Accepted Manuscript The role of CXCL12 in tumor microenvironment
Wenfang Meng, Shihang Xue, Ye Chen PII: DOI: Reference:
S0378-1119(17)30828-4 doi:10.1016/j.gene.2017.10.015 GENE 42234
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Received date: Accepted date:
10 February 2017 6 October 2017
Please cite this article as: Wenfang Meng, Shihang Xue, Ye Chen , The role of CXCL12 in tumor microenvironment. The address for the corresponding author was captured as affiliation for all authors. Please check if appropriate. Gene(2017), doi:10.1016/ j.gene.2017.10.015
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ACCEPTED MANUSCRIPT Meng W et al. 2017
The Role of CXCL12 in Tumor Microenvironment Wenfang Meng1,2, Shihang Xue3, Ye Chen1,2*
Division of Clinical Genetics and Genomics, The Children's Hospital, Zhejiang University School of
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1
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Medicine, Hangzhou, Zhejiang, China
Institute of Genetics, Zhejiang University, Hangzhou, Zhejiang, China.
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Ningbo No.4 People’s Hospital, Ningbo, Zhejiang, China.
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*Corresponding author:
Ye Chen, Ph.D,
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Institute of Genetics, Zhejiang University,
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866 Yuhangtang Road, Hangzhou, Zhejiang 310058, China
Tel: +86-571-88206760; Fax: +86-571-88206497
Email: [email protected]
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Abstract The chemokine ligand C-X-C motif chemokine ligand 12(CXCL12) is a kind of small molecules of cytokines that widely expressed in diversified tissues. Recent evidence suggests that CXCL12 plays an important role in the communication of tumor
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cells with their surrounding microenvironment. The interaction of CXCL12 and its
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receptors subsequently excite the downstream signaling pathways to affect tumor
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angiogenesis, tumor cell proliferation and chemoresistance, and thus represents a
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potential target for cancer therapy. Outpouring molecules targeting CXCL12/CXCR4 axis in tumor microenvironment combined with traditional chemotherapy have drawn
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more and more attentions, which will be a promising method in anti-cancer therapies. Our review focuses on these roles of CXCL12 and summarizes strategies for treating
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cancer by disrupting this interaction with special emphasis on the CXCR4/CXCL12
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axis.
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Introduction Tumor microenvironment (TME) is the local environment of tumorigenesis and tumor growth, composed of tumor cells and surroundings such as blood vessels, the extracellular matrix (ECM), other non-malignant cells such as bone marrow-derived
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dendritic cells, mesenchymal stem/stromal cells, fibroblasts, pericytes, immune cells,
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and the expression of their products, metabolic material, and also signaling molecules
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(Fig.1) (Junttila and de Sauvage, 2013; Quail and Joyce, 2013). TME affect whole
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process of tumors from happening to transfer, and tumor cells in turn influence the physical and chemical properties of the TME to make TME beneficial even stimulative
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to the growth of tumor(Mahadevan and Von Hoff, 2007).
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Chemokines are a very important part of the cross talk between tumor cells and the
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tumor microenvironment(Mantovani et al., 2008). Chemokine receptors and their specific chemokines control and regulate the tumor development, including leukocyte
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infiltration, tumor related angiogenesis, activation of the specific immune response to the tumor of host, stimulating tumor cell proliferation by autocrine or paracrine way, as
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well as control of tumor cell movements(Mbeunkui and Johann, 2009). The chemokine ligand C-X-C motif chemokine ligand 12 (CXCL12) and its receptor chemokine receptor 4 (CXCR4) are two key factors in the cross-talking, what makes them promising targets for cancer therapy. In this review, we summarize the role of CXCL12 in tumor growth, angiogenesis, metastasis, and TME-mediated chemoresistance.
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The CXCL12/CXCR4 axis Chemokines are small proteins possessing a common structural feature of conserved cysteine residues at the N-terminus with a molecular mass of between 8 and 10 kDa(Baggiolini, 1998). Chemokines have a common structural composition.
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According to the number of and relative spacing of the N-terminal cysteine residues,
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chemokines are divided into four families (CXC, CX3C, CC, and C)(Le et al., 2004;
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Vindrieux et al., 2009). CXCL12, also known as stromal-derived factor 1 (SDF-1), is
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widely secreted in different tissues by stromal cells, fibroblasts and epithelial cells in six different isoforms, encoded on chromosome 10q11. CXCR4 is an evolutionarily
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highly conserved G protein coupled receptor (GPCR) expressed on a great diversity of cell types, including lymphocytes, hematopoietic stem cells, endothelial cells,
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epithelial cells, stromal fibroblasts and cancer cells. This allows them to migrate along
in many
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CXCL12 gradients. It has been observed that the level of CXCL12/CXCR4 is increased types of cancer, such as breast cancer, pancreatic cancer, ovarian carcinoma,
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cervical carcinoma, leukemia diseases and the rest(Mahadevan and Von Hoff, 2007;
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Shen et al., 2009; Zeng et al., 2009; Ling et al., 2013; Kim and Park, 2014; Li et al., 2016). Furthermore, CXCR4 expression has been defined as a prognostic factor in several human tumor types. As shown in the Fig.1, in the tumor microenvironment, some conditions like hypoxia or toxins increase the levels of CXCL12 and thus generate the migration of tumor cells expressing CXCR4, leading them to safer residence constantly. And the heterotrimeric G protein dissociates into subunits (the GTP-bound α，β，and γ) when CXCR4 binding to CXCL12(Chatterjee et al., 2014),
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thus contributing to the tumor angiogenesis, tumor cell survival, proliferation and chemoresistance through the excitation of a variety of downstream signaling pathways(Burger and Kipps, 2006; Wojcechowskyj et al., 2011).
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CXCL12 enhances adhesion ability of tumor cells CXCL12 regulates adhesion of tumor cell with laminin, fibrinogen, stromal cells
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and endothelial cell by activating various cell surface adhesion molecules (e.g.
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integrins). It has been shown that CXCL12 could increase the adhesion rate of
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pancreatic cancer cells to laminin (the main component of basement membrane) and enhance the capacity of cells to penetrate the matrigel (artificial reconstruction
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basement membrane)(Mori et al., 2004). Compared with normal cells, the prostate
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cancer cells pretreated with CXCL12 significantly represented higher adhesion of
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osteosarcomas and endothelial cell lines in vitro in a dose-dependent manner(Taichman et al., 2002). In another similar assay, CXCL12 was found to increase adhesion of PC-3
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cell to the human umbilical vein endothelial cell monolayer(Kukreja et al., 2005). Moreover, CXCL12 increased the level of integrin a5β3 expression in the tumor cell
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membrane, and thus enhanced the adhesion of prostate tumor cells to human endothelium or extracellular matrix proteins laminin, collagen, and fibronectin(Engl et al., 2006). The effects of CXCL12 on the expression and activity of integrins on cell surfaces may be crucial in adhesion to fibronectin and collagen I in prostate cancer cell(Dehghani et al., 2014). The adhesion of HeLa cells to fibronectin and laminin was increased when CXCL12 was added in the medium. In ovarian cancer cell lines, CXCL12 induced integrin β1 expression which leads to the increased adhesion of
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tumor cells to laminin(Shen et al., 2009). In small cell lung cancer cell lines, CXCL12/CXCR4 interaction could induce the expression of integrin and promote adhesion of cancer cells to vascular cell adhesion molecule-1 (VCAM-1), fibronectin and collagen and also vascular endothelial cells(Hartmann et al., 2005).
