Hedgehog Signaling Pathway Is Frequently Activated in Pancreatic Neuroendocrine Tumors.
Wendy L Frankel, Mark Bloomston, Xiaoping Zhou. The Ohio State University, Columbus
Background: The Hedgehog (Hh) signaling pathway plays a critical role in embryo development and governs a diverse array of cellular processes including cell proliferation, differentiation, and tissue patterning. Aberrant activation of this pathway, either by ligand expression, activating mutation/amplification or by loss of function of the core components, has been described in a number of human cancers. Small molecule (s) of Hh inhibitor is available and has shown promising in vivo and in vitro anti-tumor activity. We assessed Hh signaling activity in a cohort of pancreatic neuroendocrine tumors (NET) using immunohistochemistry for SHH and PTCH1.
Design: Tissue microarrays were constructed from formalin-fixed, paraffin-embedded blocks of 98 primary pancreatic NET and 7 normal pancreata (controls) from departmental archives and stained with SHH, PTCH1 and Ki-67. Expression intensity for SHH and PTCH1 was scored as 0 (absent), 1+ (weak), and 2+ (modest to high). The proliferation index was assessed using the percentage of tumor cells positive for Ki-67 nuclear labelling and grouped into ≤2%, 3-20%, >20%.
Results: All 7 normal islets expressed weak levels (1+) of SHH and PTCH1. Modest to high levels (2+) of SHH and PTCH1 expression were detected in 48 (49%) and 11 (11%) NET, respectively. No expression of SHH and PTCH1 was seen in 2 (2%) and 15 (16%) tumors, respectively. Seventy-two tumors showed a proliferation index of ≤2%, 24 of 3-20%, and 4 of >20%. No association was observed between SHH or PTCH1 expression and the proliferation index in NET.
|Staining Intensity||SHH (n = 98)||PTCH1 (n = 97)|
|2+||48 (49%)||11 (11%)|
|1+||48 (49%)||71 (73%)|
|0||2 (2%)||15 (16%)|