Reciprocal epithelial-mesenchymal FGF signaling is required for cecal development

Zhang, Xiuqin; Stappenbeck, Thaddeus S.; White, Andrew C.; Lavine, Kory J.; Gordon, Jeffrey I.; Ornitz, David M.

doi:10.1242/dev.02175

Cited by 72 publications

(73 citation statements)

References 51 publications

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“…Although the gastric and colonic ICC hyperplasia is more extensive in Kit V558Δ;T669I/+ mice, suggesting that the double-mutant Kit receptor is a stronger oncogene, the GIST lesions in the cecum were significantly smaller, and the cecum appeared to be severely truncated. We speculate that the reduced size of the cecum may result from a secondary effect of ICC progenitors expressing the KIT V558Δ;T669I mutation on embryonic cecum development at the time of budding of the cecal pouch (26). It is of interest that the KIT T670I mutation is found only in imatinib-resistant GIST patients in combination with a primary KIT mutation.…”

Section: Discussionmentioning

confidence: 95%

Imatinib resistance and microcytic erythrocytosis in a Kit ^{V558Δ;T669I/+} gatekeeper-mutant mouse model of gastrointestinal stromal tumor

Bosbach

Deshpande

Rossi

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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Most gastrointestinal stromal tumors (GISTs) harbor a gain-offunction mutation in the Kit receptor. GIST patients treated with the tyrosine kinase inhibitor imatinib frequently develop imatinib resistance as a result of second-site Kit mutations. To investigate the consequences of second-site Kit mutations on GIST development and imatinib sensitivity, we engineered a mouse model carrying in the endogenous Kit locus both the Kit V558Δ mutation found in a familial case of GIST and the Kit T669I (human KIT T670I ) "gatekeeper" mutation found in imatinib-resistant GIST patients. Similar to Kit V558Δ/+ mice, Kit V558Δ;T669I/+ mice developed gastric and colonic interstitial cell of Cajal hyperplasia as well as cecal GIST. In contrast to the single-mutant Kit V558Δ/+ control mice, treatment of the Kit V558Δ;T669I/+ mice with either imatinib or dasatinib failed to inhibit oncogenic Kit signaling and GIST growth. However, this resistance could be overcome by treatment of Kit V558Δ;T669I/+ mice with sunitinib or sorafenib. Although tumor lesions were smaller in Kit V558Δ;T669I/+ mice than in single-mutant mice, both interstitial cell of Cajal hyperplasia and mast cell hyperplasia were exacerbated in Kit V558Δ;T669I/+ mice. Strikingly, the Kit V558Δ;T669I/+ mice developed a pronounced polycythemia vera-like erythrocytosis in conjunction with microcytosis. This mouse model should be useful for preclinical studies of drug candidates designed to overcome imatinib resistance in GIST and to investigate the consequences of oncogenic KIT signaling in hematopoietic as well as other cell lineages.soft tissue sarcoma | hematopoiesis | erythropoiesis | drug resistance

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Section: Discussionmentioning

confidence: 95%

Imatinib resistance and microcytic erythrocytosis in a Kit ^{V558Δ;T669I/+} gatekeeper-mutant mouse model of gastrointestinal stromal tumor

Bosbach

Deshpande

Rossi

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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“…60 Differential sensitivity to Hh signaling during fetal and adult tissue growth is not unprecedented. Indeed, in several other tissues that are not known to be major developmental Hh targets (eg, breast, prostate, and colon), 36,61,62 the Hh pathway regulates tissue remodeling in response to demands imposed by metabolic and/or inflammatory stresses during adult life. 63 During chronic cholestatic liver injury induced by BDL, myofibroblastic HSC join portal fibroblasts that accumulate in the fibrous stroma near proliferating bile ductular cells.…”

Section: Discussionmentioning

confidence: 99%

Hedgehog-mediated mesenchymal–epithelial interactions modulate hepatic response to bile duct ligation

