Clusterin expression in normal mucosa and colorectal cancer

Claus Lindbjerg Andersen, Troels Schepeler, Kasper Thornsen, Karin Birkenkamp-Demtröder, Francisco Mansilla, Lauri A Aaltonen, Søren Laurberg, Torben F Ørntoft

    Research output: Contribution to journalArticleScientificpeer-review

    Abstract

    The gene Clusterin is a target for cancer therapy in clinical trials. The indication for intervention is up-regulated Clusterin expression. Clusterin has been reported to be deregulated in multiple cancer types, including colorectal cancer (CRC). However, for CRC the studies have disagreed on whether Clusterin is up- or down-regulated by neoplastic cells. In the present study we sought to clarify the expression and distribution of Clusterin mRNAs and proteins in normal and neoplastic colorectal tissue through laser microdissection, variant-specific real time RT-PCR, immunohistochemistry, immunofluorescence, Western blotting, and array-based transcriptional profiling. At the transcript level we demonstrated the expression of two novel Clusterin transcripts in addition to the known transcript, and at the protein level we demonstrated two Clusterin isoforms. Our analysis of normal epithelial cells revealed that among these, Clusterin was only expressed by rare neuroendocrine subtype. Furthermore our analysis showed that in the normal mucosa the majority of the observed Clusterin protein originated from the stromal compartment. In tumors we found that Clusterin was de novo synthesized by non-neuroendocrine cancer cells in similar to 25% of cases. Moreover we found that the overall Clusterin level in tumors often appeared to be lower than in normal mucosa due to the stromal compartment often being suppressed in tumors. Although Clusterin in normal neuroendocrine cells showed a basal localization, the localization in cancer cells was often apical and in some cases associated with apical secretion. Collectively our results indicate that Clusterin expression is very complex. We conclude that Clusterin expression is associated with neuroendocrine differentiation in normal epithelia and that the Clusterin observed in neoplastic cells is de novo synthesized. The cases with de novo synthesized Clusterin define a distinct subgroup of CRC that may be of clinical importance as anti-Clusterin therapeutics are now in clinical trials.
    Original languageEnglish
    JournalMolecular & Cellular Proteomics
    Volume6
    Issue number6
    Pages (from-to)1039-1048
    Number of pages10
    ISSN1535-9476
    DOIs
    Publication statusPublished - 2007
    MoE publication typeA1 Journal article-refereed

    Fields of Science

    • 311 Basic medicine

    Cite this

    Andersen, C. L., Schepeler, T., Thornsen, K., Birkenkamp-Demtröder, K., Mansilla, F., Aaltonen, L. A., ... Ørntoft, T. F. (2007). Clusterin expression in normal mucosa and colorectal cancer. Molecular & Cellular Proteomics, 6(6), 1039-1048. https://doi.org/10.1074/mcp.M600261-MCP200
    Andersen, Claus Lindbjerg ; Schepeler, Troels ; Thornsen, Kasper ; Birkenkamp-Demtröder, Karin ; Mansilla, Francisco ; Aaltonen, Lauri A ; Laurberg, Søren ; Ørntoft, Torben F. / Clusterin expression in normal mucosa and colorectal cancer. In: Molecular & Cellular Proteomics. 2007 ; Vol. 6, No. 6. pp. 1039-1048.
    @article{02768bb496d94b5695a29bee344ee919,
    title = "Clusterin expression in normal mucosa and colorectal cancer",
    abstract = "The gene Clusterin is a target for cancer therapy in clinical trials. The indication for intervention is up-regulated Clusterin expression. Clusterin has been reported to be deregulated in multiple cancer types, including colorectal cancer (CRC). However, for CRC the studies have disagreed on whether Clusterin is up- or down-regulated by neoplastic cells. In the present study we sought to clarify the expression and distribution of Clusterin mRNAs and proteins in normal and neoplastic colorectal tissue through laser microdissection, variant-specific real time RT-PCR, immunohistochemistry, immunofluorescence, Western blotting, and array-based transcriptional profiling. At the transcript level we demonstrated the expression of two novel Clusterin transcripts in addition to the known transcript, and at the protein level we demonstrated two Clusterin isoforms. Our analysis of normal epithelial cells revealed that among these, Clusterin was only expressed by rare neuroendocrine subtype. Furthermore our analysis showed that in the normal mucosa the majority of the observed Clusterin protein originated from the stromal compartment. In tumors we found that Clusterin was de novo synthesized by non-neuroendocrine cancer cells in similar to 25{\%} of cases. Moreover we found that the overall Clusterin level in tumors often appeared to be lower than in normal mucosa due to the stromal compartment often being suppressed in tumors. Although Clusterin in normal neuroendocrine cells showed a basal localization, the localization in cancer cells was often apical and in some cases associated with apical secretion. Collectively our results indicate that Clusterin expression is very complex. We conclude that Clusterin expression is associated with neuroendocrine differentiation in normal epithelia and that the Clusterin observed in neoplastic cells is de novo synthesized. The cases with de novo synthesized Clusterin define a distinct subgroup of CRC that may be of clinical importance as anti-Clusterin therapeutics are now in clinical trials.",
    keywords = "311 Basic medicine",
    author = "Andersen, {Claus Lindbjerg} and Troels Schepeler and Kasper Thornsen and Karin Birkenkamp-Demtr{\"o}der and Francisco Mansilla and Aaltonen, {Lauri A} and S{\o}ren Laurberg and {\O}rntoft, {Torben F}",
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    Andersen, CL, Schepeler, T, Thornsen, K, Birkenkamp-Demtröder, K, Mansilla, F, Aaltonen, LA, Laurberg, S & Ørntoft, TF 2007, 'Clusterin expression in normal mucosa and colorectal cancer', Molecular & Cellular Proteomics, vol. 6, no. 6, pp. 1039-1048. https://doi.org/10.1074/mcp.M600261-MCP200

    Clusterin expression in normal mucosa and colorectal cancer. / Andersen, Claus Lindbjerg; Schepeler, Troels; Thornsen, Kasper; Birkenkamp-Demtröder, Karin; Mansilla, Francisco; Aaltonen, Lauri A; Laurberg, Søren; Ørntoft, Torben F.

