Malignant tumors remain the main death-caused reason of human at present. The novel strategies are necessary to be developed for improving the efficacy of cancer therapy. This study aimed to explore the effects of tumor microenvironment on cancer therapy. In order to achieve this goal, the tumor microenvironment of ALTS1C1 brain tumor was regulated by over-expressing matrix metalloproteinase-2 (MMP-2) expression followed by combination of two therapeutic approaches; radiotherapy and chemotherapy (PB221- sigma-2 receptor agonist). The study revealed that MMP2 expression which overexpressed by a bicistronic vector approach led to shortage in the median survival days of brain tumor-bearing mice. MMP2ov tumors had a higher invasive and migration ability in comparison to ALTS1C1 tumors. The microvascular density (MVD) in MMP2ov tumors was increased and vessel function was affected as shown by increasing pericytes and collagen IV coverage on blood vessels. This study also demonstrated that the overexpressing of MMP-2 diminished the anti-tumor effects of the neoadjuvant chemoradiotherapy in vitro. ALTS1C1-MMP2 cell line (ALTS1C1-MMP2ov) was more radioresistant than ALTS1C1 cell line. The administration of PB221 enhanced the efficiency of the radiotherapy in decreasing the surviving of ALTS1C1 & ALTS1C1-MMP2ov cell lines in a similar fashion. This effect appeared to be additive effect and indicated that PB221 and irradiation exert their effects at different target sites. In summary, this study provides an applicable strategy that can improve the efficiency of brain tumor treatment by combining chemotherapy with radiotherapy. This study also demonstrated the critical role of MMP2 on invasiveness of brain tumors and recruitment of pericytes into brain tumors microenvironment, which makes MMP2 a target gene for inhibition to enhance the sensitivity of brain tumors to chemoradiotherapy.

DEDICATION…………………………………………………………...……………. III
ACKNOWLEDGEMENT………………………………………………………………V
CONTENTS……………………………………………………….……………...…… VI
LIST OF FIGURES………………………………………………..…………………. VII
LIST OF ABBREVIATIONS………………………………………...………………. IX
ABSTRACT……………………………………………………………...…………… XII
INTRODUCTION………………………………………………………….………….. 01
MATERIALS & METHODS…………………………………………………………. 09
RESULTS………………………………………………………………………….……21
DISCUSSION.………………………………………………………………………..... 32
CONCLUSION & FUTURE WORK……………………………………………..…. 38
FIGURES……………………………………………………………………………… 40
REFERENCES……………………………………………………………..……….… 59

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