Omenetti

Yang

et al. 2007

Laboratory Investigation

165

227

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In bile duct-ligated (BDL) rodents, as in humans with chronic cholangiopathies, biliary obstruction triggers proliferation of bile ductular cells that are surrounded by fibrosis produced by adjacent myofibroblastic cells in the hepatic mesenchyme. The proximity of the myofibroblasts and cholangiocytes suggests that mesenchymal-epithelial crosstalk promotes the fibroproliferative response to cholestatic liver injury. Studying BDL mice, we found that bile duct obstruction induces activity of the Hedgehog (Hh) pathway, a system that regulates the viability and differentiation of various progenitors during embryogenesis. After BDL, many bile ductular cells and fibroblastic-appearing cells in the portal stroma express Hh ligands, receptor and/or target genes. Transwell cocultures of an immature cholangiocyte line that expresses the Hh receptor, Patched (Ptc), with liver myofibroblastic cells demonstrated that both cell types produced Hh ligands that enhanced each other's viability and proliferation. Further support for the concept that Hh signaling modulates the response to BDL was generated by studying PtcLacZ mice, which have an impaired ability to constrain Hh signaling due to a heterozygous deficiency of Ptc. After BDL, PtcLacZ mice upregulated fibrosis gene expression earlier than wild-type controls and manifested an unusually intense ductular reaction, more expanded fibrotic portal areas, and a greater number of lobular necrotic foci. Our findings reveal that adult livers resurrect developmental signaling systems, such as the Hh pathway, to guide remodeling of the biliary epithelia and stroma after cholestatic injury.

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“…37 and 43). FGFs are known to play important roles in the morphogenesis and expansion of developing structures, including the lung (44,45), limb (46), intestine (35,38,47), epidermis (48), and nervous system (49).…”

Section: Discussionmentioning

confidence: 99%

Growth Factor Regulation of Prostaglandin-Endoperoxide Synthase 2 (Ptgs2) Expression in Colonic Mesenchymal Stem Cells

Walker

Brown

Riehl

et al. 2010

Journal of Biological Chemistry

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We previously found that a population of colonic stromal cells that constitutively express high levels of prostaglandin-endoperoxide synthase 2 (Ptgs2, also known as Cox-2) altered their location in the lamina propria in response to injury in a Myd88-dependent manner (Brown, S. L., Riehl, T. E., Walker, M. R., Geske, M. J., Doherty, J. M., Stenson, W. F., and Stappenbeck, T. S. (2007) J. Clin. Invest. 117, 258 -269). At the time of this study, the identity of these cells and the mechanism by which they expressed high levels of Ptgs2 were unknown. Here we found that these colonic stromal cells were mesenchymal stem cells (MSCs). These colonic MSCs expressed high Ptgs2 levels not through interaction with bacterial products but instead as a consequence of mRNA stabilization downstream of Fgf9 (fibroblast growth factor 9), a growth factor that is constitutively expressed by the intestinal epithelium. This stabilization was mediated partially through a mechanism involving endogenous CUG-binding protein 2 (CUGbp2). These studies suggest that Fgf9 is an important factor in the regulation of Ptgs2 in colonic MSCs and may be a factor involved in its constitutive expression in vivo.

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Reciprocal epithelial-mesenchymal FGF signaling is required for cecal development

Cited by 72 publications

References 51 publications

Imatinib resistance and microcytic erythrocytosis in a Kit ^{V558Δ;T669I/+} gatekeeper-mutant mouse model of gastrointestinal stromal tumor

Imatinib resistance and microcytic erythrocytosis in a Kit ^{V558Δ;T669I/+} gatekeeper-mutant mouse model of gastrointestinal stromal tumor

Hedgehog-mediated mesenchymal–epithelial interactions modulate hepatic response to bile duct ligation

Growth Factor Regulation of Prostaglandin-Endoperoxide Synthase 2 (Ptgs2) Expression in Colonic Mesenchymal Stem Cells

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Reciprocal epithelial-mesenchymal FGF signaling is required for cecal development

Cited by 72 publications

References 51 publications

Imatinib resistance and microcytic erythrocytosis in a Kit V558Δ;T669I/+ gatekeeper-mutant mouse model of gastrointestinal stromal tumor

Imatinib resistance and microcytic erythrocytosis in a Kit V558Δ;T669I/+ gatekeeper-mutant mouse model of gastrointestinal stromal tumor

Hedgehog-mediated mesenchymal–epithelial interactions modulate hepatic response to bile duct ligation

Growth Factor Regulation of Prostaglandin-Endoperoxide Synthase 2 (Ptgs2) Expression in Colonic Mesenchymal Stem Cells

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Imatinib resistance and microcytic erythrocytosis in a Kit ^{V558Δ;T669I/+} gatekeeper-mutant mouse model of gastrointestinal stromal tumor

Imatinib resistance and microcytic erythrocytosis in a Kit ^{V558Δ;T669I/+} gatekeeper-mutant mouse model of gastrointestinal stromal tumor