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CXCL12 promotes tumor angiogenesis and metastasis
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CXCL12/CXCR4 axis is closely related to angiogenesis which supplying nutrient
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to tumor cells and giving rise to excretion of tumor cells metabolites efficiently.
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CXCL12 can stimulate angiogenesis directly or indirectly. Vascular endothelial growth factor (VEGF) is an important cytokine that induces tumor angiogenesis and promotes
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tumor metastasis. VEGF can induce endothelial cells to express MMP-2, MMP-9, to
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stimulate chemotaxis of endothelial cell and the formation of capillary channels, and
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thus indirectly regulate angiogenesis. Salvucci and other studies have shown that CXCL12 could induce endothelial cells to express VEGF, and VEGF in turn could
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promote the expression of CXCL12 in vascular endothelial cell(Salvucci et al., 2002). Moreover, VEGF also induces expression of CXCR4 in cancer cells in autocrine way,
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thereby promotes cancer cells’ migration along CXCL12 gradients.
Metastasis is an important biological characteristic of malignant tumors. CXCL12 can not only induce expression of matrix metalloproteinases (MMP) in cancer cells, but also up-regulate the activity of MMP in tumor microenvironment, which lead to the promoted tumor invasion and metastasis. CXCL12 could increase MMP-9 and MT1-MMP expression and activities, which regulated myeloma cells’ movement in the
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bone marrow(Parmo-Cabanas et al., 2006). By stimulating different types of cells to secrete MMP-2 CXCL12/CXCR4 axis could improve the migration of nerve cells along the corpus callosum(Mao et al., 2016). CXCR4 was highly expressed in tumor cell of patients with liver metastases of colorectal cancer, while high expression of its
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ligand CXCL12 was found in the most common metastatic sites of colorectal cancer,
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such as lymph nodes, liver, lung(Kim et al., 2006). Sun et al also confirmed that
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down-regulation of CXCR4 expression could also inhibit distant metastasis of prostate cancer(Sun et al., 2005). In addition, the use of neutralizing antibodies, specific
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peptides, and siRNAs to block CXCR4 expression significantly inhibited the metastasis
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of breast cancer to lymph nodes and lungs(Skobe et al., 2001). Though the molecular mechanism of tumor metastasis has not yet been fully elucidated, various studies have
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indicated that the role of CXCL12/CXCR4 axis is significant during the progress.
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CXCL12 contributes to tumor cell growth and survival
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Studies have shown that CXCL12/CXCR4 axis can regulate a variety of tumor cell proliferation(Kryczek et al., 2007; Wu et al., 2008). The binding of CXCL12 to its
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receptor CXCR4 can induce proliferation of various type of tumor cells by activating the extracellular signal-regulated kinase (ERK) and AKT signaling pathway. Activated ERK phosphorylates and regulates other cellular proteins and transcription factors, bringing about changes in gene expression and cell cycle process. Activated AKT plays a key role in tumor cell survival through inactivation of BCL-2 antagonist resulting in cell survival. CXCL12/CXCR4 signaling via AKT also resulted in inactivation of GSK3β and stabilization of β-catenin. Stabilized β-catenin moved to the nucleus
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activating gene transcription and promoting proliferation(Barbero et al., 2003). CXCL12-dependent tumor proliferation contributed to tumor growth by a sustained inhibition of cyclic AMP (cAMP) production(Yang et al., 2007). CXCL12 also protected CXCR4-positive cancer cells from apoptosis induced by both serum-free
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culture and chemo administration. In addition, tumor cells could express CXCL12 in
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paracrine form, stimulating tumor stromal cells to produce TNF, which in turn
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promoted tumor cell growth. These studies suggest that the CXCL12 / CXCR4 biological axis not only directly promotes cell proliferation but also indirectly through
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anti-apoptotic effects(Marchesi et al., 2004).
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Targeting the CXCR4/CXCL12 axis in tumor microenvironment
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Up to now, several molecules have been developed to target CXCL12 or CXCR4
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for the purpose of interfering with the tumor growth, and have stronger lethal effect with combination of other pharmaceuticals(Table.1). CTCE-9908 is a CXCL12
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analogue with inhibited and agonist activity. In two murine models of osteosarcoma, CTCE-9908 reduced osteosarcoma cells’ growth and adhesion, and the metastatic
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dissemination of cancer cells(Kim et al., 2008). Compared with controls receiving scrambled protein, the treatment with CTCE-9908 experimental group showed lower primary tumor growth rate in transgenic mouse model of breast cancer. In addition, CTCE-9908 gave rise to reduced protein expression of vascular endothelial growth factor (VEGF) and p-AKT/AKT(Hassan et al., 2011). Olaptesed pegol(ola-PEG), a high-affinity anti-CXCL12 spiegelmer represented as a successful agent targeting the interaction between bone marrow niches and tumor cells, thereby blocking or
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disrupting bone marrow colonization by multiple myeloma cells in a cancer xenograft model. It also diminished tumor mobilization, homing, and growth within the bone marrow niches. Combinations of ola-PEG with other chemotherapeutic agents were also likely to lead to synergistic effects(Roccaro et al., 2014). Plerixafor(AMD3100), a
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CXCR4 inhibitor and a hematopoetic stem cell mobilizer, competitively inhibited
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CXCL12 binding to CXCR4, which resulted in inhibition of initial establishment of
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prostate tumors in the bone(Conley-LaComb et al., 2016). AMD3100 blocked ligand-receptor binding of CXCL12/CXCR4 and reduced growth of ovarian cancer
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cells, in addition, modestly promoted overall survival of mice with metastatic ovarian
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cancer(Ray et al., 2011). AMD3100 undermined the interaction between tumor and stroma, inhibited the adhesion of leukemic cells and weakened the cell migration ability
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to bone marrow and niche. It also brought about mobilization of the leukemia cells to
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enhance cytotoxicity of cytrarabine(Ara-C) on account of the absence of the protection of the tumor microenvironment. Treatment of AMD3100 combined with G-CSF had a
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stronger impact on therapy induced by Ara-C(Shen et al., 2016). In mouse model of
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breast cancer, AMD3465 decreased the cancer growth and metastases of breast cancer cells, by acting on the interaction of tumor cells and the tumor microenvironment(Ling et al., 2013). Compared with the conventional method of drug delivery, the targeted delivery of CXCR4-A-mFc antagonists by oncolytic Vaccinia viruses (OVV) showed an enhanced antitumor effect in destroying tumor vasculature and inhibiting breast cancer metastasis(Gil et al., 2013). In ovarian cancer, by inhibiting the expression of CXCL12, miR-448 inhibited cell proliferation, migration and invasion, serving as
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tumor suppressor(Lv et al., 2015). As a component of Epimedium koreanum, Baohuoside I could suppress cervical and breast cancer metastasis by downregulating CXCR4 expression(Kim and Park, 2014).
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CXCR7 impact on CXCL12 biology in tumor study For many years it was believed that CXCR4 was the only receptor for CXCL12.
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When chemotactic response to T lymphocytes of CXCL12 were studied, Balabanian et
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al., found that CXCL12 bound to RDC1 (previously used as an orphan receptor) and
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anti-RDC1 monoclonal antibodies probably inhibited the chemotactic response to T lymphocytes of CXCL12(Balabanian et al., 2005). Burns et al. discovered that on the
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13th day of the CXCR4 knockout mice embryonic development, the liver cells can still
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bind CXCL12 in the study by chance. RDC1 had similarity with CXCR4 in amino acid
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conserved sequences, so renamed CXCR7(Burns et al., 2006).
