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Increased expression
of Matrix Metalloproteinases and integrins in a mouse mammary carcinoma
following Photofrin-mediated photodynamic therapy or laser-induced hyperthermia
Ferrario, Angela1,
Rucker, Natalie1, von Tiehl, Karl1
and Gomer, Charles1,2
Childrens Hospital Los Angeles1
University of Southern California Departments of Pediatrics and Radiation
Oncology2
Abstract-
Photodynamic Therapy (PDT) elicits direct tumor cell damage as well
as microvascular injury within treated tumors. We have recently shown
that PDT-mediated tumor hypoxia induces expression of vascular endothelial
growth factor (VEGF), a major regulator of angiogenesis and that antiangiogenic
therapy improves PDT-responsiveness ( Cancer Res., 60: 1637-1644, 2000
). In the current study, using the same murine BA mammary carcinoma
tumor model, we examined whether Photofrin-mediated PDT or laser-mediated
hyperthermia could serve as activators of additional pro-angiogenic
factors. These procedures often result in local inflammatory reactions.
Immunoblot analysis of tumor extracts showed induction of Matrix Metalloproteinases
(MMPs): MMP-1; MMP-3; MMP-8 and MMP-9 in treated mice as well as increased
expression of the alpha V and the beta 3 integrin chains. An increase
in the alpha V beta 3 complex was also observed as suggested by immunoprecipitation.
Gelatin zymography and activity assay of protein extracts from treated
tumors confirmed the induction of both the latent and the enzymatically
active form of gelatinase B (MMP-9) while no major changes were observed
in gelatinase A (MMP-2) activity. Interestingly, BA carcinoma cells
treated in-vitro exhibited low expression of these pro-angiogenic molecules
following PDT or hyperthermia. Moreover, PDT-mediated oxidative stress
or heat-shock did not elicit MMPs nor alpha V beta 3 integrin activation
in BA mammary carcinoma cells, in mouse brain endothelial cells (MBEL),or
macrophages (RAW 264.7) following in-vitro treatment. These results
indicate that MMPs and alpha V beta 3 expression is directly related
to in-vivo events, possibly initiated by vascular injury/inflammatory
reaction caused by the treatments and that host cells play a major role
in secreting these factors. Since up-regulation of these molecules is
often associated with angiogenesis as well as with invasive and metastatic
potential in a variety of solid tumors our results suggest that the
administration of specific inhibitors may be a useful therapeutic adjunct
for improving PDT responsiveness.
Keywords: Photodynamic
Therapy, Angiogenesis , Matrix Metalloproteinases, Integrins
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