EphA4-deleted microenvironment regulates cancer development and leukemoid reaction of the isografted 4T1 murine breast cancer via reduction of an IGF1 signal.
EphA4-deleted microenvironment regulates cancer development and leukemoid reaction of the isografted 4T1 murine breast cancer via reduction of an IGF1 signal.
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DOI：
10.1002/cam4.670
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发表时间：
2016-06
期刊：
影响因子：
4
通讯作者：
Sakaguchi K
中科院分区：
文献类型：
--
作者：
Jing X;Sonoki T;Miyajima M;Sawada T;Terada N;Takemura S;Sakaguchi K
EphA 4属于受体酪氨酸激酶（RTK）的最大家族。虽然EphA 4在中枢神经系统中高度表达，但EphA 4也与癌症进展有关。大多数研究集中在肿瘤细胞中的表达和功能。目前尚不清楚EphA 4缺失的微环境是否会影响肿瘤进展。动物和人类的一些癌症，如4 T1癌细胞，已知会产生大量的粒细胞集落刺激因子（G-CSF/Csf 3），其可以刺激骨髓增殖，如髓源性抑制细胞（MDSC），导致接受者预后不良。我们将4 T1乳腺癌细胞同种移植到EphA 4敲除和对照野生型雌性同窝小鼠中。结果表明，EphA 4缺失的宿主可以主要通过减少循环和局部组织中IGF 1的合成量来抑制原发性肿瘤生长和肿瘤转移。EphA 4缺失的微环境和延迟的肿瘤发展减少了G-CSF的产生，导致脾肿大和包括MDSC在内的类白血病反应减少，这反过来又抑制了肿瘤进展。这种抑制可以通过向小鼠提供IGF 1来逆转。然而，对于对照小鼠，过量的IGF 1供应超过需求并不能进一步加速肿瘤的生长和转移。更好地理解和重新评估IGF 1在调节肿瘤进展中的主要作用，可以进一步提高我们对肿瘤发展生态位的认识。我们的研究结果表明，EphA 4缺失的微环境损害肿瘤支持条件。结论：宿主EphA 4表达主要通过EphA 4介导的IGF 1合成信号调节肿瘤的发生。因此，靶向这一信号通路可能为癌症治疗提供潜在的治疗选择。
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. Conclusion: 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.