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Impact of the coxsackievirus and adenovirus receptor on the adenoma-carcinoma sequence of colon cancer.

Stecker K, Vieth M, Koschel A, Wiedenmann B, Röcken C, Anders M - Br. J. Cancer (2011)

Bottom Line: Compared with healthy mucosa, increased CAR-mRNA expression was found in adenomas, whereas primary cancers and metastases displayed a marked decline.At the plasma membrane, CAR was present in normal mucosa samples (93%), adenomas, and metastases (100% ea.), whereas in colon cancers, it was found less frequently (49%, P<0.0001).We conclude that CAR facilitates complex effects during colon carcinogenesis, potentially mediated by its stage-dependent subcellular distribution; high CAR expression potentially prevents apoptosis in adenomas, loss of CAR at the plasma membrane promotes growth, and dissemination of primary cancers, and high membranous CAR presence may support the establishment of distant metastases.

View Article: PubMed Central - PubMed

Affiliation: Department of Internal Medicine, Divisions of Gastroenterology and Hepatology, Charité Medical School, Campus Virchow, Augustenburgerplatz 1, Berlin 13353, Germany.

ABSTRACT

Background: Coxsackie and adenovirus receptor (CAR) has been suggested to function as a tumour suppressor. Its impact on the adenoma-carcinoma sequence of the colon, however, is unclear.

Methods: Coxsackie and adenovirus receptor was analysed in non-cancerous and neoplastic colon samples using immunohistochemistry and quantitative RT-PCR. The function of CAR in colon cancer cell lines was determined following application of CAR siRNA or ectopic expression of a human full-length CAR cDNA.

Results: Compared with healthy mucosa, increased CAR-mRNA expression was found in adenomas, whereas primary cancers and metastases displayed a marked decline. At the plasma membrane, CAR was present in normal mucosa samples (93%), adenomas, and metastases (100% ea.), whereas in colon cancers, it was found less frequently (49%, P<0.0001). Cytoplasmic CAR immunopositivity increased from normal mucosa (22%), to adenomas (73%, P=0.0006), primary cancers (83%, P<0.0001), and metastases (67%, P=0.0019). In cancer cell lines, CAR inhibition resulted in increased proliferation, whereas enforced ectopic CAR expression led to opposite results. Blocking the extracellular portion of CAR increased cell invasion in vitro. In mice, xenotransplants of colon cancer cells with enforced CAR expression formed significantly smaller tumours, whereas CAR inhibition increased the formation of liver metastases.

Conclusion: We conclude that CAR facilitates complex effects during colon carcinogenesis, potentially mediated by its stage-dependent subcellular distribution; high CAR expression potentially prevents apoptosis in adenomas, loss of CAR at the plasma membrane promotes growth, and dissemination of primary cancers, and high membranous CAR presence may support the establishment of distant metastases.

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Inhibition of CAR promotes colon cancer cell invasiveness and metastasis. Blockade of the extracellular CAR portion using the anti-CAR antibody RmcB markedly increased the number of invading colon cancer cells in vitro (arrows) (A). RNAi-mediated knockdown of CAR in SW480 cells led to a significantly increased number of metastases (arrow) to the liver (lower panel demonstrates low CAR presence in metastatic cells (arrow) in contrast to adjacent CAR positive hepatic tissue) (B).
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fig5: Inhibition of CAR promotes colon cancer cell invasiveness and metastasis. Blockade of the extracellular CAR portion using the anti-CAR antibody RmcB markedly increased the number of invading colon cancer cells in vitro (arrows) (A). RNAi-mediated knockdown of CAR in SW480 cells led to a significantly increased number of metastases (arrow) to the liver (lower panel demonstrates low CAR presence in metastatic cells (arrow) in contrast to adjacent CAR positive hepatic tissue) (B).

Mentions: The impact of CAR on invasion of colon cancer cells following blockade of the extracellular portion of CAR was assessed using an in vitro assay. Incubation with the anti-CAR antibody RmcB, known to block CAR, markedly increased the invasiveness into matrigel of DlD1 and HCT116 cell lines compared with respective controls. However, SW480 and SW620 did not invade into matrigel neither with nor without RmcB (Figure 5A).


