Expression of hepatocyte growth factor, keratinocyte growth factor and their receptors in experimental chronic pancreatitis

Otte, Jan-Michel; Schwenger, Martin; Brunke, Gabriele; Sparmann, Gisela; Emmrich, Jörg; Schmitz, Frank; Fölsch, Ulrich R.; Herzig, Karl‐Heinz

doi:10.1046/j.1365-2362.2001.00894.x

Cited by 8 publications

(6 citation statements)

References 47 publications

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“…The second objective of our study was to analyze the factors that affect preoperative plasma HGF levels. Although previous studies have shown that HGF levels are elevated in inflammatory conditions such as chronic hepatitis and pancreatitis 15, 16, we found no correlation between HGF levels and the results of the LFT. We allowed a period of 1–2 weeks after ERCP‐ and EUS‐directed biopsies before blood samples were collected; this delay was intended to minimize the effect of ensuing inflammation on the plasma levels.…”

Section: Discussioncontrasting

confidence: 99%

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Clinical value of plasma hepatocyte growth factor measurement for the diagnosis of periampullary cancer and prognosis after pancreaticoduodenectomy

Barakat

Rodriguez

Raijman

et al. 2010

Journal of Surgical Oncology

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Section: Discussioncontrasting

confidence: 99%

“…The HGF level continued to increase during the first month in two patients who had postoperative abdominal sepsis and wound infection. This finding is in accord with those of previous studies 15–17 and may in fact reflect the inflammatory process and stress of surgery.…”

Section: Discussionsupporting

confidence: 93%

Clinical value of plasma hepatocyte growth factor measurement for the diagnosis of periampullary cancer and prognosis after pancreaticoduodenectomy

Barakat

Rodriguez

Raijman

et al. 2010

Journal of Surgical Oncology

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“…Taken together, these data support the conclusion that pM concentrations of CCK acting through the high-affinity state of the CCK A receptor activate Src, which in turn associates with and phosphorylates p85, causing an increase in PI3K activity and eventually an increase in Akt activity further downstream. As stimulation of Akt is a proliferative stimulus in many cell types including in pancreatic tissues and pancreatic cancer [35-40], the activation of Akt by low concentrations of CCK might partially account for the stimulation of acinar cell growth by pM-nM doses of CCK [85] or by JMV, an agonist of the high-affinity state of the CCK A receptor [58,86-88]. These conclusions are consistent with studies showing that Akt activation by angiotensin (in mesangial cells) [89], IGF-1 (in oligodendrocytes) [90,91], lysophosphatidic acid (in corneal cells) [92] adenosine (in cardiomyocytes) [93] reactive oxygen species (in fibroblasts) [94] and by estrogen (in endothelial cells) [95], are mediated by Src family kinases.…”

Section: Discussionmentioning

confidence: 99%

“…The examination of their actions in pancreatic acinar cells is also important because PI3K/Akt signaling has been shown to play a central role in pancreatic regeneration [33] and pathological responses of pancreatic acinar cells to CCK [34], but the underlying mechanisms remain unclear. Furthermore, both aberrant signaling through growth factors or gastrointestinal hormones and Akt have been reported to occur in pancreatic pathologies, including cancer and pancreatitis [35-40]. …”

Section: Introductionmentioning

confidence: 99%

Gastrointestinal growth factors and hormones have divergent effects on Akt activation

