Sonic Hedgehog Paracrine Signaling Activates Stromal Cells to Promote Perineural Invasion in Pancreatic Cancer

Abstract

Purpose: Pancreatic cancer is characterized by stromal desmoplasia and perineural invasion (PNI). We sought to explore the contribution of pancreatic stellate cells (PSC) activated by paracrine Sonic Hedgehog (SHH) in pancreatic cancer PNI and progression.Experimental Design: In this study, the expression dynamics of SHH were examined via immunohistochemistry, real-time PCR, and Western blot analysis in a cohort of carcinomatous and nonneoplastic pancreatic tissues and cells. A series of in vivo and in vitro assays was performed to elucidate the contribution of PSCs activated by paracrine SHH signaling in pancreatic cancer PNI and progression.Results: We show that SHH overexpression in tumor cells is involved in PNI in pancreatic cancer and is an important marker of biologic activity of pancreatic cancer. Moreover, the overexpression of SHH in tumor cells activates the hedgehog pathway in PSCs in the stroma instead of activating tumor cells. These activated PSCs are essential for the promotion of pancreatic cancer cell migration along nerve axons and nerve outgrowth to pancreatic cancer cell colonies in an in vitro three-dimensional model of nerve invasion in cancer. Furthermore, the coimplantation of PSCs activated by paracrine SHH induced tumor cell invasion of the trunk and nerve dysfunction along sciatic nerves and also promoted orthotropic xenograft tumor growth, metastasis, and PNI in in vivo models.Conclusions: These results establish that stromal PSCs activated by SHH paracrine signaling in pancreatic cancer cells secrete high levels of PNI-associated molecules to promote PNI in pancreatic cancer. Clin Cancer Res; 20(16); 4326-38. Ó2014 AACR.

Smoothened antagonist GDC-0449 (Vismodegib) inhibits proliferation and triggers apoptosis in colon cancer cell lines

“…Since neoplasms and embryonic development share similar molecular signaling processes, numerous studies have examined and demonstrated the core role of Shh signaling in maintaining tumor growth and cancer cell survival (12). Vigorous proliferation was observed when the Shh pathway was upregulated in cancer cells, while inhibition of Shh had a suppressing effect (15). All of these phenomena highlight the clinical value of Shh-targeted therapy and the findings of the present study substantiated the theoretical basis for its future application in patients.…”

“…Numerous lines of evidence have shown aberrant activation of the Shh signaling pathway in cancer patients and drug intervention to block the transduction has resulted in tumor shrinking and cancer cell apoptosis in numerous types of solid tumor (12)(13)(14). In vivo and in vitro, pancreatic cancer cells have a lower proliferative and a higher apoptotic rate after intervention with an Shh antagonist (15,16). Following suppression by a specific inhibitor, malignant hepatic neoplasms also display a reduction in the degree of malignancy, such as slower proliferation and higher vulnerability to chemotherapy (17,18).…”

Honokiol suppresses pancreatic tumor growth, metastasis and desmoplasia by interfering with tumor–stromal cross-talk

“…Previous studies from our lab and elsewhere have provided strong support for the role of CXCR4 and SHH in pancreatic tumor growth, metastasis and desmoplasia by enabling bidirectional tumor-stromal cross-talk (15,17,18,(25)(26)(27). Therefore, we examined the expression status of CXCR4 and SHH in tumor sections by IHC analyses.…”

Desmoplastic Reaction In Pancreatic Ductal Adenocarcinoma

“…49 Although cross-talk between PSCs and neural elements has not yet been widely studied, recently the effects of cancer cells on neurite outgrowth in the presence and absence of PSCs was assessed. 50 It was found that nerve invasion index and the Dorsal Root Ganglion (DRG) outgrowth index were significantly increased in the presence of PSCs compared with the absence of PSCs. Additionally, the authors further showed that the interaction between cancer cells and neural cells was likely mediated via a paracrine effect of Sonic Hedgehog ligand binding to the receptor Smo on PSCs with subsequent activation of PSCs.…”