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CXCL12/CXCR4: a symbiotic bridge linking cancer cells and their stromal neighbors in oncogenic communication networks

Abstract

Increasing evidence indicates that the tumor microenvironment has critical roles in all aspects of cancer biology, including growth, angiogenesis, metastasis and progression. Although chemokines and their receptors were originally identified as mediators of inflammatory diseases, it is being increasingly recognized that they serve as critical communication bridges between tumor cells and stromal cells to create a permissive microenvironment for tumor growth and metastasis. Thus, an important therapeutic strategy for cancer is to break this communication channel and isolate tumor cells for long-term elimination. Cytokine CXCL12 (also known as stromal-derived factor 1α) and its receptor CXCR4 represent the most promising actionable targets for this strategy. Both are overexpressed in various cancer types, and this aberrant expression strongly promotes proliferation, migration and invasion through multiple signal pathways. Several molecules that target CXCL12 or CXCR4 have been developed to interfere with tumor growth and metastasis. In this article, we review our current understanding of the CXCL12/CXCR4 axis in cancer tumorigenesis and progression and discuss its therapeutic implications.

Introduction

Cancer is a major public health problem in the United States and many other parts of the world. One in four deaths in the United States is due to cancer.1 The high death rate from cancer is mainly due to metastasis and relapse and a lack of effective therapies. Increasing evidence indicates that tumor–stromal cell interactions have a crucial role in tumor initiation and progression.2 CXCL12 and its receptors, CXCR4 and CXCR7, are the key factors in the link between cancer cells and their microenvironment. CXCL12 expression is associated with patient survival, on the basis of a recent meta-analysis of microarray data on 2970 patients from 23 studies.3 Another study found that CXCL12 was the most significant predictor of disease-free survival on the basis of the expression of ~17 000 genes and 341 micro RNAs in 2129 ovarian cancer samples.4 Thus, CXCL12 may have an important role in cancer progression. This review focuses on the pathologic role of CXCL12/CXCR4/CXCR7 in cancer and the therapeutic implication of targeting this axis in cancer treatment.

The CXCL12/CXCR4 axis

CXCL12, also known as stromal-derived factor 1α, is one of the most important CXC chemokines; it is vital to normal B cell growth and cardiac tissue initiation. The CXCL12 gene is located at 10q11.1 and has 6 exons. There are three GC boxes (−451 to −446, −87 to −82 and −63 to −58) and one CAAT box (−423 to −419) on the promoter of the gene that are binding sites for transcription factors SP1 and CTF, respectively.5 CXCL12 has 68 amino acids and its molecular weight is 8 kDa. CXCL12 is expressed widely in multiple normal tissues and serum; it is also expressed by multiple immune cells, endothelial cells, cancer cells, stromal fibroblasts and stem cells.6 CXCL12 acts by binding to the seven-transmembrane G-protein-coupled receptor CXCR4. The interactions between CXCL12 and CXCR4 comprise a biological axis that affects the growth, angiogenesis and metastasis of cancer.

The CXCR4 gene is located at 2q21 and has two exons with 103 nucleotides (nt) and 1564 nt, respectively. CXCR4 has 352 amino acids and its molecular weight is 48 kDa. CXCR4 is expressed on multiple cell types, including lymphocytes, hematopoietic stem cells, endothelial cells, epithelial cells, cancer cells and stromal fibroblasts.7 The mutation of the CXCR4 gene was reported in several cancer types, such as pituitary tumor8 and familial chronic lymphocytic leukemia (CLL).9 Mutation of the CXCR4 gene was also reported in the fourth transmembrane region of CXCR4 in one colon cancer cell line and one melanoma cell line.10 Amplification of the CXCR4 gene locus was suggested to be an early event in the development of high-grade serous ovarian cancer.11

CXCL12 may also activate CXCR7. CXCR7, a seven-transmembrane G-protein-coupled receptor, can bind to CXCL12 with even greater affinity than can the CXCR4 receptor.12 CXCR7 is expressed in various normal tissues, and its expression seems to be enhanced during pathological inflammation and tumor development.13 A new study has proposed that CXCR7 is overexpressed in tumor cells and tumor endothelial cells.14 Meanwhile, CXCR7 promotes cell proliferation, angiogenesis and invasion, inducing the development and progression of cancer.15

CXCL12/CXCR4/CXCR7 expression in cancer

The level of CXCL12/CXCR4 is increased in many types of cancer, such as breast cancer,16 gastric cancer,17 pancreatic cancer,18, 19 ovarian carcinoma,20, 21 cervical carcinoma22 and oral squamous cell carcinoma.23 Cytokine-expression profiles from CLL patients’ serum revealed that three gene products, including CXCL12, were upregulated in the high stage (Rai stage III/IV) compared with low stage (Rai stage 0/I/II).24 Furthermore, CXCL12/CXCR4 expression is correlated with metastasis and prognosis. High expression of CXCR4 and CXCL12 was found to be significantly correlated with liver and lymphatic metastases17 and low overall and disease-free survival rates.18, 20, 25 Thus, CXCL12/ CXCR4 may serve as an independent predictor of poor survival in cancer patients.26, 27, 28, 29

