Protein Disulfide Isomerase Expression Is Related to the Invasive Properties of Malignant Glioma

Abstract

By serial transplantation of human glioblastoma biopsies into the brain of immunodeficient nude rats, two different tumor phenotypes were obtained. Initially, the transplanted xenografts displayed a highly invasive phenotype that showed no signs of angiogenesis. By serial transplantation in animals, the tumors changed to a less invasive, predominantly angiogenic phenotype. To identify novel proteins related to the invasive phenotype, the xenografts were analyzed using a global proteomics approach. One of the identified proteins was protein disulfide isomerase (PDI) A6 precursor. PDI is a chaperone protein that mediates integrin-dependent cell adhesion. It is both present in the cytosol and at the cell surface. We show that PDI is strongly expressed on invasive glioma cells, in both xenografts and at the invasive front of human glioblastomas. Using an in vitro migration assay, we also show that PDI is expressed on migrating glioma cells. To determine the functional significance of PDI in cell migration, we tested the effect of a PDI inhibitor, bacitracin, and a PDI monoclonal antibody on glioma cell migration and invasion in vitro. Both tumor spheroids derived from human glioblastoma xenografts in nude rat brain and cell line spheroids were used. The PDI antibody, as well as bacitracin, inhibited tumor cell migration and invasion. The anti-invasive effect of bacitracin was reversible after withdrawal of the inhibitor, indicating a specific, nontoxic effect. In conclusion, using a global proteomics approach, PDI was identified to play an important role in glioma cell invasion, and its action was effectively inhibited by bacitracin. (Cancer Res 2006; 66(20): 9895-902)

CD133 negative glioma cells form tumors in nude rats and give rise to CD133 positive cells

“…The 1st generation tumors did not exhibit contrast enhancement indicating intact vessel structures as previously described. 24,25 As in the patients, the addition of a contrast agent revealed a hyper-intense area in the high generation tumors indicating a compromised blood-brain-barrier (BBB) (Fig. 1b).…”

“…22 Furthermore, it has recently been demonstrated that CD133 negative cells from human glioblastoma multiforme (GBM) exhibit cancer stem cell properties as well, although their proliferation index was lower than for CD133 positive cells. 23 Thus, the role of CD133 positive cells versus other cell populations in brain tumor initiation and progression is still uncertain.We have previously developed a human glioma model by implanting human GBM biopsy spheroids into the brains of nude rats, 24,25 and showed that these tumors express a number of stem cell markers. 24 The establishment of naive human GBM biopsy material into a host of a different species (rat), and the expression of primitive cell markers, indicate a high cellular adaptability.…”

“…We have previously developed a human glioma model by implanting human GBM biopsy spheroids into the brains of nude rats, 24,25 and showed that these tumors express a number of stem cell markers. 24 The establishment of naive human GBM biopsy material into a host of a different species (rat), and the expression of primitive cell markers, indicate a high cellular adaptability.…”

Protein disulfide isomerases are antibody targets during immune-mediated tumor destruction

“…Among the antigens, the human ortholog of PDI manifested immunogenicity in a limited number of cancer patients, whereas the closely related disulfide isomerase ERp5 elicited humoral reactions that were temporally associated with clinically significant anti-tumor effects in 4 different solid and hematologic malignancies. Because ERp5 facilitates immune escape through the enhancement of MICA shedding 53 and may also promote tumor cell invasion through modifying surface thiols, 56,57 our results raise the possibility that this disulfide isomerase may be a useful target for cancer immunotherapy.…”

Protein Disulfide Isomerase: Structure, Mechanism of Oxidative Protein Folding and Multiple Functional Roles

“…The mechanism involved in these diseases states include suppression of apoptosis by PDI which results in the progression of tumor growth and metastasis. Cell surface PDI is also implicated in cancer progression and administering anti-PDI monoclonal antibodies inhibits the invasion of glioma cells [70] . This further validates that PDI promotes survival and progression of various forms of cancer cells.…”