Wnt and Hedgehog Signaling Pathway Activation in Cutaneous Fibrosing Disorders: A Tissue Microarray Study
Katy Linskey, Jonathan Kay, Lyn M Duncan, Rosalynn M Nazarian. Massachusetts General Hospital, Boston, MA; UMass Memorial Medical Center, Worcester, MA
Background: Cutaneous fibrosing disorders represent a dysregulated fibroproliferative response without a fully elucidated pathogenesis. As Wnt and Hedgehog (Hh) pathways have been implicated in fibrosis in a number of organ systems, we investigated this pathway in fibrosis in patient skin biopsies.
Design: Using a tissue microarray method and immunohistochemistry, we examined signaling molecules in the Wnt (Wnt3a, Fz2, WISP1 and WISP2) and Hh (Ihh, Shh, Ptch, Gli2, Smo) pathways and downstream mediators GSK3β, pGSK3α, Snail and β-catenin in 170 cases of cutaneous fibrosis including keloid (n=58), hypertrophic scar (HScar) (n=57), scleroderma (Scl) (n=22), nephrogenic systemic fibrosis (NSF) (n=9), scar (n=24), and normal skin (n=8) as controls.
Results: Wnt signaling was activated in all fibrosing disorders (Wnt3a, Fz2, and WISP-1 were detected in all cases). WISP-2 was expressed in all Scl cases, with higher expression compared to scar (85%; p=0.0258). HScar demonstrated decreased expression (54%) compared to normal skin (100%; p=0.0049) and scar (85%; p=0.0008). Ihh was highly expressed in fibrosis (keloid: 100%, p=0.0001; HScar: 97%, p=0.0045; Scl: 100%, p=0.0097), compared to normal (80%). No significant Shh was detected in any cases, but Gli2 and Smo were highly expressed (100% positive in all case types). GSK3β was decreased in Scl (39%) compared to NSF (77%; p=0.0168), normal (91%, p=0.0002) and scar (95%, p=0.0001). pGSK3α showed increased expression in keloid (92%, p<0.0001), HScar (83%, p<0.0001) and NSF (72%, p=0.0422) compared to normal (40%), which had similar expression to scleroderma (44%). Snail showed expression in 100% of keloid, HScar and Scl cases which significantly differed from normal (59%, p<0.0001 for all). Snail was only moderately expressed in NSF (71%) compared to Scl (p=0.0021). Nuclear localization of β-catenin was increased in keloid (80%, p=0.003), HScar (78%, p=0.027), NSF (100%, p=0.002) compared to normal (46%). β-catenin staining in Scl (21%) was significantly decreased compared to NSF (p=0.0001), but not when compared to normal (p=0.139).
Conclusions: Wnt and Hh (via Ihh and not Shh) signaling was activated in cutaneous fibrosing disorders in human tissue; however unlike keloid, HScar and NSF which display GSK3β and pGSK3α expression as well as β-catenin stabilization, the pathogenesis of fibrosis in Scl may occur through an alternate pathway. These results provide a rationale for targeting of the Wnt and Hh pathways in development of therapeutics.
Monday, March 4, 2013 9:30 AM
Poster Session I Stowell-Orbison/Surgical Pathology/Autopsy Awards Poster Session # 66, Monday Morning