Membrane-associated CXCR7 is expressed on many tumor cell lines, on activated
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endothelial cells, on fetal liver cells, and on T lymphocytes(Balabanian et al., 2005;
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Burns et al., 2006). The expression of CXCR7 was found to be strongly positive in 97% (106/109)
human
breast
cancer
vascular
endothelial
cells
detected
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immunohistochemistry, but almost undetectable in normal mammary vascular endothelial cells(Miao et al., 2007). Studies have shown that CXCR7 could reduce tumor cell apoptosis and promote its proliferation. Compared with wild-type cells, after 5 days’ treatment, the number of viable cells in CXCR7-transfected MDA MB 435s cells was significantly higher, although no difference was found in the total cells(Burns
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et al., 2006). CXCR7 also regulated expression of pro-angiogenic factors interleukin-8 and vascular endothelial growth factor, which may be involved in the regulation of angiogenesis(Wang et al., 2008). CXCL12/CXCR7 axis is also involved in the tumor invasion and metastasis process. Compared with wild-type cells, the number of cells
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adhered to human dermal microvascular endothelial cells (HDMEC) was significantly
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higher, and the invasive ability of CXCR7-over-expressed prostate cancer or C4-2B
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cells was higher in the presence of CXCL12. CXCR7 enhanced the invasiveness and metastasis of tumor cells by regulating the levels of cell adhesion molecules (FN1,
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CDH11 and CD44) and matrix metalloproteinase (MMP), such as MMP3, MMP10,
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MMP11 and HPSE(Wang et al., 2008). In vitro experiments it was also confirmed that CXCR7-transfected MDA MB 435s cells were more adherent to human umbilical vein
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endothelial cells (HUVECs) than untransfected wild-type cells(Burns et al., 2006).
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Similarly, in in vivo experiments inducing lung metastasis model in mice injected with tumor cells in the tail vein, tumors caused by injecting cells with 4T1-CXCR7-RNAi
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into the lungs were smaller than injecting the wild-type 4T1 WT cells, while the tumors
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caused by CXCR7-over-expressed cells transferred to the lungs were larger than the wild-type 4T1 WT cells’ group, indicating that CXCR7 expression in breast cancer cells enhanced the ability to metastasize to the lungs and proliferate in the lungs(Miao et al., 2007).
Conclusion It is well recognized that the interaction between tumor cells and TME is a rising target to improve anti-cancer treatment caused by protection of TME (Fig.1). Extensive
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bench studies indicate that targeting the CXCL12/CXCR4 axis may have beneficial actions for sensitizing tumor cells to chemical therapy; however, clinical researches to date are still lagged behind due to multiple reasons such as the limit of pharmacokinetic properties. Additional studies with new agents are required to prove whether
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interference of the CXCR4/CXCL12/CXCR7 axis in TME may increase the
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effectiveness of cancer therapy, and the process of drug approval needs to be
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accelerated.
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Acknowledgements
The work was supported by the project from the Natural Science Foundation of
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Zhejiang province (R15H080001), and the "Double First-rate" project initiatives of
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Conflict of interest
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Zhejiang University.
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The authors declare no competing financial interests.
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Research 62, 1832-1837.
Vindrieux, D., Escobar, P. and Lazennec, G., 2009. Emerging roles of chemokines in prostate cancer.
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Endocr Relat Cancer 16, 663-73.
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Wang, J.H., Shiozawa, Y.S., Wang, J.C., Wang, Y., Jung, Y.H., Pienta, K.J., Mehra, R., Loberg, R. and Taichman, R.S., 2008. The role of CXCR7/RDC1 as a chemokine receptor for CXCL12/SDF-1 in
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prostate cancer. Journal of Biological Chemistry 283, 4283-4294.
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Wojcechowskyj, J.A., Lee, J.Y., Seeholzer, S.H. and Doms, R.W., 2011. Quantitative phosphoproteomics of CXCL12 (SDF-1) signaling. PLoS One 6, e24918.
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Wu, M., Chen, Q., Li, D., Li, X., Li, X., Huang, C., Tang, Y., Zhou, Y., Wang, D., Tang, K., Cao, L.,
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Shen, S. and Li, G., 2008. LRRC4 inhibits human glioblastoma cells proliferation, invasion, and proMMP-2 activation by reducing SDF-1 alpha/CXCR4-mediated ERK1/2 and Akt signaling pathways. J Cell Biochem 103, 245-55. Yang, L., Jackson, E., Woerner, B.M., Perry, A., Piwnica-Worms, D. and Rubin, J.B., 2007. Blocking CXCR4-mediated cyclic AMP suppression inhibits brain tumor growth in vivo. Cancer Res 67, 651-8. Zeng, Z.H., Shi, Y.X., Samudio, I.J., Wang, R.Y., Ling, X.Y., Frolova, O., Levis, M., Rubin, J.B., Negrin, R.R., Estey, E.H., Konoplev, S., Andreeff, M. and Konopleva, M., 2009. Targeting the leukemia
ACCEPTED MANUSCRIPT Meng W et al. 2017
microenvironment by CXCR4 inhibition overcomes resistance to kinase inhibitors and chemotherapy in
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AML. Blood 113, 6215-6224.
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Figure legends Figure 1. CXCL12/CXCR4 axis plays a critical role in regulation of tumor growth, metastasis, and development of chemoresistance. In the tumor microenvironment, cancer-associated fibroblast (CAF) and mesenchymal stem/stromal
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cells (MSC) constitutively express CXCL12, this paracrine signaling enhances the
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proliferation and survival of CXCR4-positive tumor cells. Moreover, low oxygen level
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in the microenvironment significantly improve expression of CXCL12, as well as the
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surface CXCR4 levels in tumor cells. CXCL12 binding promotes a three-dimensional CXCR4 conformation favoring Gαi protein dissociation into α and βγ subunits, and
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triggers multiple signal transduction pathways that are able to regulate intracellular calcium flux, transcription, proliferation and cell survival. Furthermore, these
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CXCR4-positive tumour cells can migrate along the CXCL12 gradient to distant
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organs, such as the CXCL12-rich bone marrow microenvironment, leading to the metastases. Evidence shows that CXCL12 agonist and CXCR4 antagonists can inhibit
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the cross-talk between tumour and stromal cells and mobilize tumor cells from this
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protective microenvironment, making them more sensitive to conventional drugs. Combination chemotherapies have been developed.
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Meng W et al. 2017
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Table 1. Effective targeting of CXCL12/CXCR4 in the microenvironment Descriptio
Indication/Conditio
n
n
Function
R4
NU
antibody
Small
BLM-induced
1070)
molecule CXCR4
Chow LN,
pulmonary and
leukocyte
Schreiner P, et
CCl4-induced
mobilization and
al. 2016
hepatic fibrosis in
decreasing
(PMID:
mice
extracellular
26998906)
D
PT E
HIV infections
AC
CE
NCT01374503
Increasing
MA
AMD070(AMD1
antagonist
RI
Healthy volunteers
ence
SC
Anti-CXC
ALX-0651
Trial number/refer
PT
Name
matrix deposition.
