SIX1 induces lymphangiogenesis and metastasis via upregulation of VEGF-C in mouse models of breast cancer
Chu-An Wang, … , J. Chuck Harrell, Heide L. Ford
Chu-An Wang, … , J. Chuck Harrell, Heide L. Ford
Published April 2, 2012
Citation Information: J Clin Invest. 2012;122(5):1895-1906. https://doi.org/10.1172/JCI59858.
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SIX1 induces lymphangiogenesis and metastasis via upregulation of VEGF-C in mouse models of breast cancer

Abstract

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.

Authors

Chu-An Wang, Paul Jedlicka, Aaron N. Patrick, Douglas S. Micalizzi, Kimberly C. Lemmer, Erin Deitsch, Matias Casás-Selves, J. Chuck Harrell, Heide L. Ford

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Figure 1

SIX1 overexpression leads to increased tumor-associated lymphangiogenesis and lymphatic invasion.

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SIX1 overexpression leads to increased tumor-associated lymphangiogenesi...
(A) SIX1-expressing tumors have an increased number of lymphatic vessels, both within the neoplastic mass (intratumoral) and within the surrounding fibroinflammatory tissue (peritumoral), compared with that in control tumors of the same size. Positive immunostaining (brown coloration, DAB) for the lymphatic marker Lyve-1 was used to identify lymphatic vessels. Representative examples of intratumoral (original magnification, ×400) and peritumoral (original magnification, ×200) lymphatic vessels, as indicated by the arrows (asterisks represent tumors). Quantification of Lyve-1–positive vessels in a subset (n = 12) of the tumors. (B) Example of peritumoral lymphatic invasion by tumor cells (H&E stain; asterisk represents tumor cells; arrowheads represent lymphatic vessels) (original magnification, ×400). Quantification of the amount of peritumoral lymphatic invasion in histologic sections of MCF7-Ctrl and MCF7-SIX1 tumors. All tumors were fixed when they reached a volume of 2 cm3; H&E-stained histologic sections were scored in a blinded manner by a pathologist. *P < 0.05.