Pancreatic Neuropathy Results in “Neural Remodeling” and Altered Pancreatic Innervation in Chronic Pancreatitis and Pancreatic Cancer

Ceyhan, Güralp O.; Demir, Ihsan Ekin; Rauch, Ulrich; Bergmann, Frank; Müller, Michael; Büchler, Markus W.; Frieß, Helmut; Schäfer, Karl‐Herbert

doi:10.1038/ajg.2009.380

Cited by 136 publications

(128 citation statements)

References 33 publications

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“…A prominent neural phenomenon in pancreatic cancer has been characterized by PNI of cancer cells, which is closely associated with the severity of intrapancreatic neuropathic alterations, including increased neural density and hypertrophy (30). Those neuropathic changes, referred to as "neural remodeling," are associated with desmoplasia in pancreatic cancer and chronic pancreatitis (2).…”

Section: Discussionmentioning

confidence: 99%

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

Zheng

et al. 2014

Clinical Cancer Research

136

113

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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.

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Section: Discussionmentioning

confidence: 99%

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

Zheng

et al. 2014

Clinical Cancer Research

136

113

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“…More recently, on the basis of the neurotropism theory, in which tumor cells invade nerves mediated by neurotrophins, a new hypothesis of PNI was raised that emphasized the reciprocal signaling interactions between the nerves and invading tumor cells (7). A recent study has shown that PNI in pancreatic cancer is associated with a remodeling of intrapancreatic nerves, and the proportion of sympathetic nerve fibers in the invaded nerves in pancreatic cancer was much smaller than in normal pancreatic nerves (11). In addition, previous studies showed that the sympathetic neurotransmitter norepinephrine (NE) was overexpressed in human pancreatic cancer tissues (12).…”

Section: Introductionmentioning

confidence: 99%

Interaction of the Sympathetic Nerve with Pancreatic Cancer Cells Promotes Perineural Invasion through the Activation of STAT3 Signaling

Guo

et al. 2013

Molecular Cancer Therapeutics

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Perineural invasion (PNI) is one of the most important causes of local recurrence and poor survival in pancreatic cancer. However, the exact mechanism of PNI is still not clear. In this study, we sought to identify the reciprocal signaling interactions between sympathetic nerves and pancreatic cancer cells and the underlying mechanisms. We used mouse dorsal root ganglia and pancreatic cancer cells cocultured in vitro, cellular and molecular biology, and animal models to evaluate the function of the sympathetic neurotransmitter norepinephrine (NE) in PNI progression and pathogenesis. NE promoted PNI of pancreatic cancer cells and increased levels of phosphorylated STAT3 in a concentration-dependent manner. NE-mediated activation of STAT3 was inhibited by blocking b-adrenergic receptors (AR) and by blocking protein kinase A, but not through blocking a-AR. Blocking STAT3 could inhibit NE-induced NGF, MMP2, and MMP9 expression and attenuate the migratory, invasive ability and PNI of pancreatic cancer cells. Furthermore, PNI of pancreatic cancer cells was blocked by treatment with a STAT3 phosphorylation inhibitor in vivo. These studies show that NE plays a critical role in pancreatic cancer PNI development and progression through the b-AR/PKA/STAT3 signaling pathway. Reciprocal signaling interactions between the sympathetic nerves and pancreatic cancer cells critically contribute to pancreatic cancer PNI pathogenesis. Inhibition of the activity of sympathetic nerves or STAT3 may be potential strategies for pancreatic cancer PNI therapy.

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“…This observation also seems to be in line with the clinical inefficiency of thoracic splanchnicectomy that involves transsection of sympathetic and sensory nerves (10). Concomitantly, nerves in CP tissues provide indicators of glial activation, since they contain reduced amounts of Sox10-immunoreactive peripheral glia and of Nestin-expressing cells in their interior (11). Therefore, at a functional level, sympathetic suppression together with glial activation seem to significantly contribute to the generation of neuropathic pain in CP.…”

Section: Functional Alterationsmentioning

confidence: 49%

“…As outlined later in this chapter several recent articles have demonstrated upregulation of signalling molecules involved in inflammation and pronociceptive mediators, but also neurotropic factors in the pancreatic parenchyma in patients with CP (31). Increased neural density and hypertrophy, sprouting and neuritis of the intrapancreatic nerves, as well as activation of glia and immune cells have also been reported in pancreatic tissue from the patients (11). Finally, as also described in detail later, several studies have reported findings compatible with central sensitization in CP.…”

Section: Pain Pathogenesismentioning

confidence: 98%

“…From the perspective of autonomic innervation, CP was reported to exhibit "neural remodeling", i.e. decreased sympathetic innervation, particularly with increasing degree of pain sensation or pancreatic neuritis (10,11). Hence, it seems that the generation of pain in CP is coupled with the suppression of pancreatic adrenergic input.…”

Section: Functional Alterationsmentioning

confidence: 99%

See 1 more Smart Citation

Pathogenesis and Treatment of Pain in Chronic Pancreatitis

Olesen

Tieftrunk²,

Ceyhan³

et al.

The Pancreapedia: Exocrine Pancreas Knowledge Base

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Pancreatic Neuropathy Results in “Neural Remodeling” and Altered Pancreatic Innervation in Chronic Pancreatitis and Pancreatic Cancer

Cited by 136 publications

References 33 publications

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

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

Interaction of the Sympathetic Nerve with Pancreatic Cancer Cells Promotes Perineural Invasion through the Activation of STAT3 Signaling

Pathogenesis and Treatment of Pain in Chronic Pancreatitis

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