foxc2+/- mice compared to wildtype mice. Collagen fibers in both groups became significantly longer (p=0.0116) and wider (p=0.0020) over time, indicating a temporal evolution of fibrosis during the remodeling phase of wound healing. Foxc2+/- mice also had significantly lower numbers of F4/80 cells (p=0.0014) compared to wildtype mice, indicating poor immune cell infiltration at the wound site. Conclusion We found that FOXC2, which is tied to cancer metastasis and lymphatic dysregulation, also impairs wound healing and promotes fibrotic tissue architecture, linking these disease states together. With FOXC2 proposed as a potential therapeutic target for cancer metastasis, its pleiomorphic downstream systemic effects should be considered and weighed against the increased risk of developing nonhealing wounds, potentially by inhibiting the immune system. Further delineation of the microenvironment, cellular events, and molecular signals during normal and Foxc2-associated abnormal wound healing will improve clinical therapies targeting this marker.