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Antitumor effects and molecular mechanisms of figitumumab, a humanized monoclonal antibody to IGF-1 receptor, in esophageal carcinoma.

Zhang T, Shen H, Dong W, Qu X, Liu Q, Du J - Sci Rep (2014)

Bottom Line: Our results showed that CP not only inhibited IGF-1 induced receptor autophosphorylation and downstream signaling, but also triggered β-arrestin1 and G protein-coupled receptor kinases (GRKs) mediated ERK1/2 activation, indicating CP as a biased agonist for IGF-1R.Inhibition of ERK1/2 enhanced the antitumor activity of CP.Furthermore, CP was a more powerful agonist for IGF-1R down-regulation than IGF-1, and dysregulation of β-arrestin1 and GRKs affected this down-regulation.

View Article: PubMed Central - PubMed

Affiliation: Institute of Oncology, Shandong Provincial Hospital Affiliated to Shandong University, Shandong University, Jinan, P.R. China.

ABSTRACT
The insulin-like growth factor type 1 receptor (IGF-1R) plays an essential role in the development of numerous cancers. Figitumumab (CP) is not only a monoclonal antibody, it also has agonist activity on IGF-1R. The antitumor activity of CP in esophageal squamous cell carcinoma (ESCC) is still unclear. In our study, we identified IGF-1R as an independent prognostic factor in ESCC patients, and investigated the antitumor effects of CP in ESCC cell lines. CP suppressed tumor growth and sensitized cells to chemotherapeutic drugs. In addition, CP inhibited cell proliferation, migration, colony forming activity and anti-apoptosis induced by IGF-1. Our results showed that CP not only inhibited IGF-1 induced receptor autophosphorylation and downstream signaling, but also triggered β-arrestin1 and G protein-coupled receptor kinases (GRKs) mediated ERK1/2 activation, indicating CP as a biased agonist for IGF-1R. Inhibition of ERK1/2 enhanced the antitumor activity of CP. Furthermore, CP was a more powerful agonist for IGF-1R down-regulation than IGF-1, and dysregulation of β-arrestin1 and GRKs affected this down-regulation. Thus, we demonstrated antitumor activities of CP on ESCC, and as a biased agonist, CP induced ERK1/2 activation and receptor down-regulation required β-arrestin1 and GRKs, suggesting a promising role for targeting IGF-1R in ESCC.

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Related in: MedlinePlus

Immunohistochemistry in resected human ESCC tumors.(a) Negative expression of IGF-1R (original magnification x400). (b) Weak cytoplasmic and membranous expression of IGF-1R in ESCC cells (x400). (c) Moderate and mainly membranous expression of IGF-1R in ESCC cells (x400). (d) Strong membranous expression of IGF-1R in ESCC cells (x400). Kaplan–Meier life-table analyses of the overall survival (OS) rate according to four categories (e) and two categories (f) of IGF-1R expression levels (P<0.000 and 0.000 respectively).
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f1: Immunohistochemistry in resected human ESCC tumors.(a) Negative expression of IGF-1R (original magnification x400). (b) Weak cytoplasmic and membranous expression of IGF-1R in ESCC cells (x400). (c) Moderate and mainly membranous expression of IGF-1R in ESCC cells (x400). (d) Strong membranous expression of IGF-1R in ESCC cells (x400). Kaplan–Meier life-table analyses of the overall survival (OS) rate according to four categories (e) and two categories (f) of IGF-1R expression levels (P<0.000 and 0.000 respectively).

Mentions: First, the expression of IGF-1R was determined in paraffin embedded ESCC tissues using immunohistochemical staining. 110 completely resected specimens from ESCC patients were obtained, whom of which, did not receive any preoperative chemoradiation therapies. There were 93 male and 17 female patients, whereby the mean age was 58.22 years. 25s of those patients did not exhibit expression of IGF-1R, whereas, 21 showed weak expression and, 48 showed moderate expression of IGF-1R. The remaining 16 patients exhibited strong expression of IGF-1R (Shown in Figures 1a, 1b, 1c and 1d). The patients were then classified into two groups; as low (including negative and weak expression of IGF-1R) and high (moderate and strong expression of IGF-1R included) expression groups for further analysis. The basic demographics of the patients stratified by IGF-1R expression are shown in Table 1. Expression of IGF-1R correlated with gender (P = 0.002), and no other correlations were found. The mean overall survival of low IGF-1R expression group was 46.46 ± 20.046 months compared with 30.89 ± 18.750 months of the high expression group. Clear distinctions were observed from the Kaplan-Meier survival curves in both of the four and two categories of IGF-1R expression (Shown in Figure 1e and 1f), and the P values were less than 0.001 for both. In multivariate Cox analysis for the patients' overall survival, IGF-1R expression together with lymph node metastasis and cell differentiation were independent and significant prognostic factors (Table 2).