Impact of the coxsackievirus and adenovirus receptor on the adenoma-carcinoma sequence of colon cancer.

Stecker K, Vieth M, Koschel A, Wiedenmann B, Röcken C, Anders M - Br. J. Cancer (2011)

Inhibition of CAR promotes colon cancer cell invasiveness and metastasis. Blockade of the extracellular CAR portion using the anti-CAR antibody RmcB markedly increased the number of invading colon cancer cells in vitro (arrows) (A). RNAi-mediated knockdown of CAR in SW480 cells led to a significantly increased number of metastases (arrow) to the liver (lower panel demonstrates low CAR presence in metastatic cells (arrow) in contrast to adjacent CAR positive hepatic tissue) (B).
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3101933&req=5

fig5: Inhibition of CAR promotes colon cancer cell invasiveness and metastasis. Blockade of the extracellular CAR portion using the anti-CAR antibody RmcB markedly increased the number of invading colon cancer cells in vitro (arrows) (A). RNAi-mediated knockdown of CAR in SW480 cells led to a significantly increased number of metastases (arrow) to the liver (lower panel demonstrates low CAR presence in metastatic cells (arrow) in contrast to adjacent CAR positive hepatic tissue) (B).
Mentions: The impact of CAR on invasion of colon cancer cells following blockade of the extracellular portion of CAR was assessed using an in vitro assay. Incubation with the anti-CAR antibody RmcB, known to block CAR, markedly increased the invasiveness into matrigel of DlD1 and HCT116 cell lines compared with respective controls. However, SW480 and SW620 did not invade into matrigel neither with nor without RmcB (Figure 5A).

Bottom Line: Compared with healthy mucosa, increased CAR-mRNA expression was found in adenomas, whereas primary cancers and metastases displayed a marked decline.At the plasma membrane, CAR was present in normal mucosa samples (93%), adenomas, and metastases (100% ea.), whereas in colon cancers, it was found less frequently (49%, P<0.0001).We conclude that CAR facilitates complex effects during colon carcinogenesis, potentially mediated by its stage-dependent subcellular distribution; high CAR expression potentially prevents apoptosis in adenomas, loss of CAR at the plasma membrane promotes growth, and dissemination of primary cancers, and high membranous CAR presence may support the establishment of distant metastases.

View Article: PubMed Central - PubMed

Affiliation: Department of Internal Medicine, Divisions of Gastroenterology and Hepatology, Charité Medical School, Campus Virchow, Augustenburgerplatz 1, Berlin 13353, Germany.

ABSTRACT

Background: Coxsackie and adenovirus receptor (CAR) has been suggested to function as a tumour suppressor. Its impact on the adenoma-carcinoma sequence of the colon, however, is unclear.

Methods: Coxsackie and adenovirus receptor was analysed in non-cancerous and neoplastic colon samples using immunohistochemistry and quantitative RT-PCR. The function of CAR in colon cancer cell lines was determined following application of CAR siRNA or ectopic expression of a human full-length CAR cDNA.

Results: Compared with healthy mucosa, increased CAR-mRNA expression was found in adenomas, whereas primary cancers and metastases displayed a marked decline. At the plasma membrane, CAR was present in normal mucosa samples (93%), adenomas, and metastases (100% ea.), whereas in colon cancers, it was found less frequently (49%, P<0.0001). Cytoplasmic CAR immunopositivity increased from normal mucosa (22%), to adenomas (73%, P=0.0006), primary cancers (83%, P<0.0001), and metastases (67%, P=0.0019). In cancer cell lines, CAR inhibition resulted in increased proliferation, whereas enforced ectopic CAR expression led to opposite results. Blocking the extracellular portion of CAR increased cell invasion in vitro. In mice, xenotransplants of colon cancer cells with enforced CAR expression formed significantly smaller tumours, whereas CAR inhibition increased the formation of liver metastases.

Conclusion: We conclude that CAR facilitates complex effects during colon carcinogenesis, potentially mediated by its stage-dependent subcellular distribution; high CAR expression potentially prevents apoptosis in adenomas, loss of CAR at the plasma membrane promotes growth, and dissemination of primary cancers, and high membranous CAR presence may support the establishment of distant metastases.

Show MeSH
Related in: MedlinePlus