Abstract
Malignant tumors remain the main death-caused reason of human at present. The novel strategies are necessary to be developed for improving the efficiency of cancer therapy. This study is aimed to explore the effects of tumor microenvironment on cancer therapy and two approaches were utilized to achieve the goal: (1) To attract or activate tumor-associate macrophages (TAMs) by over-expressing interleukin-3 (IL-3) in TRAMP-C1 prostate tumor model; (2) To regulate the tumor microenvironment of ALTS1C1 brain tumor by suppressing matrix metalloproteinase-2 (MMP-2) expression. The first study showed that the co-expression of IL-3 enhanced the anti-tumor effect of HSV-TK/GCV therapy in vivo, but not in vitro. The IL3-activated IL-4 dominant lymphocytes became IFN- dominant lymphocytes after combined therapy. The therapeutic effect was inhibited by macrophage depletion using carrageen treatment or nitric oxide blockage using L-NAME administration. This study demonstrated that IL-3 enhanced HSV-TK/GCV therapy by a macrophage- or NO-dependent anti-tumor pathway. The second study showed that MMP2 expression inhibited by siRNA approach led to the prolonged median survival days of brain tumor-bearing mice. MMP2kd tumors had smaller tumor size and lower Ki67 proliferating index than parental tumors. The invasive ability was decreased as demonstrated by fewer infiltrating islands and lower invasive marker GLUT-1 expression in MMP2kd tumors. More interesting is that microvascular density (MVD) in MMP2kd tumors was not reduced but vessel function was impaired as shown by decreasing pericyte coverage on blood vessels. This study also demonstrated that radiation prolonged the survival days of MMP2kd tumor-bearing mice significantly. In summary, this study provides a feasible strategy that can improve the efficacy of prostate tumor treatment by combining IL-3 with suicide gene therapy. This study also demonstrated the critical role of MMP2 on invasiveness of brain tumors and recruitment of pericytes into brain tumor microenvironment and MMP2 inhibition enhanced the effect of radiotherapy.