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. 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.

Identification of feature genes for smoking-related lung adenocarcinoma based on gene expression profile data

“…Importantly, studies have found that several members of Eph receptor kinase family have been found to be overexpressed in various cancers 27,28. For instance, EPHA4 expression is frequently functionally altered in breast cancer, gastric cancer, pancreatic adenocarcinoma, and lung adenocarcinoma 29–32. Given the role of EPHA4 in SVM classifier, we speculated that EPHA4 may serve as a smoking-related biomarker in lung adenocarcinoma.…”

Knockdown of GSG2 inhibits prostate cancer progression in�vitro and in�vivo

“…The results revealed that knockdown of GSG2 inhibited the phosphorylation of EphA4, EphA5, EphA6, EphA7, EphB3, FER, IGF-IR, Itk, JAK2, JAK3, LTK, Lyn, M-CSFR, MUSK, NGFR, PDGFR-α, ROS, SRMS, TXK, Tyk2 and ZAP70 in PCa cells compared with those infected with shCtrl. According to previous studies, EphA4, EphA5, EphA6 and EphA7 promote angiogenesis and PCa metastasis, and are associated with human PCa progression (29,(31)(32)(33). FER kinase serves a central role in breast cancer metastasis and PCa cell proliferation (34).…”

Direct interaction of receptor tyrosine kinases, EphA4 and PDGFRβ, plays an important role in the proliferation of neural stem cells

“…Cell-cell contact-dependent signaling pathway from ephrins to Ephs (forward signaling) or from Ephs to ephrins (reverse signaling) regulates many physiological and developmental processes. Bidirectional signaling possesses many functions, including neural stem cell maintenance and plasticity regulation in the proliferation zone of adult brain, 6,7 neuron migration, 8 axon guidance, 9 angiogenesis, 10 bone homeostasis, 11 embryonic patterning, 12 tumorgenesis, [13][14][15][16][17][18] insulin secretion, 19 and so on. EphA4 expression is very high in the brain, and recently, EphA4 has been proposed to be implicated in Alzheimer's disease (AD), 20,21 Parkinson's disease (PD), 22,23 amyotrophic lateral sclerosis (ALS), 24 and other neurodegenerative diseases.…”