Limits...
EpCAM is overexpressed in local and metastatic prostate cancer, suppressed by chemotherapy and modulated by MET-associated miRNA-200c/205.

Massoner P, Thomm T, Mack B, Untergasser G, Martowicz A, Bobowski K, Klocker H, Gires O, Puhr M - Br. J. Cancer (2014)

Bottom Line: Oppositely, re-induction of the epithelial phenotype through miRNAs miR-200c and miR-205, two inducers of mesenchymal-to-epithelial transition (MET), led to re-induction of EpCAM in chemoresistant cells.Furthermore, we prove that EpCAM cleavage, the first step of EpCAM signalling takes place in prostate cancer cells but in contrast to other cancer entities, EpCAM has no measurable impact on the proliferative behaviour of prostate cells, in vitro.In conclusion, our data confirm that EpCAM overexpression is an early event during prostate cancer progression.

View Article: PubMed Central - PubMed

Affiliation: 1] Experimental Urology, Department of Urology, Innsbruck Medical University, Innsbruck, Austria [2] Department of Otorhinolaryngology, Head and Neck Surgery, Ludwig-Maximilians-University, Munich, Germany.

ABSTRACT

Background: Expression of epithelial cell adhesion molecule (EpCAM) is deregulated in epithelial malignancies. Beside its role in cell adhesion, EpCAM acts as signalling molecule with tumour-promoting functions. Thus, EpCAM is part of the molecular network of oncogenic receptors and considered an interesting therapeutic target.

Methods: Here, we thoroughly characterised EpCAM expression on mRNA and protein level in comprehensive tissue studies including non-cancerous prostate specimens, primary tumours of different grades and stages, metastatic lesions, and therapy-treated tumour specimens, as well as in prostate cancer cell lines.

Results: Epithelial cell adhesion molecule was overexpressed at mRNA and at protein level in prostate cancer tissues and cell lines. Altered EpCAM expression was an early event in prostate carcinogenesis with an upregulation in low-grade cancers and further induction in high-grade tumours and metastatic lesions. Interestingly, EpCAM was repressed upon induction of epithelial-to-mesenchymal transition (EMT) following chemotherapeutic treatment with docetaxel. Oppositely, re-induction of the epithelial phenotype through miRNAs miR-200c and miR-205, two inducers of mesenchymal-to-epithelial transition (MET), led to re-induction of EpCAM in chemoresistant cells. Furthermore, we prove that EpCAM cleavage, the first step of EpCAM signalling takes place in prostate cancer cells but in contrast to other cancer entities, EpCAM has no measurable impact on the proliferative behaviour of prostate cells, in vitro.

Conclusions: In conclusion, our data confirm that EpCAM overexpression is an early event during prostate cancer progression. Epithelial cell adhesion molecule displays a dynamic, heterogeneous expression and associates with epithelial cells rather than mesenchymal, chemoresistant cells along with processes of EMT and MET.

Show MeSH

Related in: MedlinePlus

EpCAM protein is increased, expressed in primary and metastatic tissue of PCa patients. Statistical analyses of tissue microarrays reveal that EpCAM protein is significantly elevated in PCa compared to normal prostate tissue (A). EpCAM protein expression increases with Gleason score (GSC, B) and tumour stage (C) compared to normal prostate tissue. (D) Representative cores for benign, low GSC, high GSC, and metastatic prostate tissue. Co-staining of EpCAM (brown) and p63 (blue, marker for basal cells) ensured correct discrimination between benign and cancer glands. Semiquantitative analysis was performed applying quickscore criteria. Statistics were calculated using Mann–Whitney U testing. ***, P<0.001; bar, 100 μM. IRS, immunoreactivity staining score.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4150273&req=5

fig2: EpCAM protein is increased, expressed in primary and metastatic tissue of PCa patients. Statistical analyses of tissue microarrays reveal that EpCAM protein is significantly elevated in PCa compared to normal prostate tissue (A). EpCAM protein expression increases with Gleason score (GSC, B) and tumour stage (C) compared to normal prostate tissue. (D) Representative cores for benign, low GSC, high GSC, and metastatic prostate tissue. Co-staining of EpCAM (brown) and p63 (blue, marker for basal cells) ensured correct discrimination between benign and cancer glands. Semiquantitative analysis was performed applying quickscore criteria. Statistics were calculated using Mann–Whitney U testing. ***, P<0.001; bar, 100 μM. IRS, immunoreactivity staining score.