HIV-1 entry
NCT00089466
inhibitor
HIV infections,X4
HIV-1 entry
tropic virus
inhibitor
HIV infections
Inhibiting membrane fusion
NCT00361101
NCT00063804
ACCEPTED MANUSCRIPT Meng W et al. 2017
and viral entry
Small
Glioma,Anaplastic
HSC mobilization NCT01339039
bil, plerixafor)
molecule
Astrocytoma,Anapla
in patients with
CXCR4
stic
NHL and multiple
antagonist
Oligodendroglioma,
myeloma
PT
AMD3100(Mozo
RI
Mixed Anaplastic
NU
Acute Myeloid
SC
Oligoastrocytoma
NCT01141543
Leukemic Cells
MA
Leukemia(AML)
Mobilization of
Chronic lymphocytic
NCT01373229
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D
leukemia
Mobilization and
Neoplasms
Transplantation
CE
Hematologic
NCT00914849
of HLA-Matched
AC
Sibling Donor Hematopoietic Stem Cells
Chronic
Make CLL/SLL
Lymphocytic
cells more
Leukemia
sensitive to being
NCT00694590
ACCEPTED MANUSCRIPT Meng W et al. 2017
(CLL);Small
killed by
Lymphocytic
rituximab
Lymphoma (SLL)
Disrupting the
Leukemia(AML)
interaction
NCT00512252
PT
Acute Myeloid
RI
between AML
SC
blasts and the
MA
NU
marrow
D
Myelokathexis
AC
CE
PT E
(WHIM syndrome)
microenvironmen t
Mobilizing
NCT00967785
hematopoietic stem cells
Multiple
Stem cell
Myeloma;Lymphom
mobilization
NCT02098109
a, Non-Hodgkin
Lymphoma
Mobilization and Collection of Peripheral Hematopoietic
NCT02221492
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Stem Cells
Mobilization of
,Neuroblastoma,
Haematopoietic
Brain Tumors
Stem Cells Into
NCT01288573
PT
Ewing sarcoma
RI
Peripheral Blood,
Mobilize
Multiple Myeloma
NCT00396383
SC
Peripheral Blood
NU
Progenitor Cells
AC
CE
PT E
D
MA
Healthy volunteers
Peripheral Blood
NCT00082329
Hematopoietic Progenitor Cell Mobilization with G-CSF
Chronic
Interrupting
Lymphocytic
communication
Leukemia,
between stromal
Lymphoma,
cells and cancer
NCT01610999
Multiple Myeloma
AMD3465
CXCR4
Primary Chronic
Enhancing
Zeng Z,
Lymphocytic
chemotherapy-in
Samudio IJ, et
ACCEPTED MANUSCRIPT Meng W et al. 2017
Leukemia,Acute
duced apoptosis
al. 2006
Myelogenous
(PMID:
Leukemia
17172414)
Acute Myeloid
Mobilized of
Leukemia
AML cells and
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antagonist
Zeng, Z. H., et al. 2009
RI
progenitor cells to (PMID: 18955566)
SC
the blood
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circulation
Allosteric
ATI-2341
AC
CE
PT E
D
MA
agonist
Baohuoside I
Mobilizer of bone
Tchernychev,
marrow
B., et al. 2010
polymorphonucle
(PMID:
ar neutrophils and
21139054)
hematopoietic stem and progenitor cells
CXCR4
cervical cancer and
Suppression of
Kim, B. and B.
expression
breast cancer
cancer metastasis
Park, et al. 2014 (PMID:
regulator
25407882)
BL-8040
Peptide
Acute Myeloid
NCT01838395
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(T140
(BKT-140)
Leukemia
analogue) Mobilization of
Leukemia
leukemic blasts
Chronic Myeloid
Mobilization of
Leukemia
CML leukemia
NCT02502968
NCT02115672
RI
PT
Acute Myeloid
SC
stem cells
Peptide (T140
PT E
(BKT-140)
Multiple Myeloma
D
BL-8040
MA
NU
Healthy volunteers
AC
BMS-936564
CE
analogue)
(MDX-1338)
Mobilization of
NCT02073019
Hematopoietic Stem Cells
Induction of the
NCT01010880
exit of blood cells from the bone marrow to the peripheral blood
Anti-CXC
Acute Myeloid
R4
Leukemia,Diffuse
antibody
large B-cell leukemia,Follicular lymphoma
NCT01120457
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Acute Myeloid
NCT02305563
Leukemia
Jurkat human
Mobilizer of
agonist
lymphoblastoid cell
polymorphonucle
al. 2005
peptide
line
ar neutrophil and
(PMID:
hematopoietic
15730853)
PT
CXCR4
SC
CTCE-0021
NCT01359657
RI
Multiple myeloma
Pelus, L. M., et
CXCL12
CTCE-9908
MA
NU
stem and
prostate cancer
Decreasing the
Wong, D., et
invasion of tumor
al. 2014
D
mimetic
progenitor cells
esophageal cancer
AC
CE
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(PMID: 24472670)
Reducing
Drenckhan, A.,
metastases and
et al. 2013
growth of tumor
(PMID: 23117118)
prostate tumor
Reduction of
Porvasnik, S.,
tumor cell
et al. 2009
proliferation
(PMID:
ACCEPTED MANUSCRIPT Meng W et al. 2017
19588526)
breast cancer
Reduction of
Huang, E. H.,
metastases
et al. 2009
Faber A,
mimetic
bone marrow
Roderburg C,
recovery
et al. 2007
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Mobilization
MA
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organic
D
Small
KRH-1636
AC
CE
molecule
LY2510924
19482312)
CXCL12
NU
CTCE-0214
RI
PT
(PMID:
CXCR4
Metastatic Clear Cell
antagonist
Renal Cell
(PMID: 17541466)
Anti–HIV-1
Ichiyama K, et
activity
al. 2003 (PMID: 12642669)
NCT01391130
Carcinoma
Extensive Stage Small Cell Lung Carcinoma
NCT01439568
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Small
MSX122
anti-tumor
Solid Tumors
organic
NCT00591682
activity
molecule
Healthy Volunteers
Effect in
NCT00976378
PT
Anti-CXC L12
autologous stem
antibody
cell
RI
NOX-A12
SC
transplantation
MA
NU
HSC transplantation
PT E
D
Multiple myeloma
Mobilization of Hematopoietic Stem Cells
Mobilization of
CE
AC
POL6326
Small
Metastatic Breast
molecule
Cancer
NCT01521533
plasma cells
Chronic lymphocytic Mobilization of leukemia
NCT01194934
NCT01486797
CLL cells
NCT01837095
Hematological
Mobilization and
Malignancies
Transplantation of HLA-Matched Sibling Donor
NCT01413568
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Hematopoietic Stem Cells
Hematopoietic
Multiple Myeloma
NCT01105403
PT
stem cell
Healthy volunteers
RI
mobilization
Hematopoietic
NCT01841476
SC
stem cell
Multiple
antagonist
Myeloma， Non-Hod
stem cell
gkin
mobilization
MA
CXCR4
Hematopoietic
NCT01018979
D
TG-0054
NU
mobilization
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Lymphoma， Hodgki
AC
CE
n Disease
Multiple
Hematopoietic
Myeloma， Non-Hod
stem cell
gkin
mobilization
NCT01458288
Lymphoma， Hodgki n Disease
Multiple
Mobilizing
Myeloma， Non-Hod
hematopoietic
NCT02104427
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stem cells
Lymphoma， Hodgki
combined with
n Disease
G-CSF
Healthy volunteers
Mobilization of
NCT00822341
PT
gkin
CXCR4
Chronic
Decreasing cell
Li, S. H., et al.
