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Epidermal Growth Factor-Like Protein-7
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This entry is adapted from the peer-reviewed paper 10.3390/cancers13051014

Cancer growth and metastasis require interactions with the extracellular matrix (ECM), which is home to many biomolecules that support the formation of new vessels and cancer growth. One of these biomolecules is epidermal growth factor-like protein-7 (EGFL7). EGFL7 alters cellular adhesion to the ECM and migratory behavior of tumor and immune cells contributing to tumor metastasis. EGFL7 is engaged in the formation of new vessels and changes in ECM stiffness. One of its binding partners on the endothelial and cancer cell surface is beta 3 integrin. Beta 3 integrin pathways are under intense investigation in search of new therapies to kill cancer cells. All these properties enable EGFL7 to contribute to drug resistance. 

beta 3 integrin integrin cancer drug resistance angiocrine factor angiogenesis EGFR EGFL7

1. Introduction

Tumor growth and metastasis rely on the tumor vascular network for adequate delivery of oxygen and nutrients [1]. Tumor endothelial cells (ECs) are the cellular building blocks of the nutrient-carrying vasculature. During tumor growth, activated ECs expand and form new capillaries in a process called angiogenesis [2]. These capillaries and vessels carry nutrients to hungry cancer cells and ensure proper oxygen delivery.

ECs release so-called angiocrine factors [3], which include the angiogenic factor vascular endothelial growth factor-A (VEGF-A), Jagged1 (Jag1), endothelin, enzymes such as tissue-type plasminogen activator [3], and epidermal growth factor-like protein-7 (EGFL7) [4]. EGFL7 is produced by cancer-associated ECs [4][5] and certain tumor cell types [4][6].

EGFL7 controls intercellular and cell–matrix communication, which are key features of tumor progression and metastasis, by hijacking the receptor tyrosine kinase epidermal growth factor receptor (EGFR), integrin, and Notch signaling pathways [6][7][8].

EGFL7 modulates cell migration by interacting with extracellular matrix (ECM) sensing integrins [9]. Integrins are a family of cell surface receptors that help cells to interact with the extracellular microenvironment, thereby controlling cell anchorage and movement. Integrins exist as heterodimers with noncovalently linked alpha and beta subunits and link the cytoskeleton with the ECM [10]. Integrins are mechanotransducers and key factors during cell migration and are thereby implicated in many steps of cancer progression, starting with primary tumor development to metastasis, cancer stem cell development, and drug resistance (reviewed in [11]). EGFL7 interacts with two of the most studied integrins in cancer—namely, alphaV:beta 3 (ITGAV:ITGB3) and the alpha5:beta1 integrin (ITGA5:ITGB1).

Integrins bind to a wide range of ECM proteins containing the arginylglycylaspartic acid (RGD)-motif. EGFL7 is one of those ECM proteins with a conserved RGD/Glutamine-Glycine-Asparagine (QGD) motif [12]. The RGD motif is exposed once EGFL7 attaches to the ECM but is hidden in the soluble form of EGFL7 [13]. The ITGAV:ITGB3 integrin can bind to fibronectin, collagen, fibrinogen, thrombospondin, and EGFL7, among others [7]. EGFL7 with its RGD motif competes for binding to ITGAV:ITGB3 integrin with matrix metalloproteinase2 (MMP2), fibronectin, and collagen IV. ITGB3 has important roles in angiogenesis, tumor metastasis, and drug resistance, leading to the development of novel specific RGD-like ligands for use in anti-tumor therapy (reviewed in [14]).

2. Epidermal Growth Factor-Like Protein-7

Mouse and human EGFL7 were cloned in 2003 by Soncin [5]. EGFL7 is a molecule that contains an N-terminal signaling sequence, followed by a cysteine-rich Emilin-like (EMI) domain and two epidermal growth factor-like (EGF-like) domains [5] (Figure 1a). The microRNA-126 gene (miR126) is located within intron 7 of the EGFL7 gene. Studies on the effects of miR126 in tumorigenesis are not covered in this review.

