[HTML][HTML] SIX1 induces lymphangiogenesis and metastasis via upregulation of VEGF-C in mouse models of breast cancer

CA Wang, P Jedlicka, AN Patrick… - The Journal of …, 2012 - Am Soc Clin Investig
CA Wang, P Jedlicka, AN Patrick, DS Micalizzi, KC Lemmer, E Deitsch, M Casás-Selves
The Journal of clinical investigation, 2012Am Soc Clin Investig
An association between lymph node metastasis and poor prognosis in breast cancer was
observed decades ago. However, the mechanisms by which tumor cells infiltrate the
lymphatic system are not completely understood. Recently, it has been proposed that the
lymphatic system has an active role in metastatic dissemination and that tumor-secreted
growth factors stimulate lymphangiogenesis. We therefore investigated whether SIX1, a
homeodomain-containing transcription factor previously associated in breast cancer with …
An association between lymph node metastasis and poor prognosis in breast cancer was observed decades ago. However, the mechanisms by which tumor cells infiltrate the lymphatic system are not completely understood. Recently, it has been proposed that the lymphatic system has an active role in metastatic dissemination and that tumor-secreted growth factors stimulate lymphangiogenesis. We therefore investigated whether SIX1, a homeodomain-containing transcription factor previously associated in breast cancer with lymph node positivity, was involved in lymphangiogenesis and lymphatic metastasis. In a model in which human breast cancer cells were injected into immune-compromised mice, we found that SIX1 expression promoted peritumoral and intratumoral lymphangiogenesis, lymphatic invasion, and distant metastasis of breast cancer cells. SIX1 induced transcription of the prolymphangiogenic factor VEGF-C, and this was required for lymphangiogenesis and lymphatic metastasis. Using a mouse mammary carcinoma model, we found that VEGF-C was not sufficient to mediate all the metastatic effects of SIX1, indicating that SIX1 acts through additional, VEGF-C–independent pathways. Finally, we verified the clinical significance of this prometastatic SIX1/VEGF-C axis by demonstrating coexpression of SIX1 and VEGF-C in human breast cancer. These data define a critical role for SIX1 in lymphatic dissemination of breast cancer cells, providing a direct mechanistic explanation for how VEGF-C expression is upregulated in breast cancer, resulting in lymphangiogenesis and metastasis.
The Journal of Clinical Investigation