Correlation Between Polyploidy Formation And Tumor Chemo-resistance

ObjectiveCancer is a major threat to human health. Chemotherapy, an essential method of systemic therapy, plays an important role in cancer treatment. Spindle poisons, such as taxol and docetaxel, are the first-line chemotherapeutic drugs commonly used in the treatment of gynecologic tumors. It was observed that in the initial phase of the chemotherapy the tumors was sensitive to the drugs, but the majority of the tumors showed chemo-resistance or relapsed in the subsequent chemotherapeutic stages. In some cases, chemo-resistance was observed even in the initial treatment phase.The mechanisms of chemo-resistance are complex and diverse. Research on the mechanisms of spindle poison induced resistance is currently focused on the multidrug resistance genes. Previous study in our lab showed that in the process of spindle poison treatment breast cancer cell line HCC1806underwent apoptosis and another breast cancer cell line MDA-MB-231cells formed polyploidy cells. Eventually these polyploidy cells escaped from the chemotherapy, obtained the capacity of immortalization, and exhibited multidrug resistance. It was speculated that these "survivors" escaped from the chemotherapy was one of the reasons causing chemo-resistance and the tumor recurrence. Several studies found similar results that polyploidy cells were insensitive to radiotherapy and chemotherapy because of their genetic instability. Due to the subcloning characteristics of the polyploid cells, prognosis of the polyploid tumor was even poorer. Thus, the hypothesis was that the polyploidy tumor induced by spindle poisons may play an important role in tumor chemo-resistance.Preliminary study in our lab explored the possible mechanism of apoptosis escape and chemo-resistance in the polyploidy tumor cells. It was found that in the apoptosis pathway there was an aberrant expression of the anti-apoptotic gene Bcl-2, which produced a significant effect in the process of polyploidy formation induced by spindle poisons and chemo-resistance. Apoptotic pathway is the main pathway on which spindle poisons act. The functions of monitoring points in the apoptotic pathway are very important. Studies have shown that Bcl-2, as the intersection point of apoptosis signal transduction pathways, could enhance the resistance of the cells to most DNA damage factors. Combined with our pre-studies, the results suggested that the role of Bcl-2overexpression in the polyploidy tumor formation and chemo-resistance process is very important. It is likely to become an important entry point for follow-up studies against polyploidy tumor resistance.The question was whether resistant recurrent tumors with above changes were due to the spindle poison treatment. In this study, using FISH and IHC to detect the clinical tumor tissue were performed to further explore the correlation between polyploidy formation induced by spindle poison and tumor chemo-resistance, and the significance of Bcl-2expression in the whole process.MethodsThe clinical and pathological data of15tumor cases were collected before and after the spindle poison treatment. They were divided into recurrent chemo-resistance group and undergoing neoadjuvant chemotherapy group. DNA ploidys were detected using the Fluorescence in situ hybridization (FISH) before and after spindle poison treatment. The expression of Bcl-2was measured by the immune histochemical method before and after chemotherapy.Results1、Recurrent chemo-resistant tumors group:In the9cases, the number of polyploidy cells increased significantly after the recurrence (P=0.001). The Bcl-2expression in the drug-resistance tissue was significantly higher than that before the treatment, and the over expression of Bcl-2had a positive correlation with the increased number of polyploidy cells (r=0.791, P <0.05)2、Neoadjuvant chemotherapy group: In the6cases, there were4cases showing that polyploidy cell numbers were increased after standard chemotherapy treatment courses (average chemotherapy treatment course are4.25courses). Among the4cases,3cases showed the Bcl-2over expression. Finally2cases among3cases of Bcl-2overexpression showed chemo-resistance after7chemotherapy treatment courses. Polyploidy numbers did not increase in these2cases, corresponding to the Bcl-2that the expression was not increased in1case.Conclusion1、Polyploidy tumor formation after chemotherapy with taxane may be an important symbol of chemo-resistance.2、The overexpression of antiapoptotic gene Bcl-2was an important regulatory factor in the process of polyploidy tumor formation and chemo-resistance.3、The mechanism of polyploidy tumor chemo-resistance is muti-gene involved,4、Regulation of the expression of key genes in apoptotic pathway, such as over expression of Bcl-2, may effectively inhibit the polyploidy tumor and chemo-resistance. The reaction of tumor cells to spindle poison in vitro tests (polyploid formation or apoptosis) may provide a reference for both chemo regimen selection and prediction of cancer patients’prognosis.