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Colon cancer cells expressing cell surface GRP78 as a marker for reduced tumorigenicity

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Abstract

Background

The glucose regulated heat shock protein 78 (GRP78) is a central regulator of ER (endoplasmic reticulum) stress due to its pro-survival property. Up regulated GRP78 expression in tumor cells has been correlated with aggressive malignancies whereas some reports have predicted an improved prognosis. Over-expression of GRP78 in the ER promotes its localization to the cell surface on several cell types including tumor cells.

Methods

In order to elucidate whether GRP78 receptor positive and negative tumor cells manifest different properties in colorectal cancer, we first artificially separated GRP78 positive and negative sub-populations from HM7 and HCT116 cell lines using anti GRP78 antibody coated magnetic beads.

Results

Only GRP78 negative cells were highly proliferative, induced significant growth in tumor size in nude mice and metastasized to the liver in a human metastatic colorectal carcinoma model in mice. In contrast, GRP78 positive cells manifested reduced proliferation, colony formation, tumor growth and liver metastases. The reduced tumorigenicity of GRP78 positive subpopulation was abrogated by silencing GRP78 expression using siRNA oligomers. In our efforts to induce cell surface GRP78, we subjected the cells to doxorubicin and taxol that increased significantly the percent of GRP78 positive population. Cells pre-incubated with doxorubicin exhibited reduced proliferation and tumor growth in mice.

Conclusion

This study demonstrates the significance of cell surface GRP78 in colon cancer, which may be used as a marker for reduced tumorigenicity.

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Acknowledgments

The authors wish to express their gratitude to Ms. Sara Dominitz for excellent editorial assistance

Conflict of interest

The authors declare no conflict of interests.

Ethical standards

The in vivo models were raised according to the Institutional Animal Care and Use Committee of Tel Aviv University conforming to the NIH Guide for the Care and Use of Laboratory Animals.

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Authors and Affiliations

  1. Felsenstein Medical Research Center, Tel-Aviv University Sackler School of Medicine, Rabin Medical Center, Beilinson Campus, Petach Tikva, 49100, Israel

    Britta Hardy & Annat Raiter

  2. Department of Pathology, Rabin Medical Center, Petach Tikva, Israel

    Maxim Yakimov

  3. Department of Gastroenterology, Rabin Medical Center, Petach Tikva, Israel

    Alexander Vilkin & Yaron Niv

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  1. Britta Hardy
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  2. Annat Raiter
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  3. Maxim Yakimov
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Correspondence to Britta Hardy.

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Hardy, B., Raiter, A., Yakimov, M. et al. Colon cancer cells expressing cell surface GRP78 as a marker for reduced tumorigenicity. Cell Oncol. 35, 345–354 (2012). https://doi.org/10.1007/s13402-012-0094-4

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  • DOI: https://doi.org/10.1007/s13402-012-0094-4

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