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Figure 1. (a) Model structure of the EGFL7 protein. EGFL7 contains two EGF-like repeats: an arg-gly-asp integrin-binding motif (RGD) and an Emilin-like region. (b) The regulatory network of EGLF7. EGFL7 binds via its RGD domain to ITGAV:ITGB3 integrin and causes among others FAK autophosphorylation. EGFL7 competes for binding to the integrin with the ECM molecules fibronectin, MMP2, and collagen IV. The Emilin-like region of EGFL7 interacts with Notch receptor 1–4 and Notch ligands DLL4 and Jag1 and suppresses Notch signaling, resulting in impaired NIC translocation into the nucleus and reduced Hey1/2 and Hes1 transcription. EGFL7 binding to EGFR results in the activation of the signaling pathways extracellular signal-regulated kinase (ERK) and AKT, among others. EGFL7 competes for binding to EGFR with EGF. Abbreviations: EGF, epidermal growth factor; EGFL7, epidermal growth factor-like protein 7; EGFR, epidermal growth factor receptor; ERK, extracellular signal-regulated kinase; FAK, focal adhesion kinase); MMP2, matrix metalloproteinase 2; DLL4, delta like-protein 4; Jag1, Jagged1; NIC, Notch intracellular domain; ECM, extracellular matrix.

The EGFL7 gene locus contains binding sites for the transcription factors Krüppel-like factor 2 (KLF2) [15] and SMAD1/5 [16][17]. EGFL7 expression was upregulated on ECs by the blood-flow-sensitive transcription factor KLF2a after ITGB1-mediated induction [18] and by SMAD transcription factors after the binding of bone morphogenic protein-9 to the transmembrane anaplastic lymphoma kinase 1 receptor [16][17].

Whilst high expression is found during embryonic and neonatal development [19], EGFL7 is downregulated in almost all mature tissues except in the adult mouse lung, with lower expression in the heart, ovary, uterus, and kidneys [20]. EGFL7 expression rises again during vascular injury [21], during pregnancy, in regenerating endothelium following arterial injury, in growth plate injury [12], in atherosclerotic plaques, and in growing tumors, often mainly in tumor ECs [4].

EGFL7 is a 41-kDa secreted signaling factor [4][5] that can be deposited into the ECM. EGFL7 contains a positive C- and a negative N-terminus, enabling the formation of EGFL7 oligomers that are deposited in the ECM in a head-to-tail fashion (Figure 2). It was recently shown that docking of the EGFL7 protein into both fibers and individual aggregates of the EC extracellular space requires the microfibrillar component microfibrillar-associated glycoprotein-1 and fibronectin [17]. The study demonstrated that docking of EGFL7 to the ECM is required for its effects on lysyl oxidase (LOX) activity, but that ECM binding was not necessary to mediate its effect on endothelial adhesion molecule expression or Hairy/enhancer-of-split related with YRPW motif protein 2 (Hey2) expression along the Notch pathway (Figure 1).

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Figure 2. EGFL7 alters tumor growth and metastasis by suppressing the production of immune cells and their recruitment into the growing tumors, vessel permeability, ECM stiffness—all of which contribute to drug resistance. T cell adhesion and rolling and transmigration through the EC are required for T cells to cross the vascular barrier. EGFL7 allows the tumor to escape from the anti-tumor immune response by preventing terminal T cell differentiation in the thymus and inhibiting T cell recruitment via suppression of the adhesion molecules ICAM and VCAM on ECs. EGFL7 prevents adhesion molecule transcription after tumor necrosis factor alpha (TNFa) stimulation by blocking Nuclear factor kappa B (NFkB) signaling. EGFL7 controls ECM stiffness by interacting with LOXL2 so as to mitigate covalent crosslinking of collagen or elastin. ITGB1 integrin on ECs and ITGB3 integrin on cancer cells [22] induce the expression of transcription factor KLF2 which enhances EGFL7 expression, resulting in enhanced cell proliferation. Myelosuppressive drugs such as bortezomib were shown to enhance KLF2-mediated upregulation of ITGB3 and EGFL7. Abbreviations: KLF2, Krüppel-like factor 2; ETP, early thymic progenitor; LOXL2, lysyl oxidase-like 2.

