Figure 6.

Cancer‐related circulation G‐CSF was reduced by EphA4 deficiency. (A) G‐CSF ELISA assay showed that plasma G‐CSF level was very low and there was no significant difference between the two genotypes of tumor‐free mice. (B) EphA4‐KO tumor‐bearing mice without IGF1 administration showed a significant reduction in G‐CSF circulation level, which was enhanced by IGF1 treatment up to a level similar to that observed in WT tumor‐bearing mice. (WT: n = 12; KO: n = 6 of each treatment of 5–7 week paired tumor‐bearing mice). (C) The level of IGF1 was significantly less in EphA4‐KO tumor‐free mice compared with ‐WT tumor‐free mice (n = 6 of each genotype of tumor‐free mice). (D) IGF1 treatment in EphA4‐KO mice was unable to maintain IGF1 concentration in the blood to the WT level of an endogenous IGF1, although the treatment could enhance the tumor growth. (WT: n = 12; KO: n = 6 of each treatment of 5–7 week paired tumor‐bearing mice). (E) The vicious cycle (surrounded by blue dotted line) was regulated by EphA4‐mediated IGF1 synthesis pathway. The vicious cycle means that IGF1 increases tumor growth which enhanced plasma G‐CSF level. The increased G‐CSF level stimulates the myeloproliferation and extramedullary hematopoiesis (EMH) leading to a production of myeloid‐derived suppressor cells (MDSCs), which in turn promotes tumor growth and metastasis. Host EphA4 deficiency impaired the tumor progression vicious cycle mainly via decreasing IGF1 synthesis, and others (black dotted lines) such as FGFR pathway (mentioned in context) and unknown molecules.