Metastasis is a life-threatening feature of
cancer and is primarily responsible for
cancer patient mortality. Cross talk between
tumor cells and endothelium is important for
tumor progression and
metastasis. However, very little is known about the mechanisms by which endothelial cells (ECs) that are close to
tumor cells, respond to the
tumor cells during
tumor progression and
metastasis. In this study, we exploited the use of EC-specific signal transducer activator of transcription 3 (STAT3) knockout mice to investigate the role of STAT3 in ECs in
tumor progression and
metastasis. We found that the loss of STAT3 in ECs did not affect primary
Lewis lung carcinoma (LLC)
tumor growth, but it reduced in vivo LLC
metastasis in experimental and spontaneous
metastasis models. Mechanistically, STAT3 activation upregulated
cell adhesion molecule expression, including
E-selectin and
P-selectin, in murine endothelial MS-1 cells treated with
tumor cell-
conditioned media in vitro and in pre-metastatic lungs of
tumor-bearing mice in vivo. We also found that both
E-selectin and
P-selectin were, at least in part, responsible for STAT3-induced adhesion and invasion of LLC cells through an EC monolayer. However,
tumor cell-
conditioned media from B16F10
melanoma cells did not activate STAT3 in MS-1 cells. As a result, EC STAT3 knockout did not affect B16F10
melanoma cell
metastasis. In addition, various human
cancer cells activated STAT3 in human ECs (HUVECs), resulting in increased
cell adhesion molecule expression. Collectively, our findings demonstrate that STAT3 activation in ECs promotes
tumor metastasis through the induction of
cell adhesion molecules, demonstrating a role for ECs in response to
tumor cells during
tumor metastasis.