antagonist
Lymphocytic
viability,
2016 (PMID:
migration;inhibit
27725861)
AC
CE
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D
MA
NU
Leukemia
SC
WZ811
RI
stem cell
tumor growth;make higher sensitivity to docetaxel
ACCEPTED MANUSCRIPT Meng W et al. 2017
Abbreviations
CXCL12： C-X-C motif chemokine ligand 12
Tumor microenvironment
GPCR：
G protein coupled receptor
CXCR4：
chemokine receptor 4
CXCR7：
chemokine receptor 7
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VCAM-1： vascular cell adhesion molecule-1
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RI
PT
TME：
Vascular endothelial growth factor
MMP：
matrix metalloproteinases
ERK：
extracellular signal-regulated kinase
Ara-C：
cytrarabine
ECM:
extracellular matrix
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CE
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D
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VEGF：
HDMEC：
human dermal microvascular endothelial cell
MSC：
mesenchymal stem/stromal cell
HUVEC:
CAF:
human umbilical vein endothelial cell
cancer-associated fibroblast
Wenfang Meng, Shihang Xue, Ye Chen PII: DOI: Reference:
S0378-1119(17)30828-4 doi:10.1016/j.gene.2017.10.015 GENE 42234
To appear in:
Gene
Received date: Accepted date:
10 February 2017 6 October 2017
Please cite this article as: Wenfang Meng, Shihang Xue, Ye Chen , The role of CXCL12 in tumor microenvironment. The address for the corresponding author was captured as affiliation for all authors. Please check if appropriate. Gene(2017), doi:10.1016/ j.gene.2017.10.015
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ACCEPTED MANUSCRIPT Meng W et al. 2017
The Role of CXCL12 in Tumor Microenvironment Wenfang Meng1,2, Shihang Xue3, Ye Chen1,2*
Division of Clinical Genetics and Genomics, The Children's Hospital, Zhejiang University School of
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1
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Medicine, Hangzhou, Zhejiang, China
Institute of Genetics, Zhejiang University, Hangzhou, Zhejiang, China.
3
Ningbo No.4 People’s Hospital, Ningbo, Zhejiang, China.
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2
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*Corresponding author:
Ye Chen, Ph.D,
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Institute of Genetics, Zhejiang University,
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866 Yuhangtang Road, Hangzhou, Zhejiang 310058, China
Tel: +86-571-88206760; Fax: +86-571-88206497
Email: [email protected]
ACCEPTED MANUSCRIPT Meng W et al. 2017
Abstract The chemokine ligand C-X-C motif chemokine ligand 12(CXCL12) is a kind of small molecules of cytokines that widely expressed in diversified tissues. Recent evidence suggests that CXCL12 plays an important role in the communication of tumor
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cells with their surrounding microenvironment. The interaction of CXCL12 and its
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receptors subsequently excite the downstream signaling pathways to affect tumor
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angiogenesis, tumor cell proliferation and chemoresistance, and thus represents a
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potential target for cancer therapy. Outpouring molecules targeting CXCL12/CXCR4 axis in tumor microenvironment combined with traditional chemotherapy have drawn
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more and more attentions, which will be a promising method in anti-cancer therapies. Our review focuses on these roles of CXCL12 and summarizes strategies for treating
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cancer by disrupting this interaction with special emphasis on the CXCR4/CXCL12
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axis.
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Introduction Tumor microenvironment (TME) is the local environment of tumorigenesis and tumor growth, composed of tumor cells and surroundings such as blood vessels, the extracellular matrix (ECM), other non-malignant cells such as bone marrow-derived
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dendritic cells, mesenchymal stem/stromal cells, fibroblasts, pericytes, immune cells,
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and the expression of their products, metabolic material, and also signaling molecules
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(Fig.1) (Junttila and de Sauvage, 2013; Quail and Joyce, 2013). TME affect whole
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process of tumors from happening to transfer, and tumor cells in turn influence the physical and chemical properties of the TME to make TME beneficial even stimulative
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to the growth of tumor(Mahadevan and Von Hoff, 2007).
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Chemokines are a very important part of the cross talk between tumor cells and the
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tumor microenvironment(Mantovani et al., 2008). Chemokine receptors and their specific chemokines control and regulate the tumor development, including leukocyte
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infiltration, tumor related angiogenesis, activation of the specific immune response to the tumor of host, stimulating tumor cell proliferation by autocrine or paracrine way, as
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well as control of tumor cell movements(Mbeunkui and Johann, 2009). The chemokine ligand C-X-C motif chemokine ligand 12 (CXCL12) and its receptor chemokine receptor 4 (CXCR4) are two key factors in the cross-talking, what makes them promising targets for cancer therapy. In this review, we summarize the role of CXCL12 in tumor growth, angiogenesis, metastasis, and TME-mediated chemoresistance.
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The CXCL12/CXCR4 axis Chemokines are small proteins possessing a common structural feature of conserved cysteine residues at the N-terminus with a molecular mass of between 8 and 10 kDa(Baggiolini, 1998). Chemokines have a common structural composition.
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According to the number of and relative spacing of the N-terminal cysteine residues,
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chemokines are divided into four families (CXC, CX3C, CC, and C)(Le et al., 2004;
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Vindrieux et al., 2009). CXCL12, also known as stromal-derived factor 1 (SDF-1), is
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widely secreted in different tissues by stromal cells, fibroblasts and epithelial cells in six different isoforms, encoded on chromosome 10q11. CXCR4 is an evolutionarily
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highly conserved G protein coupled receptor (GPCR) expressed on a great diversity of cell types, including lymphocytes, hematopoietic stem cells, endothelial cells,
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epithelial cells, stromal fibroblasts and cancer cells. This allows them to migrate along
in many
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CXCL12 gradients. It has been observed that the level of CXCL12/CXCR4 is increased types of cancer, such as breast cancer, pancreatic cancer, ovarian carcinoma,
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cervical carcinoma, leukemia diseases and the rest(Mahadevan and Von Hoff, 2007;
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Shen et al., 2009; Zeng et al., 2009; Ling et al., 2013; Kim and Park, 2014; Li et al., 2016). Furthermore, CXCR4 expression has been defined as a prognostic factor in several human tumor types. As shown in the Fig.1, in the tumor microenvironment, some conditions like hypoxia or toxins increase the levels of CXCL12 and thus generate the migration of tumor cells expressing CXCR4, leading them to safer residence constantly. And the heterotrimeric G protein dissociates into subunits (the GTP-bound α，β，and γ) when CXCR4 binding to CXCL12(Chatterjee et al., 2014),
ACCEPTED MANUSCRIPT Meng W et al. 2017
thus contributing to the tumor angiogenesis, tumor cell survival, proliferation and chemoresistance through the excitation of a variety of downstream signaling pathways(Burger and Kipps, 2006; Wojcechowskyj et al., 2011).
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CXCL12 enhances adhesion ability of tumor cells CXCL12 regulates adhesion of tumor cell with laminin, fibrinogen, stromal cells
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and endothelial cell by activating various cell surface adhesion molecules (e.g.
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integrins). It has been shown that CXCL12 could increase the adhesion rate of
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pancreatic cancer cells to laminin (the main component of basement membrane) and enhance the capacity of cells to penetrate the matrigel (artificial reconstruction
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basement membrane)(Mori et al., 2004). Compared with normal cells, the prostate
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cancer cells pretreated with CXCL12 significantly represented higher adhesion of
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osteosarcomas and endothelial cell lines in vitro in a dose-dependent manner(Taichman et al., 2002). In another similar assay, CXCL12 was found to increase adhesion of PC-3
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cell to the human umbilical vein endothelial cell monolayer(Kukreja et al., 2005). Moreover, CXCL12 increased the level of integrin a5β3 expression in the tumor cell
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membrane, and thus enhanced the adhesion of prostate tumor cells to human endothelium or extracellular matrix proteins laminin, collagen, and fibronectin(Engl et al., 2006). The effects of CXCL12 on the expression and activity of integrins on cell surfaces may be crucial in adhesion to fibronectin and collagen I in prostate cancer cell(Dehghani et al., 2014). The adhesion of HeLa cells to fibronectin and laminin was increased when CXCL12 was added in the medium. In ovarian cancer cell lines, CXCL12 induced integrin β1 expression which leads to the increased adhesion of
ACCEPTED MANUSCRIPT Meng W et al. 2017
tumor cells to laminin(Shen et al., 2009). In small cell lung cancer cell lines, CXCL12/CXCR4 interaction could induce the expression of integrin and promote adhesion of cancer cells to vascular cell adhesion molecule-1 (VCAM-1), fibronectin and collagen and also vascular endothelial cells(Hartmann et al., 2005).