Mentions: We next extended our study to EpCAM protein data. In total, 179 prostate tissues from 104 patients were stained using immunohistochemistry. Epithelial cell adhesion molecule was overexpressed in malignant tissues compared to benign, non-cancerous prostate tissues (Figure 2A). Overexpression of EpCAM appeared more pronounced at protein level than at mRNA level (4.2±2.1-fold vs 2.3±0.9-fold overexpressed in PCa, protein vs mRNA level, respectively). Elevated expression of EpCAM was an early event in PCa, which was detectable as early as in local low-grade cancer (Gleason score, GSC ⩽7 including GSC 7 with Gleason pattern 3+4), in high-grade cancer (GSC⩾7 including GSC 7 with Gleason pattern 4+3) and in overt metastases (bone, n=10; lymph node, n=6). Epithelial cell adhesion molecule protein was increased in cancers of high GSC, in cancers of advanced stages and in metastases (Figure 2B–D), but remained unchanged in cancers harbouring ERG rearrangements (Tomlins et al, 2005) compared to ERG normal cancers (data not shown). Although we observed a further increase in expression of EpCAM in PCa metastases (Figure 2C), data need to be considered with caution since sample size was limited because metastases are not routinely surgically removed. We conclude from this study that EpCAM is overexpressed in local and metastatic PCa, and induction of EpCAM expression is an early event in prostate carcinogenesis.


EpCAM is overexpressed in local and metastatic prostate cancer, suppressed by chemotherapy and modulated by MET-associated miRNA-200c/205.

Massoner P, Thomm T, Mack B, Untergasser G, Martowicz A, Bobowski K, Klocker H, Gires O, Puhr M - Br. J. Cancer (2014)

EpCAM protein is increased, expressed in primary and metastatic tissue of PCa patients. Statistical analyses of tissue microarrays reveal that EpCAM protein is significantly elevated in PCa compared to normal prostate tissue (A). EpCAM protein expression increases with Gleason score (GSC, B) and tumour stage (C) compared to normal prostate tissue. (D) Representative cores for benign, low GSC, high GSC, and metastatic prostate tissue. Co-staining of EpCAM (brown) and p63 (blue, marker for basal cells) ensured correct discrimination between benign and cancer glands. Semiquantitative analysis was performed applying quickscore criteria. Statistics were calculated using Mann–Whitney U testing. ***, P<0.001; bar, 100 μM. IRS, immunoreactivity staining score.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4150273&req=5