Berna

Tapia

Sancho

et al. 2009

Cellular Signalling

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Akt is a central regulator of apoptosis, cell growth and survival. Growth factors and some G-proteincoupled receptors (GPCR) regulate Akt. Whereas growth-factor activation of Akt has been extensively studied, the regulation of Akt by GPCR's, especially gastrointestinal hormones/ neurotransmitters, remains unclear. To address this area, in this study the effects of GI growth factors and hormones/neurotransmitters were investigate in rat pancreatic acinar cells which are high responsive to these agents. Pancreatic acini expressed Akt and 5 of 7 known pancreatic growth-factors stimulate Akt phosphorylation (T308, S473) and translocation. These effects are mediated by p85 phosphorylation and activation of PI3K. GI hormones increasing intracellular cAMP had similar effects. However, GI-hormones/neurotransmitters[CCK, bombesin,carbachol] activating phospholipase C (PLC) inhibited basal and growth-factor-stimulated Akt activation. Detailed studies with CCK, which has both physiological and pathophysiological effects on pancreatic acinar cells at different concentrations, demonstrated CCK has a biphasic effect: at low concentrations(pM) stimulating Akt by a Src-dependent mechanism and at higher concentrations(nM) inhibited basal and stimulated Akt translocation, phosphorylation and activation, by de-phosphorylating p85 resulting in decreasing PI3K activity. This effect required activation of both limbs of the PLC-pathway and a protein tyrosine phosphatase, but was not mediated by p44/42 MAPK, Src or activation of a serine phosphatase. Akt inhibition by CCK was also found in vivo and in Panc-1 cancer cells where it inhibited serum-mediated rescue from apoptosis. These results demonstrate that GI growth factors as well as gastrointestinal hormones/neurotransmitters with different cellular basis of action can all regulate Akt phosphorylation in pancreatic acinar cells. This regulation is complex with phospholipase C agents such as CCK, because both stimulatory and inhibitory effects can be seen, which are mediated by different mechanisms.

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“…Both HGF and MET are elevated in multiple cancers, including PDAC , and are associated with increased tumour cell invasion, distant metastases, and poor prognosis . MET has also recently been suggested to be a marker for pancreatic cancer stem cells and its expression is elevated in a model of chronic pancreatitis, a risk factor for PDAC . Based on the accumulating evidence on the importance of HGF/MET signalling in tumourigenesis, various small and large molecule inhibitors have entered preclinical and clinical development .…”

Section: Introductionmentioning

confidence: 99%

PAK1 mediates pancreatic cancer cell migration and resistance to MET inhibition

Zhou¹,

Jubb²,

Lyle³

et al. 2014

The Journal of Pathology

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Pancreatic adenocarcinoma (PDAC) is a major unmet medical need and a deeper understanding of molecular drivers is needed to advance therapeutic options for patients. We report here that p21-activated kinase 1 (PAK1) is a central node in PDAC cells downstream of multiple growth factor signalling pathways, including hepatocyte growth factor (HGF) and MET receptor tyrosine kinase. PAK1 inhibition blocks signalling to cytoskeletal effectors and tumour cell motility driven by HGF/MET. MET antagonists, such as onartuzumab and crizotinib, are currently in clinical development. Given that even highly effective therapies have resistance mechanisms, we show that combination with PAK1 inhibition overcomes potential resistance mechanisms mediated either by activation of parallel growth factor pathways or by direct amplification of PAK1. Inhibition of PAK1 attenuated in vivo tumour growth and metastasis in a model of pancreatic adenocarcinoma. In human tissues, PAK1 is highly expressed in a proportion of PDACs (33% IHC score 2 or 3; n = 304) and its expression is significantly associated with MET positivity (p < 0.0001) and linked to a widespread metastatic pattern in patients (p = 0.067). Taken together, our results provide evidence for a functional role of MET/PAK1 signalling in pancreatic adenocarcinoma and support further characterization of therapeutic inhibitors in this indication.

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Expression of hepatocyte growth factor, keratinocyte growth factor and their receptors in experimental chronic pancreatitis

Abstract: The significant increase of HGF and c-met expression suggests an essential role of this growth factor in the morphological changes during the development of chronic pancreatitis. Changes in the expression of KGF and KGFR are less pronounced.

Cited by 8 publications

References 47 publications

Clinical value of plasma hepatocyte growth factor measurement for the diagnosis of periampullary cancer and prognosis after pancreaticoduodenectomy

Clinical value of plasma hepatocyte growth factor measurement for the diagnosis of periampullary cancer and prognosis after pancreaticoduodenectomy

Gastrointestinal growth factors and hormones have divergent effects on Akt activation

PAK1 mediates pancreatic cancer cell migration and resistance to MET inhibition

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