Limits...
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.


Related in: MedlinePlus

Phenotype of epidermal growth factor receptor (EGFR) inhibitor-treated pancreatic neuroendocrine tumorigenesis (PNET) tumors from RT2 mice. (A) Average percentage of dividing tumor cells (BrdU-positive) in vehicle- or erlotinib-treated mice following 1 week of treatment. (B-C) Representative micrographs of tumors from (B) vehicle- or (C) erlotinib-treated RT2 mice stained with an anti-BrdU antibody (200x). (D) Average percentage of apoptotic tumor cells (TdT-mediated dUTP-biotin nick end-labeling [TUNEL] positive) in tumors from vehicle- or erlotinib-treated mice following 1 week of treatment. (E-F) Representative micrographs of (E) vehicle- or (F) erlotinib-treated tumors stained with an anti-digoxigenin antibody following Tunel procedure (200x). (G) Average number of blood vessels per field (FITC-positive continuous segments) in vehicle- or erlotinib-treated mice following 1 week of treatment. (H-I) Representative micrographs of (H) vehicle- or (I) erlotinib-treated tumors that were collected following systemic perfusion with FITC-lectin to visualize the functional tumor vasculature (green); counterstaining with DAPI reveals the cellularity (blue) (200x). The panels are representative of 2 fields of tissue sections obtained from tumors in at least 4 treated RT2 mice. (N = number of independent tumors analyzed per treatment group). *P < 0.001. **P < 0.02.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC2958675&req=5

fig2-1947601909358722: Phenotype of epidermal growth factor receptor (EGFR) inhibitor-treated pancreatic neuroendocrine tumorigenesis (PNET) tumors from RT2 mice. (A) Average percentage of dividing tumor cells (BrdU-positive) in vehicle- or erlotinib-treated mice following 1 week of treatment. (B-C) Representative micrographs of tumors from (B) vehicle- or (C) erlotinib-treated RT2 mice stained with an anti-BrdU antibody (200x). (D) Average percentage of apoptotic tumor cells (TdT-mediated dUTP-biotin nick end-labeling [TUNEL] positive) in tumors from vehicle- or erlotinib-treated mice following 1 week of treatment. (E-F) Representative micrographs of (E) vehicle- or (F) erlotinib-treated tumors stained with an anti-digoxigenin antibody following Tunel procedure (200x). (G) Average number of blood vessels per field (FITC-positive continuous segments) in vehicle- or erlotinib-treated mice following 1 week of treatment. (H-I) Representative micrographs of (H) vehicle- or (I) erlotinib-treated tumors that were collected following systemic perfusion with FITC-lectin to visualize the functional tumor vasculature (green); counterstaining with DAPI reveals the cellularity (blue) (200x). The panels are representative of 2 fields of tissue sections obtained from tumors in at least 4 treated RT2 mice. (N = number of independent tumors analyzed per treatment group). *P < 0.001. **P < 0.02.

Mentions: To investigate the possibility that Egfr activation was involved in the pathobiology of these PNET tumors, we treated cohorts of RT2 mice with different EGFR inhibitors (gefitinib, CI-1033, erlotinib) for 3 to 4 weeks beginning at 11 to 12 weeks of age, a stage at which small adenoma are already present. Gefitinib and erlotinib are specific inhibitors of EGFR,26 whereas CI-1033, in addition to blocking EGFR, also inhibits the kinase activity of Erbb2 and Erbb4 (Erbb3 does not possess intrinsic kinase activity).27 All treated cohorts of RT2 mice displayed a striking 50% to 60% decrease in tumor burden (average total tumor volume per mouse) compared to vehicle-treated cohorts (Figs. 1 D-F). The growth of these tumors was not halted but was significantly slowed upon EGFR inhibitor treatment, as shown in Figure 1F (compare vehicle treated at week 12 to erlotinib treated at week 16). Moreover, we found that treating 6-week-old RT2 mice with EGFR inhibitors (erlotinib or CI-1033) for 3 weeks resulted in a ~30% decrease in the number of islets undergoing angiogenic switching (Fig. 1G), indicating that Egfr activity also contributes to this pathological transition. A detailed phenotypic analysis revealed that treated tumors displayed no decrease in tumor cell proliferation (assayed by BrdU incorporation) as compared to vehicle-treated tumors (Figs. 2 A-C) but had a markedly elevated apoptotic index (assayed by TdT-mediated dUTP-biotin nick end-labeling [TUNEL] staining) (Figs. 2 D-F) and significantly decreased vascular density (assayed by counting FITC-lectin perfused vessels) (Figs. 2 G-I).