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CXCL12 promotes tumor angiogenesis and metastasis
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CXCL12/CXCR4 axis is closely related to angiogenesis which supplying nutrient
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to tumor cells and giving rise to excretion of tumor cells metabolites efficiently.
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CXCL12 can stimulate angiogenesis directly or indirectly. Vascular endothelial growth factor (VEGF) is an important cytokine that induces tumor angiogenesis and promotes
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tumor metastasis. VEGF can induce endothelial cells to express MMP-2, MMP-9, to
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stimulate chemotaxis of endothelial cell and the formation of capillary channels, and
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thus indirectly regulate angiogenesis. Salvucci and other studies have shown that CXCL12 could induce endothelial cells to express VEGF, and VEGF in turn could
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promote the expression of CXCL12 in vascular endothelial cell(Salvucci et al., 2002). Moreover, VEGF also induces expression of CXCR4 in cancer cells in autocrine way,
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thereby promotes cancer cells’ migration along CXCL12 gradients.
Metastasis is an important biological characteristic of malignant tumors. CXCL12 can not only induce expression of matrix metalloproteinases (MMP) in cancer cells, but also up-regulate the activity of MMP in tumor microenvironment, which lead to the promoted tumor invasion and metastasis. CXCL12 could increase MMP-9 and MT1-MMP expression and activities, which regulated myeloma cells’ movement in the
ACCEPTED MANUSCRIPT Meng W et al. 2017
bone marrow(Parmo-Cabanas et al., 2006). By stimulating different types of cells to secrete MMP-2 CXCL12/CXCR4 axis could improve the migration of nerve cells along the corpus callosum(Mao et al., 2016). CXCR4 was highly expressed in tumor cell of patients with liver metastases of colorectal cancer, while high expression of its
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ligand CXCL12 was found in the most common metastatic sites of colorectal cancer,
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such as lymph nodes, liver, lung(Kim et al., 2006). Sun et al also confirmed that
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down-regulation of CXCR4 expression could also inhibit distant metastasis of prostate cancer(Sun et al., 2005). In addition, the use of neutralizing antibodies, specific
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peptides, and siRNAs to block CXCR4 expression significantly inhibited the metastasis
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of breast cancer to lymph nodes and lungs(Skobe et al., 2001). Though the molecular mechanism of tumor metastasis has not yet been fully elucidated, various studies have
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indicated that the role of CXCL12/CXCR4 axis is significant during the progress.
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CXCL12 contributes to tumor cell growth and survival
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Studies have shown that CXCL12/CXCR4 axis can regulate a variety of tumor cell proliferation(Kryczek et al., 2007; Wu et al., 2008). The binding of CXCL12 to its
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receptor CXCR4 can induce proliferation of various type of tumor cells by activating the extracellular signal-regulated kinase (ERK) and AKT signaling pathway. Activated ERK phosphorylates and regulates other cellular proteins and transcription factors, bringing about changes in gene expression and cell cycle process. Activated AKT plays a key role in tumor cell survival through inactivation of BCL-2 antagonist resulting in cell survival. CXCL12/CXCR4 signaling via AKT also resulted in inactivation of GSK3β and stabilization of β-catenin. Stabilized β-catenin moved to the nucleus
ACCEPTED MANUSCRIPT Meng W et al. 2017
activating gene transcription and promoting proliferation(Barbero et al., 2003). CXCL12-dependent tumor proliferation contributed to tumor growth by a sustained inhibition of cyclic AMP (cAMP) production(Yang et al., 2007). CXCL12 also protected CXCR4-positive cancer cells from apoptosis induced by both serum-free
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culture and chemo administration. In addition, tumor cells could express CXCL12 in
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paracrine form, stimulating tumor stromal cells to produce TNF, which in turn
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promoted tumor cell growth. These studies suggest that the CXCL12 / CXCR4 biological axis not only directly promotes cell proliferation but also indirectly through
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anti-apoptotic effects(Marchesi et al., 2004).
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Targeting the CXCR4/CXCL12 axis in tumor microenvironment
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Up to now, several molecules have been developed to target CXCL12 or CXCR4
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for the purpose of interfering with the tumor growth, and have stronger lethal effect with combination of other pharmaceuticals(Table.1). CTCE-9908 is a CXCL12
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analogue with inhibited and agonist activity. In two murine models of osteosarcoma, CTCE-9908 reduced osteosarcoma cells’ growth and adhesion, and the metastatic
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dissemination of cancer cells(Kim et al., 2008). Compared with controls receiving scrambled protein, the treatment with CTCE-9908 experimental group showed lower primary tumor growth rate in transgenic mouse model of breast cancer. In addition, CTCE-9908 gave rise to reduced protein expression of vascular endothelial growth factor (VEGF) and p-AKT/AKT(Hassan et al., 2011). Olaptesed pegol(ola-PEG), a high-affinity anti-CXCL12 spiegelmer represented as a successful agent targeting the interaction between bone marrow niches and tumor cells, thereby blocking or
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disrupting bone marrow colonization by multiple myeloma cells in a cancer xenograft model. It also diminished tumor mobilization, homing, and growth within the bone marrow niches. Combinations of ola-PEG with other chemotherapeutic agents were also likely to lead to synergistic effects(Roccaro et al., 2014). Plerixafor(AMD3100), a
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CXCR4 inhibitor and a hematopoetic stem cell mobilizer, competitively inhibited
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CXCL12 binding to CXCR4, which resulted in inhibition of initial establishment of
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prostate tumors in the bone(Conley-LaComb et al., 2016). AMD3100 blocked ligand-receptor binding of CXCL12/CXCR4 and reduced growth of ovarian cancer
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cells, in addition, modestly promoted overall survival of mice with metastatic ovarian
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cancer(Ray et al., 2011). AMD3100 undermined the interaction between tumor and stroma, inhibited the adhesion of leukemic cells and weakened the cell migration ability
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to bone marrow and niche. It also brought about mobilization of the leukemia cells to
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enhance cytotoxicity of cytrarabine(Ara-C) on account of the absence of the protection of the tumor microenvironment. Treatment of AMD3100 combined with G-CSF had a
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stronger impact on therapy induced by Ara-C(Shen et al., 2016). In mouse model of
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breast cancer, AMD3465 decreased the cancer growth and metastases of breast cancer cells, by acting on the interaction of tumor cells and the tumor microenvironment(Ling et al., 2013). Compared with the conventional method of drug delivery, the targeted delivery of CXCR4-A-mFc antagonists by oncolytic Vaccinia viruses (OVV) showed an enhanced antitumor effect in destroying tumor vasculature and inhibiting breast cancer metastasis(Gil et al., 2013). In ovarian cancer, by inhibiting the expression of CXCL12, miR-448 inhibited cell proliferation, migration and invasion, serving as
ACCEPTED MANUSCRIPT Meng W et al. 2017
tumor suppressor(Lv et al., 2015). As a component of Epimedium koreanum, Baohuoside I could suppress cervical and breast cancer metastasis by downregulating CXCR4 expression(Kim and Park, 2014).
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CXCR7 impact on CXCL12 biology in tumor study For many years it was believed that CXCR4 was the only receptor for CXCL12.
