title: Colon cancer cells expressing cell surface GRP78 as a marker for reduced tumorigenicity.
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.
  
  
  CONCLUSIONS
  This study demonstrates the significance of cell surface GRP78 in colon cancer, which may be used as a marker for reduced tumorigenicity.
authors.affiliation: Felsenstein Medical Research Center, Tel-Aviv University Sackler School of Medicine, Rabin Medical Center, Beilinson Campus, Petach Tikva, 49100, Israel. bhardy@post.tau.ac.il
authors.forename: Britta
authors.initials: B
authors.lastname: Hardy
authors.forename: Annat
authors.initials: A
authors.lastname: Raiter
authors.forename: Maxim
authors.initials: M
authors.lastname: Yakimov
authors.forename: Alexander
authors.initials: A
authors.lastname: Vilkin
authors.forename: Yaron
authors.initials: Y
authors.lastname: Niv
mesh_terms: D000818:Animals; D014408:Biomarkers, Tumor / Q000378:metabolism*; D002462:Cell Membrane / Q000378:metabolism*; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000473:pathology*; D003110:Colonic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D000091342:Endoplasmic Reticulum Chaperone BiP; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D045325:HCT116 Cells; D006360:Heat-Shock Proteins / Q000378:metabolism*; D006801:Humans; D018189:Immunomagnetic Separation; D008113:Liver Neoplasms / Q000556:secondary; D051379:Mice; D008807:Mice, Inbred BALB C; D014410:Tumor Stem Cell Assay
chemical_list: D014408:Biomarkers, Tumor; D000091342:Endoplasmic Reticulum Chaperone BiP; C000717247:HSPA5 protein, human; D006360:Heat-Shock Proteins; C000717248:Hspa5 protein, mouse