Distribution of multidrug resistance associated proteins in different histological subtypes and stages in operable non small cell lung cancer. A tissue microarray study

摘要

The aim of this retrospective study was to comparatively investigate the expression of the three drug-resistance related proteins P-glycoprotein (P-gp), multidrug- resistance protein 1 (MRP1), and lung resistence protein (LRP), in non-small cell lung cancer (NSCLC) tissues using tissue microarray technology. Methods: Tumor specimens from 179 patients were analyzed by immunohistochemistry and data were statistically analyzed by SPSS. Results: The mean expression levels of tumor tissues in the case of P-gp and LRP did not exceed the one of normal epithelia, while MRP1 was significantly enhanced in NSCLC. No associations were observed between higher grading and P-glycoprotein expression (p <0.8) as well as lower grading and MRP1 expression in the case of adenocarcinoma (p <0.05). We also did not find any association between the immunohistochemical expression of MrP1, Lrp, Pgp, grading and staging. Conclusions: Ourdata point towards a major role of MRP1 in the intrinsic reatment resistance of NSCLC. Note The both first authors have an equal contribution. Introduction Almost all non-small cell lung cancer (NSCLC), representing approximately 85% of all lung cancers (Fry et al.1996), display intrinsic multidrug resistance (MDR), generally limiting the chance of successful chemotherapy (Ihde and Minna 1991). This is one reason why lung cancer is currently a leading cause of cancer death worldwide. As the enhanced resistance of NSCLC cells affects a diverse range of antineoplastic drugs currently in clinical use, it is believed that several protection mechanisms are cooperatively active in NSCLC cells. This multi-factorial in vivo MDR phenotype is also re- flected by a distinct chemoresistance of NSCLC cells in vitro (Scagliotti et al. 1999; Doyle 1993). Members of the ATP-binding cassette (ABC)-transporter family are able to confer MDR by transporting drugs in an energydependent manner out of the cell (Tan et al. 2000). P-glycoprotein (P-gp)—the archetype of an MDR molecule(Lehne 2000)—has been suggested to be of minor importance in the intrinsic chemoresistance of NSCLC cells (Doyle 1993). In contrast, a predictive value of P-gp for therapy response to paclitaxel in the case of advanced NSCLC has been suggested recently (Yeh et al. 2003). We and others have shown that the multidrug- resistance protein 1 (MRP1) is intrinsically expressed and functionally active in NSCLC cells and correlates inversely with chemosensitivity against diverse antineoplastic drugs (Young et al. 2001; Giaccone et al. 1996; Narasaki et al. 1997; Berger et al. 1997). Also, a correlation between MRP3 and MRP1, as well as of both transporter molecules with chemoresistance, has been described in unselected NSCLC cell lines (Zouny et al. 2001). The lung resistance-related protein (LRP), another marker for chemoresistance in vitro and in vivo, does not belong to the ABC-transporter family. It recently turned out to be the main component of the vault, the largest ribonucleoparticle known so far (Scheffer et al. 1995). Despite an overexpression in several drug-selected cell models (Kickhoefer et al. 1998), the precise cellular role of vaults is currently unclear. We have shown that LRP is differently expressed in NSCLC cell lines and correlates with resistance to cisplatin but not to several other drugs (Berger et al. 2000). In order to further characterize the intrinsic, multifactorial MDR phenotype of NSCLC cells in vivo we comparatively investigated the expression of the MDRproteins P-gp, MRP1 and LRP and Tpoisomerase II α with regards to the histological subtype of NSCLC , staging , and grading. Materials and methods Study population and tumor samples. 179 consecutive patients diagnosed with early stage and operable NSCLC between years 1996 and 2001 were enrolled in this study. Out of these 58 were adenocarcinomas (20 GI, 38 GII), 106 were sqamous cell carcinomas (35 GI, 50 G2, 21 G3) and 15 large cell carcinomas (G3) . The patient population consisted of 150 mal