Novel roles of Src in cancer cell epithelial-to-mesenchymal transition, vascular permeability, microinvasion and metastasis

Abstract

The Src-family kinases (SFKs), an intracellularly located group of non-receptor tyrosine kinases are involved in oncogenesis. The importance of SFKs has been implicated in the promotion of tumor cell motility, proliferation, inhibition of apoptosis, invasion and metastasis. Recent evidences indicate that specific effects of SFKs on epithelial-to-mesenchymal transition (EMT) as well as on endothelial and stromal cells in the tumor microenvironment can have profound effects on tumor microinvasion and metastasis. Although, having been studied extensively, these novel features of SFKs may contribute to greater understanding of benefits from Src inhibition in various types of cancers. Here we review the novel role of SFKs, particularly c-Src in mediating EMT, modulation of tumor endothelial-barrier, transendothelial migration (microinvasion) and metastasis of cancer cells, and discuss the utility of Src inhibitors in vascular normalization and cancer therapy.

c‐Src inhibitor selectively inhibits triple‐negative breast cancer overexpressed Vimentin in vitro and in vivo

“…Importantly, c‐Src is a critical adaptor protein to modulate focal adhesion molecule responses related with caveolin‐1, paxillin, and p130CAS . These focal adhesion signals are closely associated with metastatic potential of TNBC . How vimentin and c‐Src link together to modulate EMT in TNBC remains unclear.…”

Gold nanoparticles attenuate metastasis by tumor vasculature normalization and epithelial–mesenchymal transition inhibition

“…Tumor cells undergoing EMT display low cell surface expressions of E-cadherin, which maintain epithelial connections with neighboring cells, yet they further develop a mesenchymal cell-like cytoskeletal structure, including high levels of vimentin, and acquire the ability to leave the primary tumor mass and invade into surrounding tissues and the circulatory system. 27 There are many factors that contribute to the progression of EMT. One of these factors is hypoxia.…”

Convergence of eicosanoid and integrin biology: Role of Src in 12-LOX activation

“…Together with 12-HETE, it has been found on cancer exosomes, as has c-Src [7, 54–55], and the ITGB4 pathway appears to be regulated by micro RNAs such as miR182-5p, which is also predicted to regulate Src [56–58]. These proteins contribute to overlapping networks as well [4], where, for example, MMP9 induction can be seen by Src-mediated or ITGB4/12LOX-mediated signaling [16, 35]. …”

“…Integrins can be regulated by phosphorylation through the action of the c-Src family kinases (SFKs), non-receptor protein tyrosine kinases that mediate signal transduction during cellular differentiation, adhesion and migration [16–18]. Motivated by the observation that integrin β4 has potential tyrosine phosphorylation sites in its cytoplasmic tail, Giancotti et al revealed that β4 functions with SFKs as a binary receptor tyrosine kinase (RTK) that affects both activation and deactivation signals [19].…”