EGFL7 facilitates angiogenesis and tumorigenesis. It stimulates the recruitment and proliferation of embryonic or human brain ECs [7][23] and primary mouse embryonic fibroblasts [21]. EGFL7, through its multiple binding partners and cellular receptors (reviewed in [24]), can be found on various cell types, including tumor cells and ECs (Figure 1b). EGFL7 can bind to the NOTCH1–4 extracellular domain through its Emilin-like region [25]. EGFL7 competes with the Notch ligands Jag1 and Jag2 for Notch binding and inhibits Notch signaling (Figure 1b). EGFL7 competes with the Notch ligand Delta-like-4 for Notch4 binding on ECs, while suppressing Notch downstream signals like Hey1 and Hairy/enhancer-of-split 1 (Hes1) and promotes angiogenesis [23]. In acute myeloid leukemia, a hematopoietic blood cell cancer, recombinant EGFL7 inhibited DELTA-like 4-mediated Notch activation while anti-EGFL7 in combination with Dll4 increased Notch activation and induced apoptosis.

EGFL7 can also bind to the EGF receptor on the cell membrane, which results in the activation of the signaling pathways mitogen-activated protein kinase/extracellular signal-regulated kinase (ERK) and phosphatidylinositol-3-kinase/AKT [6][26] (Figure 1b). It was reported that EGFL7 binds to EGFR wildtype but not to the active mutant EGFR variant III, leading to b-catenin activation and upregulation of EGFL7 expression and tumor growth [27]. Binding of EGFL7 to EGFR enhanced cell migration of hepatocellular carcinoma cells and increased intrahepatic and pulmonary metastases in murine liver cancer models but did not alter tumor cell proliferation [28]. On the cellular level, EGFL7–EGFR binding caused phosphorylation of the cytoplasmic protein focal adhesion kinase (FAK) [28]. It is interesting to note that EGFR is expressed on intratumoral vessels but not vessels in non-tumor tissues [29][30][31][32][33], which would suggest that EGFL7 binding to EGFR could drive tumor-angiogenesis. But studies so far indicate that the EGFL7-driven pro-angiogenic effects are mainly mediated by Notch receptor or integrin and not by EGFR signaling [16][34].

EGFL7 enhanced migration of the siman virus 40-mouse microvascular endothelial (SVEC) cell line and resulted in the phosphorylation of ERK1/2, FAK, and STAT5 [12]. EGFL7 treatment of EGFL7-induced SVEC migration was blocked in the presence of RGD peptides, demonstrating the involvement of integrin signaling in EC migration. FAK is activated upon integrin or growth factor receptor signaling, resulting in the autophosphorylation at tyrosine (Y) 397. FAK is a key mediator of integrin signaling through its association with focal adhesion proteins, such as paxillin and talin. The role of FAK as both a cytosol and nuclear protein contributing to cancer progression has been recently reviewed by Murphey et al. [35].

Integrins mediate cell adhesion to the ECM. Adhesions serve as traction points and as signaling centers during cell migration [36]. There is an optimal strength of attachment that allows sufficient adhesion for traction at the cell front and yet allows for efficient release at the rear [37]. Integrin activation in protrusions regulates actin polymerization and myosin II activity through Rho-family GTPases such as Cdc42, Rac1, and RhoA [38]. EGFL7 potentiates EC migration on fibronectin-coated plates through binding to ITGAV:ITGB3 integrin [7], resulting in the activation of the downstream target GTPase Cdc42. EGFL7 cannot directly bind to ITGA5:ITGB1 integrin but enhanced angiogenesis involving this integrin [13][39]. Mechanistically, EGFL7 binding to ITGAV:ITGB3 integrin blocked the endocytosis of fibronectin-associated ITGA5:ITGB1 integrin [13] and ITGAV:ITGB3 and resulted in the upregulation of both integrins on the EC surface, allowing focal adhesion maturation, hydrolysis of Rac1-GFP, and enhanced migration speed of ECs on fibronectin surfaces [40].

EGFL7 controls proliferation in melanoma, hepatocellular carcinoma, and clear cell renal cell carcinoma [41][42][43] through one of its receptors. Blood cell cancers such as acute myeloid leukemia (AML) or the plasma cell malignancy multiple myeloma (MM) have dysfunctional integrin and Notch signaling [44][45][22]. EGFL7 caused acute myeloid leukemia (AML) blast proliferation [46]. Anti-EGFL7 blocking antibody through reactivation of Notch signaling in AML cells induced cell differentiation and apoptosis in vitro and in vivo [46]. Our group demonstrated that malignant plasma cells from patients with MM adhere to ECM-deposited EGFL7 and that their cell growth and survival required EGFL7 binding to ITGB3 [22]. These studies demonstrate that EGFL7 could be a potential cancer target.

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