Antitumor effects and molecular mechanisms of figitumumab, a humanized monoclonal antibody to IGF-1 receptor, in esophageal carcinoma.

Zhang T, Shen H, Dong W, Qu X, Liu Q, Du J - Sci Rep (2014)

Immunohistochemistry in resected human ESCC tumors.(a) Negative expression of IGF-1R (original magnification x400). (b) Weak cytoplasmic and membranous expression of IGF-1R in ESCC cells (x400). (c) Moderate and mainly membranous expression of IGF-1R in ESCC cells (x400). (d) Strong membranous expression of IGF-1R in ESCC cells (x400). Kaplan–Meier life-table analyses of the overall survival (OS) rate according to four categories (e) and two categories (f) of IGF-1R expression levels (P<0.000 and 0.000 respectively).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4215295&req=5

f1: Immunohistochemistry in resected human ESCC tumors.(a) Negative expression of IGF-1R (original magnification x400). (b) Weak cytoplasmic and membranous expression of IGF-1R in ESCC cells (x400). (c) Moderate and mainly membranous expression of IGF-1R in ESCC cells (x400). (d) Strong membranous expression of IGF-1R in ESCC cells (x400). Kaplan–Meier life-table analyses of the overall survival (OS) rate according to four categories (e) and two categories (f) of IGF-1R expression levels (P<0.000 and 0.000 respectively).
Mentions: First, the expression of IGF-1R was determined in paraffin embedded ESCC tissues using immunohistochemical staining. 110 completely resected specimens from ESCC patients were obtained, whom of which, did not receive any preoperative chemoradiation therapies. There were 93 male and 17 female patients, whereby the mean age was 58.22 years. 25s of those patients did not exhibit expression of IGF-1R, whereas, 21 showed weak expression and, 48 showed moderate expression of IGF-1R. The remaining 16 patients exhibited strong expression of IGF-1R (Shown in Figures 1a, 1b, 1c and 1d). The patients were then classified into two groups; as low (including negative and weak expression of IGF-1R) and high (moderate and strong expression of IGF-1R included) expression groups for further analysis. The basic demographics of the patients stratified by IGF-1R expression are shown in Table 1. Expression of IGF-1R correlated with gender (P = 0.002), and no other correlations were found. The mean overall survival of low IGF-1R expression group was 46.46 ± 20.046 months compared with 30.89 ± 18.750 months of the high expression group. Clear distinctions were observed from the Kaplan-Meier survival curves in both of the four and two categories of IGF-1R expression (Shown in Figure 1e and 1f), and the P values were less than 0.001 for both. In multivariate Cox analysis for the patients' overall survival, IGF-1R expression together with lymph node metastasis and cell differentiation were independent and significant prognostic factors (Table 2).

Bottom Line: Our results showed that CP not only inhibited IGF-1 induced receptor autophosphorylation and downstream signaling, but also triggered β-arrestin1 and G protein-coupled receptor kinases (GRKs) mediated ERK1/2 activation, indicating CP as a biased agonist for IGF-1R.Inhibition of ERK1/2 enhanced the antitumor activity of CP.Furthermore, CP was a more powerful agonist for IGF-1R down-regulation than IGF-1, and dysregulation of β-arrestin1 and GRKs affected this down-regulation.

View Article: PubMed Central - PubMed

Affiliation: Institute of Oncology, Shandong Provincial Hospital Affiliated to Shandong University, Shandong University, Jinan, P.R. China.

ABSTRACT
The insulin-like growth factor type 1 receptor (IGF-1R) plays an essential role in the development of numerous cancers. Figitumumab (CP) is not only a monoclonal antibody, it also has agonist activity on IGF-1R. The antitumor activity of CP in esophageal squamous cell carcinoma (ESCC) is still unclear. In our study, we identified IGF-1R as an independent prognostic factor in ESCC patients, and investigated the antitumor effects of CP in ESCC cell lines. CP suppressed tumor growth and sensitized cells to chemotherapeutic drugs. In addition, CP inhibited cell proliferation, migration, colony forming activity and anti-apoptosis induced by IGF-1. Our results showed that CP not only inhibited IGF-1 induced receptor autophosphorylation and downstream signaling, but also triggered β-arrestin1 and G protein-coupled receptor kinases (GRKs) mediated ERK1/2 activation, indicating CP as a biased agonist for IGF-1R. Inhibition of ERK1/2 enhanced the antitumor activity of CP. Furthermore, CP was a more powerful agonist for IGF-1R down-regulation than IGF-1, and dysregulation of β-arrestin1 and GRKs affected this down-regulation. Thus, we demonstrated antitumor activities of CP on ESCC, and as a biased agonist, CP induced ERK1/2 activation and receptor down-regulation required β-arrestin1 and GRKs, suggesting a promising role for targeting IGF-1R in ESCC.

Show MeSH
Related in: MedlinePlus