Epidermal growth factor-related peptides and their relevance to gastrointestinal pathophysiology

Barnard, J. A.; Beauchamp, R. Daniel; Russell, William E.; DuBois, Raymond N.; Coffey, Robert J.

doi:10.1016/0016-5085(95)90087-x

Cited by 305 publications

(178 citation statements)

References 143 publications

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“…A numbers of growth factors and cytokines have been implicated in intestinal regeneration in various animal models of intestinal damage, including transforming growth factor α and β (Barnard et al, 1995;Dignass et al, 1996), insulin-like growth factor (Howarth et al, 1998), intestinal trefoil factor (Poulsom, 1996) and keratinocyte growth factor (Farrell et al, 1998). In this study, we observed a close histopathological resemblance between the methotrexate-induced rat intestinal mucositis and the clinical gut mucositis seen in chemotherapy patients, a close temporal correlation between the upregulation of HGF and its receptor and …”

Section: Discussionmentioning

confidence: 99%

Increased expression of HGF and c-met in rat small intestine during recovery from methotrexate-induced mucositis

et al. 2000

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Summary Chemotherapy or radiotherapy often cause mucosal damage in the gut (gut mucositis) in cancer patients. As a step to investigate mechanisms underlying subsequent intestinal repair, we have examined the expression profiles of hepatocyte growth factor (HGF) and its receptor c-met, two molecules previously implicated in tissue repair, in comparison to the histopathological and proliferative changes in a rat model of methotrexate-induced small intestinal mucositis. Histological analysis of the intestinal specimens revealed crypt loss and villus atrophy with damage maximal on day 5 after methotrexate injection, and normalization of mucosal structure commencing on day 6. Crypt cell proliferation was decreased dramatically on day 3, normalized on day 4 and up-regulated on days 5 and 6. HGF and c-met protein/mRNA expression was up-regulated between days 4 and 7, with the mRNA co-localizing to the crypt and lower villus epithelium. Therefore, following methotrexate injection, a decrease in crypt cell proliferation preceded histological damage, and conversely, crypt cell hyperproliferation preceded mucosal regeneration. Up-regulation of HGF and c-met coincided with crypt hyperproliferation and mucosal recovery, suggesting a role for HGF in intestinal repair following acute injury. The crypt epithelial localization of HGF and c-met implies an autocrine or paracrine mechanism of HGF action. All these procedures were approved by the Animal Ethics Committee of the Women's and Children's Hospital, Adelaide, Australia. Histopathological analysis of intestinal damage and repairTransverse sections (4 µm in thickness) of paraffin-embedded proximal jejunal specimens were stained with haematoxylin and eosin (H&E) and examined with a light microscope. A semi-quantitative histological assessment of intestinal damage was utilized to obtain an overall score of damage severity. A total score for the sample was derived from the sum of scores for 11 histopathological criteria as we have previously described (Howarth et al, 1996), including villus fusion and stunting (atrophy), disruption of brush border and surface enterocytes, disappearance of goblet cells, reduction in numbers of mitotic figures, crypt loss/architectural disruption, disruption or distortion of crypt cells, crypt abscess formation, infiltration of polymorphonuclear cells and lymphocytes and dilatation of lymphatics and capillaries. For each criterion, a score was given to represent a mild (score 1), moderate (2), severe (3), or no (0) changes. Quantitative histological analyses were also conducted to measure the changes in crypt depth and villus height in the jejunal specimens over the time course. Microscopic images were acquired and analysed. For each animal, the height and depth of ten villi and crypts respectively were measured at three tissue levels, each separated by 100 µm, and means of the 30 measurements were calculated for each animal. Although histological damage prevented accurate measurements of villus and crypt lengths in some regions, in the jejunal ...

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Section: Discussionmentioning

confidence: 99%

Increased expression of HGF and c-met in rat small intestine during recovery from methotrexate-induced mucositis

et al. 2000

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“…We next investigated whether EGF-R transactivation upon activation of PARs is mediated by release of TGF-␣, the most abundant member of the EGF-R family ligands found in normal colon and colon carcinomas (18). We first analyzed the involvement of TGF-␣ by blocking its biological activity with neutralizing antibodies.…”

Section: Blockade Of the Egf-r Ligand Binding Domain Inhibits Par2-mementioning

confidence: 99%

“…Our present findings identifying EGF-R transactivation as a central signaling element for trypsin-mediated colon cancer cell proliferation suggest that EGF-R is a key therapeutic target in colon cancer, even for the trypsin-induced colon cancer proliferation. This is in line with several other observations supporting a central role of EGF-R in mediating colon cancer progression: (i) trypsin inhibitor induces a marked decrease of EGF-R tyrosine phosphorylation (61); (ii) ligands for two other GPCRs, the prostaglandin E 2 receptor (30) and the M3 muscarinic receptor (62), also lead to colon cancer cell proliferation via EGF-R transactivation; (iii) up-regulation of the EGF-Rs and their ligands is frequent in colorectal tumors (18,63); and (iv) inhibition of EGF-R signaling pathway impairs colon tumor cell proliferation (64,65).…”

