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Differential contribution to neuroendocrine tumorigenesis of parallel egfr signaling in cancer cells and pericytes.

Nolan-Stevaux O, Truitt MC, Pahler JC, Olson P, Guinto C, Lee DC, Hanahan D - Genes Cancer (2010)

Bottom Line: Factors associated with tumor sensitivity to epidermal growth factor receptor (EGFR) inhibitors in the context of wild-type EGFR remain elusive.Upon treatment of RT2 mice with EGFR inhibitors, PNET tumors harboring wild-type, nonamplified alleles of Egfr grow at a markedly reduced rate and display a significant increase in tumor cell apoptosis, as well as reduced neovascularization.The authors identify Tgf-α and Hb-egf as key limiting mediators of separable pathological functions of Egfr in neuroendocrine tumor progression: Tgf-α mutant tumors present with an elevated apoptotic index, whereas Hb-egf mutant lesions exhibit decreased angiogenic switching and neovascularization.

View Article: PubMed Central - PubMed

Affiliation: Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA, USA.

ABSTRACT
Factors associated with tumor sensitivity to epidermal growth factor receptor (EGFR) inhibitors in the context of wild-type EGFR remain elusive. This study investigates the mechanistic basis of responsiveness to EGFR inhibitors in the RIP1-Tag2 (RT2) mouse model of pancreatic neuroendocrine tumorigenesis (PNET). Upon treatment of RT2 mice with EGFR inhibitors, PNET tumors harboring wild-type, nonamplified alleles of Egfr grow at a markedly reduced rate and display a significant increase in tumor cell apoptosis, as well as reduced neovascularization. The authors identify Tgf-α and Hb-egf as key limiting mediators of separable pathological functions of Egfr in neuroendocrine tumor progression: Tgf-α mutant tumors present with an elevated apoptotic index, whereas Hb-egf mutant lesions exhibit decreased angiogenic switching and neovascularization. This study not only associates Tgf-α and Hb-egf expression with wild-type Egfr oncogenicity but also ascribes the proangiogenic activity of Egfr in this tumor model to a novel mesenchymal Hb-egf/Egfr signaling axis, whereby endothelial and pericyte-derived Hb-egf activates Egfr specifically in tumor-associated perivascular cells, leading to increased pericyte coverage of the tumor endothelium and enhanced angiogenesis.

No MeSH data available.


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Mesenchymal-derived Hb-egf activates Egfr inside tumor pericytes. (A-B) Co-staining of Hb-egf staining (red) and Meca-32 (endothelial cell marker; green) by confocal microscopy (2,520x) reveals both cancer cell expression (red) and endothelial cell co-localization (yellow) of Hb-egf. (C) Schematic description of the orthotopic transplant experiment aimed at assessing the contribution of mesenchymal-derived Hb-egf to the angiogenic phenotype of pancreatic neuroendocrine tumorigenesis (PNET) tumors. (D) Comparison of pericyte coverage of the tumor neovasculature in wild-type (wt) versus Hb-egf mutant (Hb−/−) hosts. **P < 0.0005. (Number of tumors analyzed for each host genotype: Nwt = 11, NHb = 12.) (E-F) Representative staining of tumors for nuclei (DAPI; blue), NG2 (pericyte marker; red), and pEgfr (green) illustrating that the readily detectable pEgfr signal localized to pericytes in wild-type hosts (white arrows) (E) disappears in Hb-egf mutant hosts (F). pEgfr can be detected in cancer cells but at many-fold lower levels than in perivascular cells (see Supplementary Fig. S4). Micrographs are representative of 2 fields of 12 and 11 tumors obtained from wt or Hb-egf mutant hosts, respectively.
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fig8-1947601909358722: Mesenchymal-derived Hb-egf activates Egfr inside tumor pericytes. (A-B) Co-staining of Hb-egf staining (red) and Meca-32 (endothelial cell marker; green) by confocal microscopy (2,520x) reveals both cancer cell expression (red) and endothelial cell co-localization (yellow) of Hb-egf. (C) Schematic description of the orthotopic transplant experiment aimed at assessing the contribution of mesenchymal-derived Hb-egf to the angiogenic phenotype of pancreatic neuroendocrine tumorigenesis (PNET) tumors. (D) Comparison of pericyte coverage of the tumor neovasculature in wild-type (wt) versus Hb-egf mutant (Hb−/−) hosts. **P < 0.0005. (Number of tumors analyzed for each host genotype: Nwt = 11, NHb = 12.) (E-F) Representative staining of tumors for nuclei (DAPI; blue), NG2 (pericyte marker; red), and pEgfr (green) illustrating that the readily detectable pEgfr signal localized to pericytes in wild-type hosts (white arrows) (E) disappears in Hb-egf mutant hosts (F). pEgfr can be detected in cancer cells but at many-fold lower levels than in perivascular cells (see Supplementary Fig. S4). Micrographs are representative of 2 fields of 12 and 11 tumors obtained from wt or Hb-egf mutant hosts, respectively.

