SIX1 induces lymphangiogenesis and metastasis via upregulation of VEGF-C in mouse models of breast cancer
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
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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Research Article Oncology

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 7

SIX1 correlates with VEGF-C expression in mammary carcinoma cell lines and in human breast cancers.

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SIX1 correlates with VEGF-C expression in mammary carcinoma cell lines a...
(A) SIX1 and VEGFC expression values were retrieved from an Oncomine microarray data set (as indicated in the figure) and were plotted according to different types of cell lines or by expression value. X and y axes of the right panel indicate mRNA expression analyzed on Affymetrix U133 Plus 2.0 microarrays. (B) Representative positive and negative staining of SIX1 and VEGF-C on human breast cancer tissue sections. Original magnification, ×100. (C) Model depicting the mechanism by which SIX1 promotes metastatic dissemination. Overexpression of SIX1 leads to increased VEGF-C and stimulates lymphangiogenesis, allowing for increased escape of tumor cells through the lymphatics and increased distant metastasis. However, SIX1 is also able to augment the later stages of metastasis of cancer cells that have traveled through the vasculature, thus contributing to metastatic spread via multiple mechanisms. An extension of this finding is that while inhibitors of the VEGF-C/VEGFR3 axis may prevent lymphatic spread, inhibitors of SIX1 are expected to inhibit metastasis at multiple stages, serving as powerful antimetastatic agents.