| Abstract |
During the last years there has been a rapid development in research on the mechanisms of carcinogenesis, aiming to the better understanding of the clinical phenomena observed and to the development of pharmaceutical products with greater efficacy and less toxicity.
Normal cell growth is the result of the interplay of three fundamental processes: cell proliferation, cell differentiation and cell death. Cancer is caused by disturbances of these regulatory mechanisms resulting in uncontrolled proliferation of neoplastic cells and the inability to complete the cell differentiation program. Due to these disorders the cells exhibit progressive genomic instability, impaired cell development, and invasion ability. The biological behavior of cancer cells and the host immune responses are responsible for all cancer manifestations.
Malignant transformation is caused by the gradual accumulation of multiple mutations in essential genes. These mutations occur for a long time in cells. However, a normal cell selectively acquires the ability to proliferate without control and generates a large number of daughter cells with the same genetic features. The uncontrolled growth and division of cancer cells arises from the gradual acquisition of gene mutations that control cell growth and differentiation or apoptosis. This results in the ability of neoplastic cells to proliferate without physiological limitations. Thus, the pathogenesis of cancer involves three classes of genes. Oncogenes (e.g., ras, EGFR, erb-B, c-kit) are modified forms of normal genes called proto-oncogene that regulate normal cell growth and differentiation. The tumor suppressor genes (e.g., p53, p21,
retinoblastoma) are genes encoding proteins that inhibit cell proliferation. Finally, DNA repair genes code for proteins whose normal function is to correct errors that arise when cells duplicate their DNA prior to cell division, in order to maintain the genome integrity and DNA replication fidelity.
A common target of antitumor drugs widely used as chemotherapeutics in non-small cell lung cancer (NSCLC) is the mechanism of apoptosis. Cell apoptosis or programmed cell death, plays a regulatory and protective role in living organisms as a normal cellular process essential to maintain homeostasis. There are two major pathways of apoptosis in mammalian cells, the extrinsic and intrinsic pathways. The extrinsic pathway is activated via the Fas death receptor (CD95), which is a member of the tumor necrosis factor (TNF) receptor superfamily. When the intrinsic pathway is activated leads to the release of cytochrome-c by the mitochondria. The Bcl-2 family of proteins has an important role in regulating the intrinsic pathway of apoptosis. Both pathways result in a final common pathway involved in the activation of a cascade of proteases called caspases, resulting in the programmed cell death.
The p53 gene, the NFκB factor and the PI3K kinase play an important role in the regulation of apoptosis. p53 gene is located in the short arm of chromosome 17 and its protein product is present in almost all normal tissues. In normal cells, p53 regulates cell division. In particular, in response to DNA damage, its levels increase and prevent the cell from entering S phase of the cell cycle, thus providing enough time for DNA repair to take place. Thus, p53 acts by limiting uncontrolled cell proliferation. Loss of p53 leads to inhibition of apoptosis.
The aim of this study was to investigate the molecular and histopathological parameters that determine the resistance of NSCLC to different chemotherapeutic regimens. The study initially focused on endonucleases (enzymes involved in repairing DNA damage) and on proteins that control apoptosis (p53, p21, bcl-2).
A total of 131 consecutive patients with histologically confirmed stage ΙΙΙB-IV NSCLC were enrolled. Patients received first-line chemotherapy combinations with docetaxel-gemcitabine or docetaxel-cisplatin at the «Sotiria» Hospital of Chest Diseases of Athens. The study has been approved by the institutional ethics committee and all patients gave their informed consent for the use of the tissue material for translational research. Patient data have not been used or presented in another study.
The first results of the study were not encouraging, as the analysis in the first 100 patients failed to reveal statistically significant differences between groups of patients based on endonuclease (APE1) detection but also on the p53, p21 and bcl-2 proteins that are involved in the process of apoptosis.
Due to the above difficulties, we evaluated the correlation of BRCA1, TXR1 and TSP1 mRNA expression with treatment outcome to docetaxel-based first-line chemotherapy in patients with stage IIIB-IV NSCLC.
The BRCA1 protein is involved in DNA repair and the gene product has been associated with various tumors, including NSCLC. The BRCA1 expression is associated with sensitivity to taxane therapy and platinum resistance. TXR1 is also associated with taxane resistance by inhibiting the process of apoptosis in the cells. This activity is mediated by the transcriptional repression of thrombospondin 1 (TSP1) expression.
Our results have shown that TXR1-TSP1 mRNA levels were inversely correlated with the treatment outcome (Spearman's test: -0.37; p = 0.001), ie lower levels of TXR1 mRNA showed statistically significant correlation with higher response rates (RR; p = 0.018), higher median progression-free survival (PFS, p = 0.029) and higher mean overall survival (mOS p = 0.003). In contrast, high levels of TSP1 mRNA expression were associated with higher response rates (p = 0.035), higher PFS (p <0.001), and higher mean overall survival (p <0.001). Additionally, higher BRCA1 mRNA gene expression was significantly associated with higher response rates (p = 0.028) and elevated PFS (p = 0.021), but not with higher mean overall survival (p = 0.4). Multifactorial analysis showed that the combination of low levels of TXR1 / high TSP1 mRNA was an independent factor predicting increased PFS (HR 0.49; 95% CI: 0.32-0.76; p <0.001) and mean overall survival (HR 0.37; 95% CI: 0.2-0.58; p<0.001). The same analysis revealed that increased BRCA1 mRNA gene expression was associated with elevated PFS (HR 0.53; 95% CI: 0.37-0.78; p = 0.001).
These results indicated that the expression of TXR1-TSP1 and BRCA1 can be used as predictive marker of the NSCLC patients’ response to taxane chemotherapy.
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