Nerve Growth Factor and Artemin Are Paracrine Mediators of Pancreatic Neuropathy in Pancreatic Adenocarcinoma

Ceyhan, Güralp O.; Schäfer, Karl‐Herbert; Kerscher, Annika G.; Rauch, Ulrich; Demir, Ihsan Ekin; Kadıhasanoğlu, Mustafa; Böhm, Carolin; Müller, Michael; Büchler, Markus W.; Giese, Nathalia A.; Erkan, Mert; Frieß, Helmut

doi:10.1097/sla.0b013e3181d974d4

Cited by 91 publications

(94 citation statements)

References 44 publications

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“…This dual-effect phenomenon is reported for many trophic factors, and PRL could play such a role. For example, even though acute administration of glial cell line-derived neurotrophic factor and artemin produce hyperalgesia (19,43), the long-term systemic administration of these trophic factors is associated with neuroprotection, antihyperalgesia, and antinociception (14,30).…”

Section: Discussionmentioning

confidence: 99%

Prolactin regulates TRPV1, TRPA1, and TRPM8 in sensory neurons in a sex-dependent manner: Contribution of prolactin receptor to inflammatory pain

Patil

Ruparel

Henry

et al. 2013

American Journal of Physiology-Endocrinology and Metabolism

113

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Patil MJ, Ruparel SB, Henry MA, Akopian AN. Prolactin regulates TRPV1, TRPA1, and TRPM8 in sensory neurons in a sex-dependent manner: Contribution of prolactin receptor to inflammatory pain. Am J Physiol Endocrinol Metab 305: E1154-E1164, 2013. First published September 10, 2013; doi:10.1152/ajpendo.00187.2013 is a hormone produced in the anterior pituitary but also synthesized extrapituitary where it can influence diverse cellular processes, including inflammatory responses. Females experience greater pain in certain inflammatory conditions, but the contribution of the PRL system to sexdependent inflammatory pain is unknown. We found that PRL regulates transient receptor potential (TRP) channels in a sex-dependent manner in sensory neurons. At Ͼ20 ng/ml, PRL sensitizes TRPV1 in female, but not male, neurons. This effect is mediated by PRL receptor (PRL-R). Likewise, TRPA1 and TRPM8 were sensitized by 100 ng/ml PRL only in female neurons. We showed that complete Freund adjuvant (CFA) upregulated PRL levels in the inflamed paw of both male and female rats, but levels were higher in females. In contrast, CFA did not change mRNA levels of long and short PRL-R in the dorsal root ganglion or spinal cord. Analysis of PRL and PRL-R knockout (KO) mice demonstrated that basal responses to cold stimuli were only altered in females, and with no significant effects on heat and mechanical responses in both sexes. CFA-induced heat and cold hyperalgesia were not changed in PRL and PRL-R KO compared with wild-type (WT) males, whereas significant reduction of heat and cold post-CFA hyperalgesia was detected in PRL and PRL-R KO females. Attenuation of CFA-induced mechanical allodynia was observed in both PRL and PRL-R KO females and males. Thermal hyperalgesia in PRL KO females was restored by administration of PRL into hindpaws. Overall, we demonstrate a sex-dependent regulation of peripheral inflammatory hyperalgesia by the PRL system. prolactin receptor; transient receptor potential V1; transient receptor potential A1; transient receptor potential M8; female; inflammation; pain MANY HUMAN CHRONIC INFLAMMATORY conditions are associated with hyperprolactinemia, and this increase in prolactin (PRL) levels can lead to serious health issues related to cancer, infertility, inflammatory diseases, and body weight (11,42,48,73). Human inflammatory conditions with increased PRL serum levels include the severe form of progressive systemic sclerosis (34, 69), the active phase of systemic lupus erythematosus (37, 74), rheumatoid arthritis (44), polymyalgia rheumatica (68), and autoimmune thyroid diseases (26). Unlike chronic inflammation, acute inflammation in animals triggers an accumulation of endogenous PRL at the site of inflammation, but not in blood serum (64). Altogether, these findings suggest that acute inflammation upregulates PRL via extrapituitary mechanisms, whereas chronic inflammation induces PRL via both pituitary and extrapituitary pathways (64, 75).Elevated PRL can have modulatory effects on metabolic/ endocrine and the ...