Section: Par2 Transactivates Egf-r In Colon Cancermentioning

confidence: 99%

Protease-activated Receptor 2 in Colon Cancer

Darmoul

Gratio

Devaud

et al. 2004

Journal of Biological Chemistry

189

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Several lines of evidence suggest that tumor-derived trypsin contributes to the growth and invasion of cancer cells. We have recently shown that trypsin is a potent growth factor for colon cancer cells through activation of the G protein-coupled receptor protease-activated receptor 2 (PAR2). Here, we analyzed the signaling pathways downstream of PAR2 activation that lead to colon cancer cell proliferation in HT-29 cells. Our data are consistent with the following cascade of events upon activation of PAR2 by the serine protease trypsin or the specific PAR2-activating peptide (AP2): (i) a matrix metalloproteinasedependent release of transforming growth factor (TGF)-␣, as demonstrated with TGF-␣-blocking antibodies and measurement of TGF-␣ in culture medium; (ii) TGF-␣-mediated activation of epidermal growth factor receptor (EGF-R) and subsequent EGF-R phosphorylation; and (iii) activation of ERK1/2 and subsequent cell proliferation. The links between these events are demonstrated by the fact that stimulation of cell proliferation and ERK1/2 upon activation of PAR2 is reversed by the metalloproteinase inhibitor batimastat, TGF-␣-neutralizing antibodies, EGF-R ligand binding domain-blocking antibodies, and the EGF-R tyrosine kinase inhibitors AG1478 and PD168393. Therefore, transactivation of EGF-R appears to be a major mechanism whereby activation of PAR2 results in colon cancer cell growth. By using the Src tyrosine kinase inhibitor PP2, we further showed that Src plays a permissive role for PAR2-mediated ERK1/2 activation and cell proliferation, probably acting downstream of the EGF-R. These data explain how trypsin exerts robust trophic action on colon cancer cells and underline the critical role of EGF-R transactivation.Proteases have been increasingly recognized as important factors in pathophysiology of tumor diseases. Besides their contribution to cancer progression by the degradation of extracellular matrix proteins, there is now substantial evidence that certain proteases serve as signal molecules controlling cell functions through specific membrane receptors, the proteaseactivated receptors. PARs 1 are seven transmembrane-spanning domain G protein-coupled receptors comprising four receptors named PAR1, PAR2, PAR3, and PAR4 (1, 2). Thrombin is the physiological activator of PAR1, PAR3, and PAR4, whereas PAR2 is activated by multiple trypsin-like enzymes including trypsin and mast cell tryptase but not thrombin. The mechanism of activation of PARs was initially established for PAR1 (3) and seems to be a paradigm for the other PARs (1, 2, 4). They are irreversibly activated by a proteolytic mechanism in which the protease binds to and cleaves the amino-terminal exodomain of the receptor. This cleavage generates a new amino-terminal sequence that binds intramolecularly to the core receptor and serves as a tethered ligand. Synthetic activating peptides that mimic the tethered ligand domains of PAR1, PAR2, and PAR4 have been developed. The activation of PARs by these synthetic peptides APs is independent of rec...

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“…Thus, Cissus quadrangularis has potential usefulness for treatment of peptic ulcer disease. [30][31][32][33][34][35][36][37][38] …”

Section: Azima Tetracanthamentioning

confidence: 99%

Anti-ulcer activity of Medicinal Herbs - A Review

Anbarasan¹,

G²,

S³

et al. 2017

Int. J. Curr. Res. Chem. Pharm. Sci

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Peptic ulcer is a common disease of the Gastro Intestinal tract. Contrary to popular belief, ulcer is not caused by spicy food but instead is most commonly due to either an infection or long term use of medications. Standard treatment is a combination of d rugs including antibiotics and a proton pump inhibitors. However, many studies revealed that herbal medicines can effectively treat Peptic ulcer in humans and various animal models. In this review, attempts have been made to know about some plants which may be used in treatment or prevention of peptic ulcers. Utilising herbal medicines could be a valuable alternative to treat Pe ptic ulcer with fewer adverse effects.

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Epidermal growth factor-related peptides and their relevance to gastrointestinal pathophysiology

Cited by 305 publications

References 143 publications

Increased expression of HGF and c-met in rat small intestine during recovery from methotrexate-induced mucositis

Increased expression of HGF and c-met in rat small intestine during recovery from methotrexate-induced mucositis

Protease-activated Receptor 2 in Colon Cancer

Anti-ulcer activity of Medicinal Herbs - A Review

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