    In: Molecular & Cellular Proteomics, Vol. 6, No. 6, 2007, p. 1039-1048.

    Research output: Contribution to journalArticleScientificpeer-review

    TY - JOUR

    T1 - Clusterin expression in normal mucosa and colorectal cancer

    AU - Andersen, Claus Lindbjerg

    AU - Schepeler, Troels

    AU - Thornsen, Kasper

    AU - Birkenkamp-Demtröder, Karin

    AU - Mansilla, Francisco

    AU - Aaltonen, Lauri A

    AU - Laurberg, Søren

    AU - Ørntoft, Torben F

    PY - 2007

    Y1 - 2007

    N2 - The gene Clusterin is a target for cancer therapy in clinical trials. The indication for intervention is up-regulated Clusterin expression. Clusterin has been reported to be deregulated in multiple cancer types, including colorectal cancer (CRC). However, for CRC the studies have disagreed on whether Clusterin is up- or down-regulated by neoplastic cells. In the present study we sought to clarify the expression and distribution of Clusterin mRNAs and proteins in normal and neoplastic colorectal tissue through laser microdissection, variant-specific real time RT-PCR, immunohistochemistry, immunofluorescence, Western blotting, and array-based transcriptional profiling. At the transcript level we demonstrated the expression of two novel Clusterin transcripts in addition to the known transcript, and at the protein level we demonstrated two Clusterin isoforms. Our analysis of normal epithelial cells revealed that among these, Clusterin was only expressed by rare neuroendocrine subtype. Furthermore our analysis showed that in the normal mucosa the majority of the observed Clusterin protein originated from the stromal compartment. In tumors we found that Clusterin was de novo synthesized by non-neuroendocrine cancer cells in similar to 25% of cases. Moreover we found that the overall Clusterin level in tumors often appeared to be lower than in normal mucosa due to the stromal compartment often being suppressed in tumors. Although Clusterin in normal neuroendocrine cells showed a basal localization, the localization in cancer cells was often apical and in some cases associated with apical secretion. Collectively our results indicate that Clusterin expression is very complex. We conclude that Clusterin expression is associated with neuroendocrine differentiation in normal epithelia and that the Clusterin observed in neoplastic cells is de novo synthesized. The cases with de novo synthesized Clusterin define a distinct subgroup of CRC that may be of clinical importance as anti-Clusterin therapeutics are now in clinical trials.

    AB - The gene Clusterin is a target for cancer therapy in clinical trials. The indication for intervention is up-regulated Clusterin expression. Clusterin has been reported to be deregulated in multiple cancer types, including colorectal cancer (CRC). However, for CRC the studies have disagreed on whether Clusterin is up- or down-regulated by neoplastic cells. In the present study we sought to clarify the expression and distribution of Clusterin mRNAs and proteins in normal and neoplastic colorectal tissue through laser microdissection, variant-specific real time RT-PCR, immunohistochemistry, immunofluorescence, Western blotting, and array-based transcriptional profiling. At the transcript level we demonstrated the expression of two novel Clusterin transcripts in addition to the known transcript, and at the protein level we demonstrated two Clusterin isoforms. Our analysis of normal epithelial cells revealed that among these, Clusterin was only expressed by rare neuroendocrine subtype. Furthermore our analysis showed that in the normal mucosa the majority of the observed Clusterin protein originated from the stromal compartment. In tumors we found that Clusterin was de novo synthesized by non-neuroendocrine cancer cells in similar to 25% of cases. Moreover we found that the overall Clusterin level in tumors often appeared to be lower than in normal mucosa due to the stromal compartment often being suppressed in tumors. Although Clusterin in normal neuroendocrine cells showed a basal localization, the localization in cancer cells was often apical and in some cases associated with apical secretion. Collectively our results indicate that Clusterin expression is very complex. We conclude that Clusterin expression is associated with neuroendocrine differentiation in normal epithelia and that the Clusterin observed in neoplastic cells is de novo synthesized. The cases with de novo synthesized Clusterin define a distinct subgroup of CRC that may be of clinical importance as anti-Clusterin therapeutics are now in clinical trials.

    KW - 311 Basic medicine

    U2 - 10.1074/mcp.M600261-MCP200

    DO - 10.1074/mcp.M600261-MCP200

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    JF - Molecular & Cellular Proteomics

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    Andersen CL, Schepeler T, Thornsen K, Birkenkamp-Demtröder K, Mansilla F, Aaltonen LA et al. Clusterin expression in normal mucosa and colorectal cancer. Molecular & Cellular Proteomics. 2007;6(6):1039-1048. https://doi.org/10.1074/mcp.M600261-MCP200