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)

Phenotype of epidermal growth factor receptor (EGFR) inhibitor-treated pancreatic neuroendocrine tumorigenesis (PNET) tumors from RT2 mice. (A) Average percentage of dividing tumor cells (BrdU-positive) in vehicle- or erlotinib-treated mice following 1 week of treatment. (B-C) Representative micrographs of tumors from (B) vehicle- or (C) erlotinib-treated RT2 mice stained with an anti-BrdU antibody (200x). (D) Average percentage of apoptotic tumor cells (TdT-mediated dUTP-biotin nick end-labeling [TUNEL] positive) in tumors from vehicle- or erlotinib-treated mice following 1 week of treatment. (E-F) Representative micrographs of (E) vehicle- or (F) erlotinib-treated tumors stained with an anti-digoxigenin antibody following Tunel procedure (200x). (G) Average number of blood vessels per field (FITC-positive continuous segments) in vehicle- or erlotinib-treated mice following 1 week of treatment. (H-I) Representative micrographs of (H) vehicle- or (I) erlotinib-treated tumors that were collected following systemic perfusion with FITC-lectin to visualize the functional tumor vasculature (green); counterstaining with DAPI reveals the cellularity (blue) (200x). The panels are representative of 2 fields of tissue sections obtained from tumors in at least 4 treated RT2 mice. (N = number of independent tumors analyzed per treatment group). *P < 0.001. **P < 0.02.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2958675&req=5

fig2-1947601909358722: Phenotype of epidermal growth factor receptor (EGFR) inhibitor-treated pancreatic neuroendocrine tumorigenesis (PNET) tumors from RT2 mice. (A) Average percentage of dividing tumor cells (BrdU-positive) in vehicle- or erlotinib-treated mice following 1 week of treatment. (B-C) Representative micrographs of tumors from (B) vehicle- or (C) erlotinib-treated RT2 mice stained with an anti-BrdU antibody (200x). (D) Average percentage of apoptotic tumor cells (TdT-mediated dUTP-biotin nick end-labeling [TUNEL] positive) in tumors from vehicle- or erlotinib-treated mice following 1 week of treatment. (E-F) Representative micrographs of (E) vehicle- or (F) erlotinib-treated tumors stained with an anti-digoxigenin antibody following Tunel procedure (200x). (G) Average number of blood vessels per field (FITC-positive continuous segments) in vehicle- or erlotinib-treated mice following 1 week of treatment. (H-I) Representative micrographs of (H) vehicle- or (I) erlotinib-treated tumors that were collected following systemic perfusion with FITC-lectin to visualize the functional tumor vasculature (green); counterstaining with DAPI reveals the cellularity (blue) (200x). The panels are representative of 2 fields of tissue sections obtained from tumors in at least 4 treated RT2 mice. (N = number of independent tumors analyzed per treatment group). *P < 0.001. **P < 0.02.
Mentions: To investigate the possibility that Egfr activation was involved in the pathobiology of these PNET tumors, we treated cohorts of RT2 mice with different EGFR inhibitors (gefitinib, CI-1033, erlotinib) for 3 to 4 weeks beginning at 11 to 12 weeks of age, a stage at which small adenoma are already present. Gefitinib and erlotinib are specific inhibitors of EGFR,26 whereas CI-1033, in addition to blocking EGFR, also inhibits the kinase activity of Erbb2 and Erbb4 (Erbb3 does not possess intrinsic kinase activity).27 All treated cohorts of RT2 mice displayed a striking 50% to 60% decrease in tumor burden (average total tumor volume per mouse) compared to vehicle-treated cohorts (Figs. 1 D-F). The growth of these tumors was not halted but was significantly slowed upon EGFR inhibitor treatment, as shown in Figure 1F (compare vehicle treated at week 12 to erlotinib treated at week 16). Moreover, we found that treating 6-week-old RT2 mice with EGFR inhibitors (erlotinib or CI-1033) for 3 weeks resulted in a ~30% decrease in the number of islets undergoing angiogenic switching (Fig. 1G), indicating that Egfr activity also contributes to this pathological transition. A detailed phenotypic analysis revealed that treated tumors displayed no decrease in tumor cell proliferation (assayed by BrdU incorporation) as compared to vehicle-treated tumors (Figs. 2 A-C) but had a markedly elevated apoptotic index (assayed by TdT-mediated dUTP-biotin nick end-labeling [TUNEL] staining) (Figs. 2 D-F) and significantly decreased vascular density (assayed by counting FITC-lectin perfused vessels) (Figs. 2 G-I).

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