Recently, it was reported that CXCL12 combined with a set of other genes may serve as good prognostic biomarkers or diagnostic markers for cancers. For example, Sanz-Pamplona et al.30 have identified four organ-specific protein–protein interaction networks including organ-specific proteins that exert a range of functions allowing cell survival and growth of distant organs in human breast cancer metastases on the basis of a network-based approach. Three of these selected proteins (CXCL12, DSC2 and TFDP2) were associated with metastasis to specific organs. A recent study reported that combination of serum CXCL5, CXCL12 and carcinoembryonic antigen achieved 92.8% specificity at 75.0% sensitivity to predict distant metastasis of gastric cancer.31 In acute lymphoblastic leukemia (ALL), combination of genetic polymorphisms in the 3′-untranslated repeat (UTR) region of the CXCL12 (rs1801157) and TP53 codon 72 (rs1042522) genes may serve as susceptibility markers for ALL disease.32 Low CCL27/CCR10 and CXCL12/CXCR4 intratumoral mRNA ratios were suggested to be robust predictive factors for the development of distant metastases in primary cutaneous melanoma.33 Thus, combination of CXCL12 with some other genes may serve as better prognostic biomarkers than itself alone.

In several studies, CXCL12 expression differed in different subtypes of cancer. For example, lower expression of CXCL12 in tumor cells was seen in patients with ovarian clear cell carcinoma (n=28) than was seen in those with high-grade serous carcinoma (n=108).34 Meanwhile, patients with undifferentiated carcinoma had significantly higher plasma CXCL12 levels than did patients with serous cystadenocarcinoma.28 However, in another study, elevated levels of blood CXCL12 were found in ovarian cancer, independent of the cancer type (18 serous carcinoma, four endometrioid carcinoma, three mucinous carcinoma and two macrocellular carcinoma).35 This controversial finding may have been due to the small number of ovarian cancer cases. Nevertheless, serum CXCL12 levels may be affected by multiple cell types (for example, immune cells).

CXCR4 is overexpressed in more than 23 human cancers.36 Although CXCR4 is a membrane receptor, many studies have found that tumor cells express nuclear, cytoplasmic and membrane CXCR4 staining.29 This phenomenon may be due to CXCR4 activation by CXCL12, which induces CXCR4 internalization and specific downstream signals and leads to CXCR4 translocation from the membrane to the cytoplasm. Some recent studies have demonstrated that different expression patterns of CXCR4 by cancer cells indicate differences in the biological behavior of cancer. High expression of CXCR4 in the cytoplasm or cytomembrane of tumor cells indicates a poor prognosis, whereas high expression in the nucleus indicates a better prognosis. CXCR4 was found to be present in the cytoplasm and nuclei of tumor cells in breast cancer, and only cytoplasmic expression was associated with lymph node metastasis;16 these findings bear some similarities to those of Su et al.37 Wagner PL38 et al. discovered that cytomembrane expression of CXCR4 in lung adenocarcinoma is an independent risk factor that is associated with poor disease-free survival, whereas nuclear expression confers a survival benefit. Thus, CXCR4 may promote tumor cell proliferation and metastasis when present in the cytoplasm or cell membrane, but is prevented from exerting these effects when it is localized in the nucleus. This observation may be due to CXCR4, maintaining a close physical association with extracellular signal-regulated kinases (ERKs) and cyclophilin A in the vicinity of the nuclear membrane, which induce the phosphorylation and nuclear translocation of ERK1/2.38

CXCR7 was demonstrated to be a new factor in the CXCL12/CXCR4 axis, binding to CXCL12 with even greater affinity than CXCR4. CXCR7 was found to be overexpressed in various tumor cells, including breast, prostate, ovarian and lung cancer.39, 40 By binding to CXCL12, CXCR7 promotes cancer growth, angiogenesis and progression.

