Overexpression of resistance-related proteins (metallothioneins, glutathione-S-transferase ?, heat shock protein 27, and lung resistance-related protein) in osteosarcoma

Abstract

BACKGROUND The prognosis for patients with osteosarcoma has improved over the past 20 years, mainly due to developments in chemotherapy. Some proteins have been reported to show drug resistance. Theoretically, overexpression of some of these proteins makes treatment difficult, leading to poorer outcome. METHODS Specimens taken from conventional osteosarcomas of the extremity bones from 60 patients younger than 30 years were used. In all cases, preoperative oncostatic chemotherapy was undertaken after biopsy. If available, biopsy specimens were also used for sequential comparison. Among resistance‐related proteins, expression of metallothioneins (MTs), glutathione‐S‐transferase π (GST π), heat shock protein 27 (Hsp27), and lung resistance‐related protein (LRP) was evaluated immunohistochemically in paraffin sections. The log rank test was used for univariate analysis and the Cox regression model for multivariate analysis. RESULTS At biopsy, only overexpression of Hsp27 was associated with poor prognosis. At surgery, a relationship was observed between poor prognosis and overexpression of GST π, Hsp27, and LRP. Groups overexpressing one protein tended to overexpress another. Overexpression of these proteins in surgical specimens also correlated with histologic response to preoperative chemotherapy and clinical stage. In multivariate analysis, Hsp27 overexpression at biopsy was an independent prognostic factor. CONCLUSIONS Inherent overexpression of Hsp27 is independently related to poor outcome in osteosarcoma patients. Overexpression of GST π, Hsp27, and LRP at surgery might be associated with failure of preoperative chemotherapy. Control of the expression of these proteins may improve the outcome for patients with osteosarcoma. Cancer 1997; 79:2336‐44. © 1997 American Cancer Society.

The association of P‐glycoprotein with response to chemotherapy and clinical outcome in patients with osteosarcoma

“…The prognostic value of Pgp in patients with osteosarcoma also should be examined in the context of other proposed molecular markers, including p53, 53 ErbB2, 54 heat shock proteins, 33 and DNA sequence copy number increases, 55 among others. Although one study showed a positive correlation between p53 mutation and Pgp, 11 two other studies showed no such correlation.…”

“…Of those, 13 studies were excluded because they overlapped with another larger study (n ϭ 2 studies 24,25 ), they included no data on response to chemotherapy or clinical disease progression (n ϭ 6 studies 26 -31 ), they included no Pgp measurements (n ϭ 2 studies 32,33 ), or they included Ͻ 10 osteosarcomas or no osteosarcomas (n ϭ 3 studies 34 -36 ). Fourteen independent studies were entered in the meta-analysis (Table 1).…”

Expression of human glutathione S-transferase P1 mediates the chemosensitivity of osteosarcoma cells

“…One study of GSTP1 expression in samples from pediatric patients with osteosarcoma showed that GSTP1 expression might have a bearing on the outcome of treatment with chemotherapy (14). Another study by Bruheim et al (15) showed that the GSTP1 mRNA level was inversely correlated with doxorubicin growth inhibition in human osteosarcoma xenografts.…”

Role of HSP27 in tumor necrosis factor-α-stimulated interleukin-6 synthesis in osteoblasts

“…Although the expression level of HSP27 is reportedly quite low or hardly detectable in unstimulated osteoblasts (28), we herein showed that TNF-α-stimulated IL-6 synthesis was modulated by the HSP27 expression level and/or its phosphorylation status in osteoblast-like MC3T3-E1 cells. It has been shown that osteosarcoma specimens with overexpressed HSP27 are associated with poor prognosis (51). Although rheumatoid arthritis is mainly caused by inflammation of synovial cells, our results suggest that the expression level of HSP27 in osteoblasts may correlate to the clinical symptoms or inflammatory sings of rheumatoid arthritis patients.…”