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When chemotactic response to T lymphocytes of CXCL12 were studied, Balabanian et
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al., found that CXCL12 bound to RDC1 (previously used as an orphan receptor) and
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anti-RDC1 monoclonal antibodies probably inhibited the chemotactic response to T lymphocytes of CXCL12(Balabanian et al., 2005). Burns et al. discovered that on the
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13th day of the CXCR4 knockout mice embryonic development, the liver cells can still
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bind CXCL12 in the study by chance. RDC1 had similarity with CXCR4 in amino acid
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conserved sequences, so renamed CXCR7(Burns et al., 2006).
Membrane-associated CXCR7 is expressed on many tumor cell lines, on activated
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endothelial cells, on fetal liver cells, and on T lymphocytes(Balabanian et al., 2005;
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Burns et al., 2006). The expression of CXCR7 was found to be strongly positive in 97% (106/109)
human
breast
cancer
vascular
endothelial
cells
detected
by
immunohistochemistry, but almost undetectable in normal mammary vascular endothelial cells(Miao et al., 2007). Studies have shown that CXCR7 could reduce tumor cell apoptosis and promote its proliferation. Compared with wild-type cells, after 5 days’ treatment, the number of viable cells in CXCR7-transfected MDA MB 435s cells was significantly higher, although no difference was found in the total cells(Burns
ACCEPTED MANUSCRIPT Meng W et al. 2017
et al., 2006). CXCR7 also regulated expression of pro-angiogenic factors interleukin-8 and vascular endothelial growth factor, which may be involved in the regulation of angiogenesis(Wang et al., 2008). CXCL12/CXCR7 axis is also involved in the tumor invasion and metastasis process. Compared with wild-type cells, the number of cells
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adhered to human dermal microvascular endothelial cells (HDMEC) was significantly
RI
higher, and the invasive ability of CXCR7-over-expressed prostate cancer or C4-2B
SC
cells was higher in the presence of CXCL12. CXCR7 enhanced the invasiveness and metastasis of tumor cells by regulating the levels of cell adhesion molecules (FN1,
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CDH11 and CD44) and matrix metalloproteinase (MMP), such as MMP3, MMP10,
MA
MMP11 and HPSE(Wang et al., 2008). In vitro experiments it was also confirmed that CXCR7-transfected MDA MB 435s cells were more adherent to human umbilical vein
D
endothelial cells (HUVECs) than untransfected wild-type cells(Burns et al., 2006).
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Similarly, in in vivo experiments inducing lung metastasis model in mice injected with tumor cells in the tail vein, tumors caused by injecting cells with 4T1-CXCR7-RNAi
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into the lungs were smaller than injecting the wild-type 4T1 WT cells, while the tumors
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caused by CXCR7-over-expressed cells transferred to the lungs were larger than the wild-type 4T1 WT cells’ group, indicating that CXCR7 expression in breast cancer cells enhanced the ability to metastasize to the lungs and proliferate in the lungs(Miao et al., 2007).
Conclusion It is well recognized that the interaction between tumor cells and TME is a rising target to improve anti-cancer treatment caused by protection of TME (Fig.1). Extensive
ACCEPTED MANUSCRIPT Meng W et al. 2017
bench studies indicate that targeting the CXCL12/CXCR4 axis may have beneficial actions for sensitizing tumor cells to chemical therapy; however, clinical researches to date are still lagged behind due to multiple reasons such as the limit of pharmacokinetic properties. Additional studies with new agents are required to prove whether
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interference of the CXCR4/CXCL12/CXCR7 axis in TME may increase the
RI
effectiveness of cancer therapy, and the process of drug approval needs to be
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accelerated.
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Acknowledgements
The work was supported by the project from the Natural Science Foundation of
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Zhejiang province (R15H080001), and the "Double First-rate" project initiatives of
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Conflict of interest
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Zhejiang University.
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The authors declare no competing financial interests.
ACCEPTED MANUSCRIPT Meng W et al. 2017
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Figure legends Figure 1. CXCL12/CXCR4 axis plays a critical role in regulation of tumor growth, metastasis, and development of chemoresistance. In the tumor microenvironment, cancer-associated fibroblast (CAF) and mesenchymal stem/stromal
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cells (MSC) constitutively express CXCL12, this paracrine signaling enhances the
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proliferation and survival of CXCR4-positive tumor cells. Moreover, low oxygen level
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in the microenvironment significantly improve expression of CXCL12, as well as the
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surface CXCR4 levels in tumor cells. CXCL12 binding promotes a three-dimensional CXCR4 conformation favoring Gαi protein dissociation into α and βγ subunits, and
MA
triggers multiple signal transduction pathways that are able to regulate intracellular calcium flux, transcription, proliferation and cell survival. Furthermore, these
D
CXCR4-positive tumour cells can migrate along the CXCL12 gradient to distant
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organs, such as the CXCL12-rich bone marrow microenvironment, leading to the metastases. Evidence shows that CXCL12 agonist and CXCR4 antagonists can inhibit
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the cross-talk between tumour and stromal cells and mobilize tumor cells from this
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protective microenvironment, making them more sensitive to conventional drugs. Combination chemotherapies have been developed.
ACCEPTED MANUSCRIPT
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CE
PT E
D
MA
NU
SC
RI
PT
Meng W et al. 2017
ACCEPTED MANUSCRIPT Meng W et al. 2017
Table 1. Effective targeting of CXCL12/CXCR4 in the microenvironment Descriptio
Indication/Conditio
n
n
Function
R4
NU
antibody
Small
BLM-induced
1070)
molecule CXCR4
Chow LN,
pulmonary and
leukocyte
Schreiner P, et
CCl4-induced
mobilization and
al. 2016
hepatic fibrosis in
decreasing
(PMID:
mice
extracellular
26998906)
D
PT E
HIV infections
AC
CE
NCT01374503
Increasing
MA
AMD070(AMD1
antagonist
RI
Healthy volunteers
ence
SC
Anti-CXC
ALX-0651
Trial number/refer
PT
Name
matrix deposition.
