{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,9,20]],"date-time":"2025-09-20T18:53:44Z","timestamp":1758394424219},"reference-count":49,"publisher":"Wiley","issue":"6","license":[{"start":{"date-parts":[[2016,2,29]],"date-time":"2016-02-29T00:00:00Z","timestamp":1456704000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004420","name":"Wakayama Medical University","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100004420","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Cancer Medicine"],"published-print":{"date-parts":[[2016,6]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>EphA4 belongs to the largest family of receptor tyrosine kinases (<jats:styled-content style=\"fixed-case\">RTK<\/jats:styled-content>s). Although\u00a0EphA4 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\u2010deleted 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\u2010stimulating factors (G\u2010<jats:styled-content style=\"fixed-case\">CSF<\/jats:styled-content>\/Csf3) which can stimulate myeloproliferation, such as myeloid\u2010derived suppressor cells (<jats:styled-content style=\"fixed-case\">MDSC<\/jats:styled-content>s) leading to a poor recipient prognosis. We isografted 4T1 breast cancer cells into both EphA4\u2010knockout and control wild\u2010type female littermate mice. The results showed that the EphA4\u2010deleted host could inhibit primary tumor growth and tumor metastasis mainly by decreasing the amount of <jats:styled-content style=\"fixed-case\">IGF<\/jats:styled-content>1 synthesis in the circulation and locally tissues. The EphA4\u2010deleted microenvironment and delayed tumor development reduced the production of G\u2010<jats:styled-content style=\"fixed-case\">CSF<\/jats:styled-content> resulting in the decrease of splenomegaly and leukemoid reaction including <jats:styled-content style=\"fixed-case\">MDSC<\/jats:styled-content>s, which in turn inhibit the tumor progression. This inhibition can be reversed by supplying the mice with <jats:styled-content style=\"fixed-case\">IGF<\/jats:styled-content>1. However, an excess of <jats:styled-content style=\"fixed-case\">IGF<\/jats:styled-content>1 supply over demand to the control mice could not further accelerate the tumor growth and metastasis. A better understanding and re\u2010evaluation of the main role of <jats:styled-content style=\"fixed-case\">IGF<\/jats:styled-content>1 in regulating tumor progression could further enhance our cognition of the tumor development niche. Our findings demonstrated that EphA4\u2010deleted microenvironment impairs tumor\u2010supporting conditions. Conclusion: Host EphA4 expression regulates cancer development mainly via EphA4\u2010mediated <jats:styled-content style=\"fixed-case\">IGF<\/jats:styled-content>1 synthesis signal. Thus, targeting this signaling pathway may provide a potential therapeutic option for cancer treatment.<\/jats:p>","DOI":"10.1002\/cam4.670","type":"journal-article","created":{"date-parts":[[2016,2,29]],"date-time":"2016-02-29T10:34:10Z","timestamp":1456742050000},"page":"1214-1227","update-policy":"http:\/\/dx.doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["EphA4\u2010deleted microenvironment regulates cancer development and leukemoid reaction of the isografted 4T1 murine breast cancer via reduction of an <scp>IGF<\/scp>1 signal"],"prefix":"10.1002","volume":"5","author":[{"given":"Xuefeng","family":"Jing","sequence":"first","affiliation":[{"name":"Departments of Molecular Cell Biology and Molecular Medicine Institute of Advanced Medicine Wakayama Medical University School of Medicine  811\u20101 Kimiidera Wakayama 641\u20108509 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