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Section: Discussionmentioning

confidence: 99%

Prolactin regulates TRPV1, TRPA1, and TRPM8 in sensory neurons in a sex-dependent manner: Contribution of prolactin receptor to inflammatory pain

Patil

Ruparel

Henry

et al. 2013

American Journal of Physiology-Endocrinology and Metabolism

113

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“…Consecutive 3-mm paraffin-embedded tissue sections of colon cancer and pancreatic cancer were analyzed using protein gene product 9.5/PGP9.5; 1:1,000, Dako), Artemin & NGF (1:300, Santa-Cruz), and GAP-43 (1:1,000, Millipore) antibodies via immunohistochemistry (24). In the PGP9.5 staining, 5 nerves were randomly selected, morphologically classified according to their NI severity (ENA, PNI, and ENI) and reidentified on the immunostained consecutive sections (NGF, GAP-43, and Artemin sections) and photomicrographed at Â100 magnification.…”

Section: Immunohistochemistrymentioning

confidence: 99%

The Severity of Neural Invasion Is Associated with Shortened Survival in Colon Cancer

Liebl

Demir

Rosenberg

et al. 2013

Clinical Cancer Research

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Purpose: Neural invasion (NI) is a histopathologic feature of colon cancer that receives little consideration. Therefore, we conducted a morphologic and functional characterization of NI in colon cancer.Experimental Design: NI was investigated in 673 patients with colon cancer. Localization and severity of NI was determined and related to patient's prognosis and survival. The neuro-affinity of colon cancer cells (HT29, HCT-116, SW620, and DLD-1) was compared with pancreatic cancer (T3M4 and SU86.86) and rectal cancer cells (CMT-93) in the in vitro three-dimensional (3D)-neural-migration assay and analyzed via live-cell imaging. Immunoreactivity of the neuroplasticity marker GAP-43, and the neurotrophic-chemoattractant factors Artemin and nerve growth factor (NGF), was quantified in colon cancer and pancreatic cancer nerves. Dorsal root ganglia of newborn rats were exposed to supernatants of colon cancer, rectal cancer, and pancreatic cancer cells and neurite density was determined.Results: NI was detected in 210 of 673 patients (31.2%). Although increasing NI severity scores were associated with a significantly poorer survival, presence of NI was not an independent prognostic factor in colon cancer. In the 3D migration assay, colon cancer and rectal cancer cells showed much less neuritetargeted migration when compared with pancreatic cancer cells. Supernatants of pancreatic cancer and rectal cancer cells induced a much higher neurite density than those of colon cancer cells. Accordingly, NGF, Artemin, and GAP-43 were much more pronounced in nerves in pancreatic cancer than in colon cancer.Conclusion: NI is not an independent prognostic factor in colon cancer. The lack of a considerable biologic affinity between colon cancer cells and neurons, the low expression profile of colonic nerves for chemoattractant molecules, and the absence of a major neuroplasticity in colon cancer may explain the low prevalence and impact of NI in colon cancer.

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“…Significant neural remodeling (neural hypertrophy and increased neural density) is known to occur in pancreatic cancer [148]. However, there have not yet been any studies assessing the interactions of PSCs and neural cells.…”

Section: Psc-neural Cell Interactionsmentioning

confidence: 99%

Pancreatic Stellate Cells

Apte

Pirola

Wilson

2015

Stellate Cells in Health and Disease

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Nerve Growth Factor and Artemin Are Paracrine Mediators of Pancreatic Neuropathy in Pancreatic Adenocarcinoma

Cited by 91 publications

References 44 publications

Prolactin regulates TRPV1, TRPA1, and TRPM8 in sensory neurons in a sex-dependent manner: Contribution of prolactin receptor to inflammatory pain

Prolactin regulates TRPV1, TRPA1, and TRPM8 in sensory neurons in a sex-dependent manner: Contribution of prolactin receptor to inflammatory pain

The Severity of Neural Invasion Is Associated with Shortened Survival in Colon Cancer

Pancreatic Stellate Cells

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