HIV-1 entry
NCT00089466
inhibitor
HIV infections,X4
HIV-1 entry
tropic virus
inhibitor
HIV infections
Inhibiting membrane fusion
NCT00361101
NCT00063804
ACCEPTED MANUSCRIPT Meng W et al. 2017
and viral entry
Small
Glioma,Anaplastic
HSC mobilization NCT01339039
bil, plerixafor)
molecule
Astrocytoma,Anapla
in patients with
CXCR4
stic
NHL and multiple
antagonist
Oligodendroglioma,
myeloma
PT
AMD3100(Mozo
RI
Mixed Anaplastic
NU
Acute Myeloid
SC
Oligoastrocytoma
NCT01141543
Leukemic Cells
MA
Leukemia(AML)
Mobilization of
Chronic lymphocytic
NCT01373229
PT E
D
leukemia
Mobilization and
Neoplasms
Transplantation
CE
Hematologic
NCT00914849
of HLA-Matched
AC
Sibling Donor Hematopoietic Stem Cells
Chronic
Make CLL/SLL
Lymphocytic
cells more
Leukemia
sensitive to being
NCT00694590
ACCEPTED MANUSCRIPT Meng W et al. 2017
(CLL);Small
killed by
Lymphocytic
rituximab
Lymphoma (SLL)
Disrupting the
Leukemia(AML)
interaction
NCT00512252
PT
Acute Myeloid
RI
between AML
SC
blasts and the
MA
NU
marrow
D
Myelokathexis
AC
CE
PT E
(WHIM syndrome)
microenvironmen t
Mobilizing
NCT00967785
hematopoietic stem cells
Multiple
Stem cell
Myeloma;Lymphom
mobilization
NCT02098109
a, Non-Hodgkin
Lymphoma
Mobilization and Collection of Peripheral Hematopoietic
NCT02221492
ACCEPTED MANUSCRIPT Meng W et al. 2017
Stem Cells
Mobilization of
,Neuroblastoma,
Haematopoietic
Brain Tumors
Stem Cells Into
NCT01288573
PT
Ewing sarcoma
RI
Peripheral Blood,
Mobilize
Multiple Myeloma
NCT00396383
SC
Peripheral Blood
NU
Progenitor Cells
AC
CE
PT E
D
MA
Healthy volunteers
Peripheral Blood
NCT00082329
Hematopoietic Progenitor Cell Mobilization with G-CSF
Chronic
Interrupting
Lymphocytic
communication
Leukemia,
between stromal
Lymphoma,
cells and cancer
NCT01610999
Multiple Myeloma
AMD3465
CXCR4
Primary Chronic
Enhancing
Zeng Z,
Lymphocytic
chemotherapy-in
Samudio IJ, et
ACCEPTED MANUSCRIPT Meng W et al. 2017
Leukemia,Acute
duced apoptosis
al. 2006
Myelogenous
(PMID:
Leukemia
17172414)
Acute Myeloid
Mobilized of
Leukemia
AML cells and
PT
antagonist
Zeng, Z. H., et al. 2009
RI
progenitor cells to (PMID: 18955566)
SC
the blood
NU
circulation
Allosteric
ATI-2341
AC
CE
PT E
D
MA
agonist
Baohuoside I
Mobilizer of bone
Tchernychev,
marrow
B., et al. 2010
polymorphonucle
(PMID:
ar neutrophils and
21139054)
hematopoietic stem and progenitor cells
CXCR4
cervical cancer and
Suppression of
Kim, B. and B.
expression
breast cancer
cancer metastasis
Park, et al. 2014 (PMID:
regulator
25407882)
BL-8040
Peptide
Acute Myeloid
NCT01838395
ACCEPTED MANUSCRIPT Meng W et al. 2017
(T140
(BKT-140)
Leukemia
analogue) Mobilization of
Leukemia
leukemic blasts
Chronic Myeloid
Mobilization of
Leukemia
CML leukemia
NCT02502968
NCT02115672
RI
PT
Acute Myeloid
SC
stem cells
Peptide (T140
PT E
(BKT-140)
Multiple Myeloma
D
BL-8040
MA
NU
Healthy volunteers
AC
BMS-936564
CE
analogue)
(MDX-1338)
Mobilization of
NCT02073019
Hematopoietic Stem Cells
Induction of the
NCT01010880
exit of blood cells from the bone marrow to the peripheral blood
Anti-CXC
Acute Myeloid
R4
Leukemia,Diffuse
antibody
large B-cell leukemia,Follicular lymphoma
NCT01120457
ACCEPTED MANUSCRIPT Meng W et al. 2017
Acute Myeloid
NCT02305563
Leukemia
Jurkat human
Mobilizer of
agonist
lymphoblastoid cell
polymorphonucle
al. 2005
peptide
line
ar neutrophil and
(PMID:
hematopoietic
15730853)
PT
CXCR4
SC
CTCE-0021
NCT01359657
RI
Multiple myeloma
Pelus, L. M., et
CXCL12
CTCE-9908
MA
NU
stem and
prostate cancer
Decreasing the
Wong, D., et
invasion of tumor
al. 2014
D
mimetic
progenitor cells
esophageal cancer
AC
CE
PT E
(PMID: 24472670)
Reducing
Drenckhan, A.,
metastases and
et al. 2013
growth of tumor
(PMID: 23117118)
prostate tumor
Reduction of
Porvasnik, S.,
tumor cell
et al. 2009
proliferation
(PMID:
ACCEPTED MANUSCRIPT Meng W et al. 2017
19588526)
breast cancer
Reduction of
Huang, E. H.,
metastases
et al. 2009
Faber A,
mimetic
bone marrow
Roderburg C,
recovery
et al. 2007
SC
Mobilization
MA
PT E
organic
D
Small
KRH-1636
AC
CE
molecule
LY2510924
19482312)
CXCL12
NU
CTCE-0214
RI
PT
(PMID:
CXCR4
Metastatic Clear Cell
antagonist
Renal Cell
(PMID: 17541466)
Anti–HIV-1
Ichiyama K, et
activity
al. 2003 (PMID: 12642669)
NCT01391130
Carcinoma
Extensive Stage Small Cell Lung Carcinoma
NCT01439568
ACCEPTED MANUSCRIPT Meng W et al. 2017
Small
MSX122
anti-tumor
Solid Tumors
organic
NCT00591682
activity
molecule
Healthy Volunteers
Effect in
NCT00976378
PT
Anti-CXC L12
autologous stem
antibody
cell
RI
NOX-A12
SC
transplantation
MA
NU
HSC transplantation
PT E
D
Multiple myeloma
Mobilization of Hematopoietic Stem Cells
Mobilization of
CE
AC
POL6326
Small
Metastatic Breast
molecule
Cancer
NCT01521533
plasma cells
Chronic lymphocytic Mobilization of leukemia
NCT01194934
NCT01486797
CLL cells
NCT01837095
Hematological
Mobilization and
Malignancies
Transplantation of HLA-Matched Sibling Donor
NCT01413568
ACCEPTED MANUSCRIPT Meng W et al. 2017
Hematopoietic Stem Cells
Hematopoietic
Multiple Myeloma
NCT01105403
PT
stem cell
Healthy volunteers
RI
mobilization
Hematopoietic
NCT01841476
SC
stem cell
Multiple
antagonist
Myeloma， Non-Hod
stem cell
gkin
mobilization
MA
CXCR4
Hematopoietic
NCT01018979
D
TG-0054
NU
mobilization
PT E
Lymphoma， Hodgki
AC
CE
n Disease
Multiple
Hematopoietic
Myeloma， Non-Hod
stem cell
gkin
mobilization
NCT01458288
Lymphoma， Hodgki n Disease
Multiple
Mobilizing
Myeloma， Non-Hod
hematopoietic
NCT02104427
ACCEPTED MANUSCRIPT Meng W et al. 2017
stem cells
Lymphoma， Hodgki
combined with
n Disease
G-CSF
Healthy volunteers
Mobilization of
NCT00822341
PT
gkin
CXCR4
Chronic
Decreasing cell
Li, S. H., et al.
antagonist
Lymphocytic
viability,
2016 (PMID:
migration;inhibit
27725861)
AC
CE
PT E
D
MA
NU
Leukemia
SC
WZ811
RI
stem cell
tumor growth;make higher sensitivity to docetaxel
ACCEPTED MANUSCRIPT Meng W et al. 2017
Abbreviations
CXCL12： C-X-C motif chemokine ligand 12
Tumor microenvironment
GPCR：
G protein coupled receptor
CXCR4：
chemokine receptor 4
CXCR7：
chemokine receptor 7
NU
VCAM-1： vascular cell adhesion molecule-1
SC
RI
PT
TME：
Vascular endothelial growth factor
MMP：
matrix metalloproteinases
ERK：
extracellular signal-regulated kinase
Ara-C：
cytrarabine
ECM:
extracellular matrix
AC
CE
PT E
D
MA
VEGF：
HDMEC：
human dermal microvascular endothelial cell
MSC：
mesenchymal stem/stromal cell
HUVEC:
CAF:
human umbilical vein endothelial cell
cancer-associated fibroblast