fig2: EpCAM protein is increased, expressed in primary and metastatic tissue of PCa patients. Statistical analyses of tissue microarrays reveal that EpCAM protein is significantly elevated in PCa compared to normal prostate tissue (A). EpCAM protein expression increases with Gleason score (GSC, B) and tumour stage (C) compared to normal prostate tissue. (D) Representative cores for benign, low GSC, high GSC, and metastatic prostate tissue. Co-staining of EpCAM (brown) and p63 (blue, marker for basal cells) ensured correct discrimination between benign and cancer glands. Semiquantitative analysis was performed applying quickscore criteria. Statistics were calculated using Mann–Whitney U testing. ***, P<0.001; bar, 100 μM. IRS, immunoreactivity staining score.
Mentions: We next extended our study to EpCAM protein data. In total, 179 prostate tissues from 104 patients were stained using immunohistochemistry. Epithelial cell adhesion molecule was overexpressed in malignant tissues compared to benign, non-cancerous prostate tissues (Figure 2A). Overexpression of EpCAM appeared more pronounced at protein level than at mRNA level (4.2±2.1-fold vs 2.3±0.9-fold overexpressed in PCa, protein vs mRNA level, respectively). Elevated expression of EpCAM was an early event in PCa, which was detectable as early as in local low-grade cancer (Gleason score, GSC ⩽7 including GSC 7 with Gleason pattern 3+4), in high-grade cancer (GSC⩾7 including GSC 7 with Gleason pattern 4+3) and in overt metastases (bone, n=10; lymph node, n=6). Epithelial cell adhesion molecule protein was increased in cancers of high GSC, in cancers of advanced stages and in metastases (Figure 2B–D), but remained unchanged in cancers harbouring ERG rearrangements (Tomlins et al, 2005) compared to ERG normal cancers (data not shown). Although we observed a further increase in expression of EpCAM in PCa metastases (Figure 2C), data need to be considered with caution since sample size was limited because metastases are not routinely surgically removed. We conclude from this study that EpCAM is overexpressed in local and metastatic PCa, and induction of EpCAM expression is an early event in prostate carcinogenesis.

Bottom Line: Oppositely, re-induction of the epithelial phenotype through miRNAs miR-200c and miR-205, two inducers of mesenchymal-to-epithelial transition (MET), led to re-induction of EpCAM in chemoresistant cells.Furthermore, we prove that EpCAM cleavage, the first step of EpCAM signalling takes place in prostate cancer cells but in contrast to other cancer entities, EpCAM has no measurable impact on the proliferative behaviour of prostate cells, in vitro.In conclusion, our data confirm that EpCAM overexpression is an early event during prostate cancer progression.

View Article: PubMed Central - PubMed

Affiliation: 1] Experimental Urology, Department of Urology, Innsbruck Medical University, Innsbruck, Austria [2] Department of Otorhinolaryngology, Head and Neck Surgery, Ludwig-Maximilians-University, Munich, Germany.

ABSTRACT

Background: Expression of epithelial cell adhesion molecule (EpCAM) is deregulated in epithelial malignancies. Beside its role in cell adhesion, EpCAM acts as signalling molecule with tumour-promoting functions. Thus, EpCAM is part of the molecular network of oncogenic receptors and considered an interesting therapeutic target.

Methods: Here, we thoroughly characterised EpCAM expression on mRNA and protein level in comprehensive tissue studies including non-cancerous prostate specimens, primary tumours of different grades and stages, metastatic lesions, and therapy-treated tumour specimens, as well as in prostate cancer cell lines.

Results: Epithelial cell adhesion molecule was overexpressed at mRNA and at protein level in prostate cancer tissues and cell lines. Altered EpCAM expression was an early event in prostate carcinogenesis with an upregulation in low-grade cancers and further induction in high-grade tumours and metastatic lesions. Interestingly, EpCAM was repressed upon induction of epithelial-to-mesenchymal transition (EMT) following chemotherapeutic treatment with docetaxel. Oppositely, re-induction of the epithelial phenotype through miRNAs miR-200c and miR-205, two inducers of mesenchymal-to-epithelial transition (MET), led to re-induction of EpCAM in chemoresistant cells. Furthermore, we prove that EpCAM cleavage, the first step of EpCAM signalling takes place in prostate cancer cells but in contrast to other cancer entities, EpCAM has no measurable impact on the proliferative behaviour of prostate cells, in vitro.

Conclusions: In conclusion, our data confirm that EpCAM overexpression is an early event during prostate cancer progression. Epithelial cell adhesion molecule displays a dynamic, heterogeneous expression and associates with epithelial cells rather than mesenchymal, chemoresistant cells along with processes of EMT and MET.

Show MeSH
Related in: MedlinePlus