Regulation of CXCL12/CXCR4/CXCR7 in cancer

CXCL12/CXCR4 can be regulated by epigenetic, transcriptional and post-transcriptional factors. The regulation of CXCL12/CXCR4 expression by promoter hypermethylation is common in cancer. Recent studies have demonstrated that the CXCL12 gene modulates metastatic potential in cancer, where it controls its own regulation in an autocrine loop. Epigenetic silencing causes the loss of autocrine expression and results in an imbalance in the expression of CXCL12/CXCR4. Cancer cells that lack expression of CXCL12 but maintain overexpression of CXCR4 can selectively spread to target organs in which CXCL12 is highly secreted.41 CXCL12-promoter hypermethylation has been detected in cancer and contributes to its metastatic potential.41, 42, 43 Loss of DNA methylation in the CXCR4 promoter was detected in various types of cancer, including breast cancer,44 leading to the upregulation of CXCR4. Studies revealed that overexpression of CXCR4 was significantly related to the lymph node metastasis status, whereas decreased expression of CXCL12 mRNA was significantly associated with positive lymph node metastasis,41 demonstrating that low CXCL12 levels in cancer cells contribute to their metastatic potential. In addition, tamoxifen, similar to 5-dAzaC, led to increased levels of CXCL12 in MCF-7 breast cancer cells by reducing the methylation of the CXCL12 promoter.45

CXCL12/CXCR4 can be regulated by many factors, such as transforming growth factor-β1,46 tumor necrosis factor-α,47, 48 estradiol and C-myb. Recent studies have reported that estradiol can mediate the transcriptional regulation of CXCL12, CXCR4 and CXCR7. Estradiol enhanced the expression of both CXCL12 and CXCR4 but repressed the expression of CXCR7 in breast cancer cells.49, 50 Transcriptional factors such as c-myb,51 snail family zinc finger 2, SNAI2 (SLUG)52 and Akt1(ref. 53) can elevate CXCR4 and CXCL12 expression in cancer cells. In addition, increased hypoxia-inducible factor-2 can bind to the CXCL12 promoter under hypoxic conditions, increasing CXCL12 expression.54 P53 inhibits the expression of CXCL12 in cancers.55, 56, 57 FOXP3 overexpression in breast cancer cells significantly decreases the expression of CXCR4.58

Several recent studies revealed other regulating molecules in cancers, such as lysophosphatidic acid.59 Lysophosphatidic acid can upregulate CXCL12/CXCR4 axis expression, leading to an increased invasiveness of ovarian cancer.60 In addition, lysophosphatidic acid increases CXCL12 expression by activating the autocrine transforming growth factor-β1-Smad signaling pathway in human adipose tissue-derived mesenchymal stem cells.59

CD164 is a type I integral transmembrane sialomucin that has been reported to havea role in the proliferation, adhesion and differentiation of hematopoietic stem cells.61, 62 A recent study reported that CD164 promotes HCT116 colon cancer cell proliferation and metastasis by regulating the CXCR4 signaling pathway.63 In ovarian cancer, CD164 in the nucleus can induce activation of the CXCR4 promoter,64 increasing the amounts of CXCR4 and CXCL12 (Figure 1).

Figure 1
figure1

Regulatory network of CXCL12/CXCR4. CXCL12/CXCR4 expression can be regulated by methylation, enhancers, many signaling factors and post-transcriptional mechanisms, such as microRNAs (miRNAs).

HOXA9 is a DNA-binding transcription factor that may regulate gene expression, differentiation and morphogenesis. The expression of HOXA9 in epithelial ovarian cancer cells induced the transcriptional activation of transforming growth factor-β2, which acted in a paracrine manner on fibroblasts to induce CXCL12 expression.65

CD40 is a co-stimulatory molecule found on antigen-presenting cells that is required for their activation. CD24 is a glycoprotein expressed at the surface of B lymphocytes and differentiating neuroblasts. Recent studies reported that CD40(ref. 66) and CD24(ref. 67) can upregulate CXCR4, inducing ovarian cancer cell migration. In addition, Prostaglandin E (2)(ref. 68) and interleukin (IL)-2(ref. 69) can induce CXCR4 expression in stromal cells such as cancer-associated myeloid-derived suppressor cells and CD4 (+) CD25 (+) FOXP3 (+) regulatory T cells, leading to the migration of these cells toward the chemokine CXCL12 in the tumor microenvironment.

Recently, researchers found that CXCL12/CXCR4 can be regulated by post-transcriptional mechanisms, including micro RNAs in various tumors. CXCL12 expression in cancer cells is targeted by many microRNAs, such as miR-1,70 miR-126,71, 72 miR-140,73 miR-141,74 miR-146a-5p,75 miR-27a and miR-27b,76 miR-430 77 and miR-886-3p.78 CXCR4 can be regulated by miR-1,70 miR-9,79, 80 miR-126,81 miR-146a,82 miR-150,83 miR-199-5p,84 miR-494-3p,85 miR-133b,86 miR-139 87 and miR-224.88 Moreover, miR-200a can increase CXCR4 expression in cancer cells.89 CXCR7 can be regulated by miR-430.77 The microRNAs that target CXCL12/CXCR4/CXCR7 may suppress cancer development and progression (Figure 1). On the basis of tests in breast cancer patients, miR-146a was recently patented as a CXCR4 antagomir by the Italian Ministry of Health.90

Effects of CXCL12/CXCR4 on cancer and its mechanism

CXCL12 affects cancer biology mainly via the following two mechanisms: (a) by direct autocrine effects that promote cancer cell growth, metastasis and angiogenesis and (b) by indirect effects, including the recruitment of CXCR4-expressing cancer cells to CXCL12-expressing organs or CXCR4-positive stromal cells to tumor sites.39 CXCL12 functions as a growth and survival factor and as a pro-angiogenic factor for cancer cell growth. It can attract CXCR4-expressing cancer cells to distant organs to initiate metastasis.

