E-poster Presentation 2014 World Cancer Congress

A novel IGF1 signalling pathway regulated by EphA4 delays cancer development induced by 4T1 murine breast cancer isografts (#1044)

Xuefeng Jing 1 , Takashi Sonoki 1 , Masayasu Miyajima 1 , Takahiro Sawada 1 , Kenryo Furushima 1 , Nanako Terada 1 , Daiki Arai 1 , Kazuki Kawakami 1 , Kazushige Sakaguchi 1
  1. Wakayama Medical University, Wakayama City, JAPAN, Japan

Background:

EphA4 belongs to a large family of receptor tyrosine kinases that play critical roles in cancer progression. We have previously reported that the absence of EphA4 expression decreased the amount of IGF1 in the circulation and tissues, which contributed to the short stature. 4T1 breast cancer are known to produce a large amount of granulocyte colony‑stimulating Factor which can cause splenomegaly and leukemoid reaction associated with a poor prognosis.

Aim:

To investigate whether EphA4 deletion microenvironment affects tumor progression and leukemoid reaction in a novel IGF1 production pathway.

Methods:

We isografted mouse breast cancer cells (4T1) into the mammary fatpad of both EphA4-knockout (KO) and control female mice. Recombinant human IGF1 was subcutaneously injected into the EphA4-KO mice for 9 weeks starting 4 weeks before grafting 4T1 cells. The control mice were treated with saline alone for the same period. The parameters evaluated in vivo were tumor growth, metastasis, peripheral blood leukocyte number and splenomegaly.

Results:

Both the size of primary tumors and the distribution of metastatic tumors were markedly reduced in EphA4-KO mice without IGF1 injection than those in control EphA4 wild type (WT) littermate mice. Furthermore, splenomegaly and leukemoid reaction were markedly severer in control WT mice. The EphA4-KO mice treated with IGF1 gained a significant amount of tumor weight as well as increased metastatic tumor numbers and showed an enhanced leukemoid reaction to almost the level of the control mice without significant difference. However, IGF1 injection could not enhance splenomegaly.

Conclusions:

EphA4-deleted microenvironment displays an impaired tumor-supporting condition. The absence of EphA4 delays tumor development and reduces leukemoid reaction by decreasing IGF1 in the circulation and tissues. EphA4 appears to be involved in the augmentation of both leukemoid reaction and splenomegaly, but the latter might not directly be mediated by an IGF1 signal. Our findings may prove a new therapeutic target..