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Pathobiological implications of the expression of EGFR, pAkt, NF-κB and MIC-1 in prostate cancer stem cells and their progenies.

Mimeault M, Johansson SL, Batra SK - PLoS ONE (2012)

Bottom Line: The progression of prostate cancers (PCs) to locally invasive, androgen-independent and metastatic disease states is generally associated with treatment resistance and disease relapse.Moreover, the results have indicated that the EGF-EGFR signaling pathway can provide critical functions for the self-renewal of side population (SP) cells endowed with stem cell-like features from highly invasive WPE1-NB26 cells.Also, the targeting of these oncogenic products induced the caspase-dependent apoptosis in chemoresistant SP WPE1-NB26 cells and enhanced their sensibility to the cytotoxic effects induced by docetaxel.

View Article: PubMed Central - PubMed

Affiliation: Department of Biochemistry and Molecular Biology, College of Medicine, University of Nebraska Medical Center, Omaha, Nebraska, United States of America.

ABSTRACT
The progression of prostate cancers (PCs) to locally invasive, androgen-independent and metastatic disease states is generally associated with treatment resistance and disease relapse. The present study was undertaken to establish the possibility of using a combination of specific oncogenic products, including epidermal growth factor receptor (EGFR), pAkt, nuclear factor-kappaB (NF-κB) and macrophage inhibitory cytokine-1 (MIC-1) as biomarkers and therapeutic targets for optimizing the management of patients with localized PC at earlier disease stages. The immunohistochemical and immunofluorescence data have revealed that the expression levels of EGFR, Ser(473)-pAkt, NF-κB p65 and MIC-1 proteins were significantly enhanced in the same subset of 76 cases of prostatic adenocarcinoma specimens during the disease progression and these biomarkers were expressed in a small subpopulation of CD133(+) PC cells and the bulk tumor mass of CD133(-) PC cells. Importantly, all of these biomarkers were also overexpressed in 80-100% of 30 PC metastasis bone tissue specimens. Moreover, the results have indicated that the EGF-EGFR signaling pathway can provide critical functions for the self-renewal of side population (SP) cells endowed with stem cell-like features from highly invasive WPE1-NB26 cells. Of therapeutic interest, the targeting of EGFR, pAkt, NF-κB or MIC-1 was also effective at suppressing the basal and EGF-promoted prostasphere formation by SP WPE1-NB26 cells, inducing disintegration of SP cell-derived prostaspheres and decreasing the viability of SP and non-SP WPE1-NB26 cell fractions. Also, the targeting of these oncogenic products induced the caspase-dependent apoptosis in chemoresistant SP WPE1-NB26 cells and enhanced their sensibility to the cytotoxic effects induced by docetaxel. These findings suggest that the combined use of EGFR, pAkt, NF-κB and/or MIC-1 may represent promising strategies for improving the accuracy of current diagnostic and prognostic methods and efficacy of treatments of PC patients in considering the disease heterogeneity, thereby preventing PC progression to metastatic and lethal disease states.

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Related in: MedlinePlus

Comparison of the composite scores of expression levels of EGFR, Ser473-pAkt, NF-κB p65 and MIC-1 in non-malignant and malignant tissues from PC patients.Box plots showing the expression levels of (a) EGFR, (b) Ser473-pAkt, (c) NF-κB p65 and (d) MIC-1 during PC progression to metastatic disease stages. *, P<0.0001, indicates a significant increase between the composite scores obtained for prostatic adenocarcinoma and PC bone metastasis specimens relative to composite scores obtained for normal prostatic tissues.
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pone-0031919-g002: Comparison of the composite scores of expression levels of EGFR, Ser473-pAkt, NF-κB p65 and MIC-1 in non-malignant and malignant tissues from PC patients.Box plots showing the expression levels of (a) EGFR, (b) Ser473-pAkt, (c) NF-κB p65 and (d) MIC-1 during PC progression to metastatic disease stages. *, P<0.0001, indicates a significant increase between the composite scores obtained for prostatic adenocarcinoma and PC bone metastasis specimens relative to composite scores obtained for normal prostatic tissues.

