The effect of hyperbaric oxygen treatment on malignant progression in different breast cancer models in vivo
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Background: Hypoxia is an important feature of most solid tumors and has shown to serve as a mediator for aggressive tumor growth and malignant progression of cancer. A correlation between low oxygen tension in tumors and increased predisposition for metastatic dissemination through epithelial to mesenchymal transition (EMT) has been reported. Research has shown significant anti-malignant effects of hyperbaric oxygen (HBO) treatment on chemically-induced and murine breast tumors. Thus, to establish whether HBO has a general effect on breast cancer, the overall aim of the present study was to target the hypoxic tumor microenvironment by enhancing oxygenation in human and murine breast cancer models. We investigated the effect of HBO on growth and metastasis of human and murine breast cancer cells in vivo, in addition to establish expression of major EMT markers and thus the metastatic potential. Methods: A total of 24 balb/c and 12 nod/scid female mice were injected with 5 x 105 breast cancer cells (human MDA-231 or murine 4T1 and 4T1-L) into the mammary fat pad at day 1. After tumor development the mice were divided into HBO treatment and control groups. Treatment consisted of 2.5 bar HBO exposure for 90 minutes, from day 7 post injection and every third day for 22, 25 or 53 days (4T1, 4T1-L and MDA-231 respectively) and non-treatment at normal atmospheric pressure. Mice with 4T1-L tumors were also used for biophotonic imaging to visualize cancer cells in vivo. Primary tumors were investigated for N- and E-cadherin expression by western blot and organs (lung and liver) were used for metastasis detection by histomorphometric quantification. Results and conclusion: Repeated HBO treatment significantly reduced tumor growth and metastasis to lungs in the human (MDA- 231) and murine (4T1-L) breast cancer model without affecting the murine 4T1 model. In vivo imaging of balb/c mice with 4T1-L tumors confirmed reduced tumor size compared to control but detected no metastases to distant sites. HBO treatment influenced EMT through downregulation of N-cadherin expression in human (MDA-231) primary tumors. The reduced metastatic potential could in part be attributed to this downregulation. Thus, HBO might be a possible potential adjuvant treatment of human breast cancer, although further research is needed.