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Background:

The role of stress has been previously described to increase tumorigenesis via upregulation of VEGF and MMPs. To determine the host vs. tumor cell contribution to stress induced tumor growth, we utilized a MMP-9 knockout orthotopic mouse model of ovarian cancer.

Methods and Materials:

Confirmed MMP-9 knockout female athymic mice were inoculated with either HeyA8 (2.5 x 105 cells/mouse) or SKOV3ip1 (1.0 x 106 cells/mouse) human ovarian cancer cell lines one week after induction of stress through physical restraint for 2 hours daily (controls were food and water deprived for the same length of time). The role of VEGF and MMP-9 was determined using either bevacizumab or liposomal MMP-9 SiRNA, respectively in the in vivo experiments. Mice were sacrificed at the termination of the experiments. Tumors were collected, weighed and analyzed by immunohistochemistry for VEGF and human MMP-9.

Results:

Chronic stress resulted in increased tumor burden when compared to non-stressed animals (0.300±0.28 g vs. 0.12±0.08 g, p=0.02); furthermore, it significantly upregulated human MMP9 (p=0.032) and VEGF (p=0.016). With beta-blockade intended to abrogate the effects of stress, stressed mice consistently had higher tumor burden when compared to their counterparts treated with propanolol (0.49±0.28 g vs. 0.09 ±0.07 g, p=0.0025) while treated mice shared similar tumor burden as mice that were non-stressed (0.12±0.11 g, p=ns). Finally, with upregulation of human MMP-9 and VEGF already established in our previous in vivo experiments, we sought to negate their effects through SiRNA and VEGF monoclonal antibody, respectively. Mice that were stressed without therapy had significantly higher tumor load than stressed mice that were treated with either SiRNA against human MMP-9 (0.65±0.46 g vs. 0.29±0.39 g, p=0.041) or bevacizumab (0.65±0.46 g vs. 0.11±0.07 g, p=0.01) while the latter groups had similar tumor weights as the non-stressed mice with and without these treatments (all p=ns).

Conclusion:

Chronic stress plays an important role in the upregulation of tumor derived MMP-9 and VEGF, which account for increased tumor growth and progression.

98th AACR Annual Meeting-- Apr 14-18, 2007; Los Angeles, CA