Mentions: The results from immunohistochemical analyses have indicated a very weak to undetectable immunostaining for EGFR, Ser473-pAkt, NF-κB p65 and MIC-1 in normal prostatic tissues of biopsy and adjacent non-malignant prostatic tissues from PC patients (Figure 1). In contrast, an enhanced expression of all of these biomarkers was detected in 66–75% of the 76 cases of prostatic adenocarcinomas (Gleason scores = 6–10) analyzed versus normal prostate tissues and associated with the stages (T2–T4) of the disease progression (Table 1). More particularly, a weak cytoplasmic and membrane immunostaining for the EGFR protein were detected only in a small number of basal and luminal prostatic epithelial cells in non-malignant prostatic tissues while its expression varied from moderate to strong within the cytoplasm and at the membrane respectively, in the malignant epithelial cells localized in the intermediate and luminal compartments in a subset of primary prostatic adenocarcinoma specimens (Figure 1a). The staining intensity associated with the EGFR protein expression was enhanced in 68% of 76 cases of primary prostatic adenocarcinoma specimens analyzed, as compared with the normal prostatic tissue from biopsy (Table 1). Moreover, the composite score value obtained for EGFR expression in PC specimens (3.4±0.4) was significantly superior to the value for normal prostate tissues (0.4±0.2); *p<0.0001) (Figure 2a). As shown in Figure 1b and c, the activated Ser473-pAkt phosphorylated form was also overexpressed in 66% of 76 cases of the prostatic adenocarcinomas analyzed and detected in the cytoplasm in PC epithelial cells whereas an enhanced expression of the p65 subunit NF-κB transcription factor occurred in 75% of 76 cases of prostatic adenocarcinomas and was mainly detected in cytoplasm and nuclei of PC epithelial cells. The composite score values obtained for Ser473-pAkt and NF-kB p65 expression in PC specimens (3.3±0.4 and 2.7±0.3) were significantly enhanced as compared to the value for normal prostate tissues (0.3±0.1 and 0.3±0.2; p<0.0001), respectively (Figure 2b and c). In addition, a stronger positive immunostaining was also seen for the MIC-1 protein in the cytoplasm and near the membrane in PC epithelial cells as well as for secreted MIC-1 in tumor stroma in 71% of 76 cases of prostatic adenocarcinomas as compared to normal and adjacent non-malignant prostate tissues analyzed (Figure 1d). The composite score value obtained for MIC-1 expression in PC specimens (3.7±0.4.) was significantly enhanced relative to the value for normal prostate tissues (0.4±0.3; *p<0.0001) (Figure 2d). Importantly, the results have also indicated that Ser473-pAkt, NF-κB p65 and MIC-1 were co-expressed with EGFR in the same subset corresponding at about 54–62% of PC tissue specimens analyzed suggesting that these oncogenic signaling elements may all cooperate to promote the malignant transformation of PC epithelial cells during disease progression to a locally advanced disease state (Table 1).


Pathobiological implications of the expression of EGFR, pAkt, NF-κB and MIC-1 in prostate cancer stem cells and their progenies.

Mimeault M, Johansson SL, Batra SK - PLoS ONE (2012)

Comparison of the composite scores of expression levels of EGFR, Ser473-pAkt, NF-κB p65 and MIC-1 in non-malignant and malignant tissues from PC patients.Box plots showing the expression levels of (a) EGFR, (b) Ser473-pAkt, (c) NF-κB p65 and (d) MIC-1 during PC progression to metastatic disease stages. *, P<0.0001, indicates a significant increase between the composite scores obtained for prostatic adenocarcinoma and PC bone metastasis specimens relative to composite scores obtained for normal prostatic tissues.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3285632&req=5