Mentions: Given that Hb-egf is expressed in tumor cells as well as in tumor endothelial cells (Figs. 8 A and B) and pericytes (Fig. 6A), we sought to establish which reservoir of Hb-egf was responsible for mediating the proangiogenic activity of Egfr. To this end, we obtained an Hb-egf cancer cell line from an Hb-egf mutant RT2-derived tumor and implanted it orthotopically in the pancreas of 8 syngeneic wild-type mice or 8 Hb-egf mutant mice (see schematic in Fig. 8C). This Hb-egf mutant cell line produced tumors in both genetic backgrounds, but the pericyte coverage of the tumor neovasculature was decreased by ~24% in tumors recovered from Hb-egf mutant hosts compared to tumors recovered from wild-type hosts (Fig. 8D). The vascular density of tumors grown in the Hb-egf mutant hosts was also decreased by ~20% compared to tumors grown in wild-type hosts (data not shown). Moreover, perivascular Egfr phosphorylation, while less prominent in the orthotopically transplanted tumors than in spontaneous tumors arising in RT2 mice, was nonetheless almost entirely eliminated in orthotopic tumors grown in Hb-egf mutant hosts (Figs. 8 E and F).


Differential contribution to neuroendocrine tumorigenesis of parallel egfr signaling in cancer cells and pericytes.

Nolan-Stevaux O, Truitt MC, Pahler JC, Olson P, Guinto C, Lee DC, Hanahan D - Genes Cancer (2010)

Mesenchymal-derived Hb-egf activates Egfr inside tumor pericytes. (A-B) Co-staining of Hb-egf staining (red) and Meca-32 (endothelial cell marker; green) by confocal microscopy (2,520x) reveals both cancer cell expression (red) and endothelial cell co-localization (yellow) of Hb-egf. (C) Schematic description of the orthotopic transplant experiment aimed at assessing the contribution of mesenchymal-derived Hb-egf to the angiogenic phenotype of pancreatic neuroendocrine tumorigenesis (PNET) tumors. (D) Comparison of pericyte coverage of the tumor neovasculature in wild-type (wt) versus Hb-egf mutant (Hb−/−) hosts. **P < 0.0005. (Number of tumors analyzed for each host genotype: Nwt = 11, NHb = 12.) (E-F) Representative staining of tumors for nuclei (DAPI; blue), NG2 (pericyte marker; red), and pEgfr (green) illustrating that the readily detectable pEgfr signal localized to pericytes in wild-type hosts (white arrows) (E) disappears in Hb-egf mutant hosts (F). pEgfr can be detected in cancer cells but at many-fold lower levels than in perivascular cells (see Supplementary Fig. S4). Micrographs are representative of 2 fields of 12 and 11 tumors obtained from wt or Hb-egf mutant hosts, respectively.
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Related In: Results  -  Collection

