title: EphA4-deleted microenvironment regulates cancer development and leukemoid reaction of the isografted 4T1 murine breast cancer via reduction of an IGF1 signal.
abstract: 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.
authors.affiliation: Departments of Molecular Cell Biology and Molecular Medicine, Institute of Advanced Medicine, Wakayama Medical University, School of Medicine, 811-1 Kimiidera, Wakayama, 641-8509, Japan.
authors.forename: Xuefeng
authors.initials: X
authors.lastname: Jing
authors.affiliation: Departments of Hematology/Oncology, University Hospital, Wakayama Medical University, School of Medicine, 811-1 Kimiidera, Wakayama, 641-8509, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Sonoki
authors.affiliation: Laboratory Animal Center, Wakayama Medical University, School of Medicine, 811-1 Kimiidera, Wakayama, 641-8509, Japan.
authors.forename: Masayasu
authors.initials: M
authors.lastname: Miyajima
authors.affiliation: Departments of Molecular Cell Biology and Molecular Medicine, Institute of Advanced Medicine, Wakayama Medical University, School of Medicine, 811-1 Kimiidera, Wakayama, 641-8509, Japan.
authors.forename: Takahiro
authors.initials: T
authors.lastname: Sawada
authors.affiliation: Departments of Molecular Cell Biology and Molecular Medicine, Institute of Advanced Medicine, Wakayama Medical University, School of Medicine, 811-1 Kimiidera, Wakayama, 641-8509, Japan.
authors.forename: Nanako
authors.initials: N
authors.lastname: Terada
authors.affiliation: Department of Hygiene, Wakayama Medical University, School of Medicine, 811-1 Kimiidera, Wakayama, 641-8509, Japan.
authors.forename: Shigeki
authors.initials: S
authors.lastname: Takemura
authors.affiliation: Departments of Molecular Cell Biology and Molecular Medicine, Institute of Advanced Medicine, Wakayama Medical University, School of Medicine, 811-1 Kimiidera, Wakayama, 641-8509, Japan.
authors.forename: Kazushige
authors.initials: K
authors.lastname: Sakaguchi
mesh_terms: D000818:Animals; D015415:Biomarkers; D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D004195:Disease Models, Animal; D005260:Female; D017353:Gene Deletion; D015870:Gene Expression; D017930:Genes, Reporter; D016179:Granulocyte Colony-Stimulating Factor / Q000097:blood / Q000378:metabolism; D006411:Hematopoiesis, Extramedullary / Q000235:genetics; D007334:Insulin-Like Growth Factor I / Q000378:metabolism*; D007955:Leukemoid Reaction / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D009362:Neoplasm Metastasis; D036122:Receptor, EphA4 / Q000235:genetics*; D015398:Signal Transduction; D013163:Splenomegaly; D047368:Tumor Burden; D059016:Tumor Microenvironment / Q000235:genetics*
chemical_list: D015415:Biomarkers; D016179:Granulocyte Colony-Stimulating Factor; D007334:Insulin-Like Growth Factor I; D036122:Receptor, EphA4
keywords: 4T1 breast cancer; EphA4; G-CSF; IGF1; leukemoid reaction