pone-0031919-g002: Comparison of the composite scores of expression levels of EGFR, Ser473-pAkt, NF-κB p65 and MIC-1 in non-malignant and malignant tissues from PC patients.Box plots showing the expression levels of (a) EGFR, (b) Ser473-pAkt, (c) NF-κB p65 and (d) MIC-1 during PC progression to metastatic disease stages. *, P<0.0001, indicates a significant increase between the composite scores obtained for prostatic adenocarcinoma and PC bone metastasis specimens relative to composite scores obtained for normal prostatic tissues.
Mentions: The results from immunohistochemical analyses have indicated a very weak to undetectable immunostaining for EGFR, Ser473-pAkt, NF-κB p65 and MIC-1 in normal prostatic tissues of biopsy and adjacent non-malignant prostatic tissues from PC patients (Figure 1). In contrast, an enhanced expression of all of these biomarkers was detected in 66–75% of the 76 cases of prostatic adenocarcinomas (Gleason scores = 6–10) analyzed versus normal prostate tissues and associated with the stages (T2–T4) of the disease progression (Table 1). More particularly, a weak cytoplasmic and membrane immunostaining for the EGFR protein were detected only in a small number of basal and luminal prostatic epithelial cells in non-malignant prostatic tissues while its expression varied from moderate to strong within the cytoplasm and at the membrane respectively, in the malignant epithelial cells localized in the intermediate and luminal compartments in a subset of primary prostatic adenocarcinoma specimens (Figure 1a). The staining intensity associated with the EGFR protein expression was enhanced in 68% of 76 cases of primary prostatic adenocarcinoma specimens analyzed, as compared with the normal prostatic tissue from biopsy (Table 1). Moreover, the composite score value obtained for EGFR expression in PC specimens (3.4±0.4) was significantly superior to the value for normal prostate tissues (0.4±0.2); *p<0.0001) (Figure 2a). As shown in Figure 1b and c, the activated Ser473-pAkt phosphorylated form was also overexpressed in 66% of 76 cases of the prostatic adenocarcinomas analyzed and detected in the cytoplasm in PC epithelial cells whereas an enhanced expression of the p65 subunit NF-κB transcription factor occurred in 75% of 76 cases of prostatic adenocarcinomas and was mainly detected in cytoplasm and nuclei of PC epithelial cells. The composite score values obtained for Ser473-pAkt and NF-kB p65 expression in PC specimens (3.3±0.4 and 2.7±0.3) were significantly enhanced as compared to the value for normal prostate tissues (0.3±0.1 and 0.3±0.2; p<0.0001), respectively (Figure 2b and c). In addition, a stronger positive immunostaining was also seen for the MIC-1 protein in the cytoplasm and near the membrane in PC epithelial cells as well as for secreted MIC-1 in tumor stroma in 71% of 76 cases of prostatic adenocarcinomas as compared to normal and adjacent non-malignant prostate tissues analyzed (Figure 1d). The composite score value obtained for MIC-1 expression in PC specimens (3.7±0.4.) was significantly enhanced relative to the value for normal prostate tissues (0.4±0.3; *p<0.0001) (Figure 2d). Importantly, the results have also indicated that Ser473-pAkt, NF-κB p65 and MIC-1 were co-expressed with EGFR in the same subset corresponding at about 54–62% of PC tissue specimens analyzed suggesting that these oncogenic signaling elements may all cooperate to promote the malignant transformation of PC epithelial cells during disease progression to a locally advanced disease state (Table 1).

Bottom Line: The progression of prostate cancers (PCs) to locally invasive, androgen-independent and metastatic disease states is generally associated with treatment resistance and disease relapse.Moreover, the results have indicated that the EGF-EGFR signaling pathway can provide critical functions for the self-renewal of side population (SP) cells endowed with stem cell-like features from highly invasive WPE1-NB26 cells.Also, the targeting of these oncogenic products induced the caspase-dependent apoptosis in chemoresistant SP WPE1-NB26 cells and enhanced their sensibility to the cytotoxic effects induced by docetaxel.

View Article: PubMed Central - PubMed

Affiliation: Department of Biochemistry and Molecular Biology, College of Medicine, University of Nebraska Medical Center, Omaha, Nebraska, United States of America.

ABSTRACT
The progression of prostate cancers (PCs) to locally invasive, androgen-independent and metastatic disease states is generally associated with treatment resistance and disease relapse. The present study was undertaken to establish the possibility of using a combination of specific oncogenic products, including epidermal growth factor receptor (EGFR), pAkt, nuclear factor-kappaB (NF-κB) and macrophage inhibitory cytokine-1 (MIC-1) as biomarkers and therapeutic targets for optimizing the management of patients with localized PC at earlier disease stages. The immunohistochemical and immunofluorescence data have revealed that the expression levels of EGFR, Ser(473)-pAkt, NF-κB p65 and MIC-1 proteins were significantly enhanced in the same subset of 76 cases of prostatic adenocarcinoma specimens during the disease progression and these biomarkers were expressed in a small subpopulation of CD133(+) PC cells and the bulk tumor mass of CD133(-) PC cells. Importantly, all of these biomarkers were also overexpressed in 80-100% of 30 PC metastasis bone tissue specimens. Moreover, the results have indicated that the EGF-EGFR signaling pathway can provide critical functions for the self-renewal of side population (SP) cells endowed with stem cell-like features from highly invasive WPE1-NB26 cells. Of therapeutic interest, the targeting of EGFR, pAkt, NF-κB or MIC-1 was also effective at suppressing the basal and EGF-promoted prostasphere formation by SP WPE1-NB26 cells, inducing disintegration of SP cell-derived prostaspheres and decreasing the viability of SP and non-SP WPE1-NB26 cell fractions. Also, the targeting of these oncogenic products induced the caspase-dependent apoptosis in chemoresistant SP WPE1-NB26 cells and enhanced their sensibility to the cytotoxic effects induced by docetaxel. These findings suggest that the combined use of EGFR, pAkt, NF-κB and/or MIC-1 may represent promising strategies for improving the accuracy of current diagnostic and prognostic methods and efficacy of treatments of PC patients in considering the disease heterogeneity, thereby preventing PC progression to metastatic and lethal disease states.

Show MeSH
Related in: MedlinePlus