Thalidomide attenuates mammary cancer associated-inflammation, angiogenesis and tumor growth in mice

Abstract

Thalidomide has proven to exert anti-inflammatory, anti-proliferative and anti-angiogenic activities in both neoplastic and non-neoplastic conditions. We investigated the effects of this compound on key components (blood vessel formation, inflammatory cell recruitment/activation, cytokine production) of 4T1 mammary tumor in mice. In addition, tumor growth and lung metastasis were evaluated. 4T1 cells were injected subcutaneously into Balb/c mice. After tumor engraftment (5days), thalidomide (150mg/kg) was administered to the treated group for 7days. Tumors of control (saline) and treated groups were sized regularly, removed 12days after inoculation and processed for biochemical and immunohistological parameters to assess neovascularization, inflammation and proliferative activity. Daily oral dose of thalidomide was able to reduce in 46% the tumor volume. The number of metastasis in the lungs was less in the thalidomide-treated group compared with the control animals. Assessment of tumor vascularization revealed a significant decrease in blood vessels formation by thalidomide. Likewise, the expression of FGF-1 showed weaker cytoplasmic positivity in the group treated with thalidomide compared with the control group. The levels of two cytokines, VEGF (pro-angiogenic) and TNF-α (pro-inflammatory) were decreased in tumor samples of thalidomide-treated group compared with the control group. Accumulation of neutrophils or macrophages in the 4T1 tumor measured by the activities of inflammatory enzymes, myeloperoxidase (MPO) for neutrophils and N-acetyl-β-D-glucosaminidase (NAG) for macrophages was inhibited by the treatment. By targeting key components of 4T1 tumor simultaneously, thalidomide was effective in attenuating tumor growth and metastasis. This approach, suppression of inflammation and angiogenesis may provide further insights for both prevention and treatment of cancer.