Plasma Shh Levels Reduced in Pancreatic Cancer Patients

Abstract

Objectives Normally, sonic hedgehog (Shh) is expressed in the pancreas during fetal development and transiently after tissue injury. Although pancreatic cancers express Shh, it is not known if the protein is secreted into the blood and whether its plasma levels change with pancreatic transformation. The goal of this study was to develop an ELISA to detect human Shh in blood, and determine the levels in subjects with and without pancreatic cancer. Methods A human Shh ELISA assay was developed, and plasma Shh levels were measured in blood samples from normal volunteers and subjects with pancreatitis or pancreatic cancer. The biological activity of plasma Shh was tested using NIH-3T3 cells. Results The average levels of Shh in human blood were lower in pancreatitis and pancreatic cancer patients than in normal individuals. Hematopoietic cells did not express Shh suggesting that Shh is secreted into the bloodstream. Plasma fractions enriched for Shh did not induce Gli-1 mRNA suggesting that the protein was not biologically active. Conclusions Shh is secreted from tissues and organs into the circulation but its activity is blocked by plasma proteins. Reduced plasma levels were found in pancreatic cancer patients, but alone were not sufficient to predict pancreatic cancer.

Reactive Glia in the Injured Brain Acquire Stem Cell Properties in Response to Sonic Hedgehog

“…Notably, neurons, astrocytes, and choroid plexus cells have been described as sources of SHH (Alvarez et al, 2011;Amankulor et al, 2009;Garcia et al, 2010;Traiffort et al, 1999), and the presence of considerable amounts of SHH in CSF (Huang et al, 2009) may help to explain why invasive injuries result in the accumulation of significant levels of the signal (Amankulor et al, 2009;Androutsellis-Theotokis et al, 2006), while the noninvasive models, such as amyloidosis or p25 induced neuronal death, do not. Interestingly, SHH is also present in human CSF and plasma (El-Zaatari et al, 2012), implying similar access to the brain after invasive injury in patients.…”

Inhibition of Hedgehog signaling in the gastrointestinal tract: Targeting the cancer microenvironment

“…Moreover, Gli1 deletion in a mouse model of pancreatic cancer generated by expressing oncogenic KRAS impedes cancer progression 22 . Although Shh levels in the pre-neoplastic pancreas increase locally, we observed a decrease rather than an increase in circulating levels of the ligand, which we concluded correlated with the increase in fibrosis accompanying cells expressing the Ptch receptor 16 . Thus both canonical and non-canonical signaling appear to participate in the progression of pancreatic cancer.…”

“…This invasive phenotype was accelerated by inflammation. Although the authors did not examine Hh signaling directly in their report, pancreatic duct cells are known to express Shh ligand when inflamed or with transformation 16 . Recent studies show that curcumin-mediated inhibition of Shh-Gli signaling will block EMT 120 .…”

“…In addition, one might query whether components of the Hh signaling pathway can be used as biomarkers 15 . Interestingly, it has recently been reported that Shh circulates in plasma raising the possibility of using the ligand as a biomarker in some cancers 16 .…”

Canonical and non-canonical Hedgehog signalling and the control of metabolism

“…Furthermore, inappropriate activation of the pathway, alone or in combination with other oncogenes is associated with the development of pancreatic adenocarcinoma (PDAC) [139,170–172]. …”