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fig8-1947601909358722: Mesenchymal-derived Hb-egf activates Egfr inside tumor pericytes. (A-B) Co-staining of Hb-egf staining (red) and Meca-32 (endothelial cell marker; green) by confocal microscopy (2,520x) reveals both cancer cell expression (red) and endothelial cell co-localization (yellow) of Hb-egf. (C) Schematic description of the orthotopic transplant experiment aimed at assessing the contribution of mesenchymal-derived Hb-egf to the angiogenic phenotype of pancreatic neuroendocrine tumorigenesis (PNET) tumors. (D) Comparison of pericyte coverage of the tumor neovasculature in wild-type (wt) versus Hb-egf mutant (Hb−/−) hosts. **P < 0.0005. (Number of tumors analyzed for each host genotype: Nwt = 11, NHb = 12.) (E-F) Representative staining of tumors for nuclei (DAPI; blue), NG2 (pericyte marker; red), and pEgfr (green) illustrating that the readily detectable pEgfr signal localized to pericytes in wild-type hosts (white arrows) (E) disappears in Hb-egf mutant hosts (F). pEgfr can be detected in cancer cells but at many-fold lower levels than in perivascular cells (see Supplementary Fig. S4). Micrographs are representative of 2 fields of 12 and 11 tumors obtained from wt or Hb-egf mutant hosts, respectively.
Mentions: Given that Hb-egf is expressed in tumor cells as well as in tumor endothelial cells (Figs. 8 A and B) and pericytes (Fig. 6A), we sought to establish which reservoir of Hb-egf was responsible for mediating the proangiogenic activity of Egfr. To this end, we obtained an Hb-egf cancer cell line from an Hb-egf mutant RT2-derived tumor and implanted it orthotopically in the pancreas of 8 syngeneic wild-type mice or 8 Hb-egf mutant mice (see schematic in Fig. 8C). This Hb-egf mutant cell line produced tumors in both genetic backgrounds, but the pericyte coverage of the tumor neovasculature was decreased by ~24% in tumors recovered from Hb-egf mutant hosts compared to tumors recovered from wild-type hosts (Fig. 8D). The vascular density of tumors grown in the Hb-egf mutant hosts was also decreased by ~20% compared to tumors grown in wild-type hosts (data not shown). Moreover, perivascular Egfr phosphorylation, while less prominent in the orthotopically transplanted tumors than in spontaneous tumors arising in RT2 mice, was nonetheless almost entirely eliminated in orthotopic tumors grown in Hb-egf mutant hosts (Figs. 8 E and F).

Bottom Line: Factors associated with tumor sensitivity to epidermal growth factor receptor (EGFR) inhibitors in the context of wild-type EGFR remain elusive.Upon treatment of RT2 mice with EGFR inhibitors, PNET tumors harboring wild-type, nonamplified alleles of Egfr grow at a markedly reduced rate and display a significant increase in tumor cell apoptosis, as well as reduced neovascularization.The authors identify Tgf-α and Hb-egf as key limiting mediators of separable pathological functions of Egfr in neuroendocrine tumor progression: Tgf-α mutant tumors present with an elevated apoptotic index, whereas Hb-egf mutant lesions exhibit decreased angiogenic switching and neovascularization.

View Article: PubMed Central - PubMed

Affiliation: Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA, USA.

ABSTRACT
Factors associated with tumor sensitivity to epidermal growth factor receptor (EGFR) inhibitors in the context of wild-type EGFR remain elusive. This study investigates the mechanistic basis of responsiveness to EGFR inhibitors in the RIP1-Tag2 (RT2) mouse model of pancreatic neuroendocrine tumorigenesis (PNET). Upon treatment of RT2 mice with EGFR inhibitors, PNET tumors harboring wild-type, nonamplified alleles of Egfr grow at a markedly reduced rate and display a significant increase in tumor cell apoptosis, as well as reduced neovascularization. The authors identify Tgf-α and Hb-egf as key limiting mediators of separable pathological functions of Egfr in neuroendocrine tumor progression: Tgf-α mutant tumors present with an elevated apoptotic index, whereas Hb-egf mutant lesions exhibit decreased angiogenic switching and neovascularization. This study not only associates Tgf-α and Hb-egf expression with wild-type Egfr oncogenicity but also ascribes the proangiogenic activity of Egfr in this tumor model to a novel mesenchymal Hb-egf/Egfr signaling axis, whereby endothelial and pericyte-derived Hb-egf activates Egfr specifically in tumor-associated perivascular cells, leading to increased pericyte coverage of the tumor endothelium and enhanced angiogenesis.

No MeSH data available.


Related in: MedlinePlus