EphA4-deleted microenvironment regulates cancer development and leukemoid reaction of the isografted 4T1 murine breast cancer via reduction of an IGF1 signal.

Xuefeng Jing, Takashi Sonoki, Masayasu Miyajima, Takahiro Sawada, Nanako Terada, Shigeki Takemura, Kazushige Sakaguchi

Cancer medicine 2016 Jun

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EphA4 belongs to the largest family of receptor tyrosine kinases (RTKs). Although EphA4 is highly expressed in the central nervous system, EphA4 has also been implicated in cancer progression. Most of the studies focus on the expression and function in tumor cells. It is unknown whether EphA4-deleted microenvironment affects tumor progression. Some of cancers in animals and humans, such as 4T1 cancer cells, are known to produce a large amount of granulocyte colony-stimulating factors (G-CSF/Csf3) which can stimulate myeloproliferation, such as myeloid-derived suppressor cells (MDSCs) leading to a poor recipient prognosis. We isografted 4T1 breast cancer cells into both EphA4-knockout and control wild-type female littermate mice. The results showed that the EphA4-deleted host could inhibit primary tumor growth and tumor metastasis mainly by decreasing the amount of IGF1 synthesis in the circulation and locally tissues. The EphA4-deleted microenvironment and delayed tumor development reduced the production of G-CSF resulting in the decrease of splenomegaly and leukemoid reaction including MDSCs, which in turn inhibit the tumor progression. This inhibition can be reversed by supplying the mice with IGF1. However, an excess of IGF1 supply over demand to the control mice could not further accelerate the tumor growth and metastasis. A better understanding and re-evaluation of the main role of IGF1 in regulating tumor progression could further enhance our cognition of the tumor development niche. Our findings demonstrated that EphA4-deleted microenvironment impairs tumor-supporting conditions. Host EphA4 expression regulates cancer development mainly via EphA4-mediated IGF1 synthesis signal. Thus, targeting this signaling pathway may provide a potential therapeutic option for cancer treatment. © 2016 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.

Citation

Xuefeng Jing, Takashi Sonoki, Masayasu Miyajima, Takahiro Sawada, Nanako Terada, Shigeki Takemura, Kazushige Sakaguchi. EphA4-deleted microenvironment regulates cancer development and leukemoid reaction of the isografted 4T1 murine breast cancer via reduction of an IGF1 signal. Cancer medicine. 2016 Jun;5(6):1214-27