Sonic hedgehog paracrine signaling regulates metastasis and lymphangiogenesis in pancreatic cancer

Abstract

Sonic hedgehog (SHH) expression is tightly regulated throughout development. In the adult, aberrant expression of SHH is associated with the onset and progression of pancreatic cancer, as evidenced by increased levels of expression in premalignant and malignant lesions of the pancreas. We investigated the hypothesis that SHH, secreted from pancreatic tumors, functions in a paracrine manner to influence the biological condition of mesenchymal and endothelial cells. Orthotopic implantation of a pancreatic tumor cell line expressing SHH (Capan-2) and a transformed primary cell line that overexpresses SHH (T-HPNE.SHH) were used to show that overexpression of SHH increased primary tumor size and metastasis. Treatment with a neutralizing antibody, 5E1, decreased primary tumor volume and inhibited metastasis. Lyve-1 þ vessels and stromal fibroblasts in tumors expressed primary cilium and showed localization of the receptor Smoothened to the primary cilium, providing evidence of active SHH signaling through this pathway. Although primary cilia are present on normal ductal cells of the pancreas, we did not observe primary cilium on the ductal tumor cells, suggesting decreased autocrine signaling through pathways mediated by the primary cilium in pancreatic cancer. These data support the hypothesis that SHH, secreted from pancreatic epithelia, is critical in establishing and regulating the tumor microenvironment and thereby contributes to progression of pancreatic cancer.

MYB Promotes Desmoplasia in Pancreatic Cancer through Direct Transcriptional Up-regulation and Cooperative Action of Sonic Hedgehog and Adrenomedullin

“…These findings were consistent with published data that has suggested mostly a paracrine signaling for pancreatic tumor cell-derived SHH (27). Inhibition of SHH was shown to decrease desmoplasia through direct activation of hedgehog signaling in PSCs (5), while it indirectly affected PC metastasis and lymphangiogenesis due to altered tumor microenvironment (28). In other reports, ADM has also been shown to be up-regulated in PC patients (29).…”

Activation of the hedgehog-signaling pathway in human cancer and the clinical implications

“…Studies also indicate that Hh signaling may be involved in different stages of carcinogenesis in different tumors. In pancreatic and esophageal cancers for example, activation of this pathway is found in both early tumors and metastatic cancer (Bailey et al, 2009;Feldmann et al, 2008;Ma et al, 2006;Pasca di Magliano and Hebrok, 2003), suggesting that Hh signaling has a significant role in carcinogenesis of these tumors. In support of these findings, transgenic mice with pancreatic-specific expression of SHH or (Sheng et al, 2004).…”

Activation of the hedgehog pathway in gastroesophageal cancers

“…Inactivation of this pathway causes developmental defects such as holoprosencephaly, 10 whereas hyperactivation of this pathway is found in most basal cell carcinomas (BCCs) and many extracutaneous cancers. [11][12][13] In pancreatic cancer for example, activation of the Hh pathway is found in both early tumors and metastatic cancer [14][15][16][17][18] . In support of there findings, transgenic mice with pancreatic-specific expression of Shh or Gli2 develop pancreatic tumors.…”