CXCL12/CXCR4 can stimulate diversified signal transduction pathways and their effect molecules; enhance the proliferation and migration of tumor cells; induce angiogenesis in tumor tissues; and promote cancer infiltration and metastasis (Figure 2).

Figure 2
figure2

CXCL12/CXCR4/CXCR7 signaling pathway. CXCL12/CXCR4 and CXCL12/CXCR7 suppress apoptosis and promote proliferation, angiogenesis and metastasis in tumors by targeting multiple signaling pathways and transcription factors.

The CXCL12/CXCR4 axis promotes proliferation, inhibits apoptosis and drives tumor growth

Recent studies have revealed that CXCL12/CXCR4 promotes tumorigenesis in cancer, such as ovarian cancer. Ovarian cancer is a complex disease that develops from multiple extraovarian origins. Granulosa cells secrete CXCL12 as a key factor that can attract and maintain malignant cells in the ovaries and promote tumorigenesis.91 Epithelial cells from the surface of the ovaries and fallopian tubes were found to stain positive for CXCL12, whereas the follicles within the ovary did not, indicating that epithelial ovarian cancer originates from either of these epithelia.92 Therefore, CXCL12/CXCR4 may have an important role in the tumorigenesis of ovarian cancer.

It is known that CXCL12 activates distinct signaling pathways, such as epidermal growth factor receptor (EGFR), mitogen-activated protein kinase (MAPK), PI3K/AKT, Wnt pathway and NF-κB to mediate cancer cell growth, migration and invasion19 (Figure 2). CXCL12 can promote the proliferation,93, 94 migration and invasion of ovarian cancer cells.60, 64, 95, 96 CXCL12/CXCR4 activation induces EGFR phosphorylation and the activation of extracellular signal-regulated kinases (ERK1/2) and Akt.93, 94 These results suggest that ‘cross-talk’ exists between the CXCL12/CXCR4 and EGFR intracellular pathways that link cell proliferation signals in cancer.93

The stimulation of tumor cell proliferation by CXCL12 may be MAPK-dependent.97, 98, 99 CXCL12 can activate Ras and MAPK.100 Activated MAPK upregulates various transcription factors, including c-Myc, which can upregulate the expression of CXCR4.19 In short, CXCL12/CXCR4 can activate the MAPK pathway, resulting in tumor cell proliferation, which in turn activates MAPK, which upregulates CXCR4 via transcription factors. Thus, there may be a positive feedback loop that promotes CXCR4 expression and further amplifies MAPK signaling.19

Furthermore, CXCL12 can modulate tumor growth via activating the PI3K/Akt pathway.97, 98, 99 Wnt signaling also has an important role in the CXCL12-induced proliferation of cancer cells. In in vitro studies, Wang et al.101 observed that CXCR4 modulated the canonical Wnt pathway and that blockade of CXCL12/CXCR4 signaling inhibited pancreatic cancer proliferation and progression in vitro via inactivation of the canonical Wnt pathway.

Besides promoting the proliferation of cancer cells, CXCL12 can suppress apoptosis. The results of a recent study102 suggest that CXCL12 expression can lead to NF-κB activation, which can suppress the apoptosis signal. In addition, CXCL12 can upregulate the anti-apoptotic gene Bcl-2 by directly inhibiting the pro-apoptotic protein BAD (Bcl-xl/Bcl-2-associated death promoter) or indirectly activating transcription factor cAMP response component-binding proteins, resulting in the inhibition of tumor cell apoptosis.

CXCL12/CXCR4 in tumor microenvironment

Recent evidence indicates that tumor–stromal cell interactions have a crucial role in tumor initiation and progression.103 The tumor microenvironment includes cellular components (fibroblasts, immune cells and endothelial cells), extracellular matrix proteins, proteolytic enzymes, growth factors and inflammatory cytokines; together, these support the tumor’s structure, growth and angiogenesis. Physiologically, CXCL12 is mainly expressed by mesenchymal stromal cells in various organs, such as the liver, lungs and bone marrow (BM). CXCR4-positive cancer cells can be recruited to these CXCL12-rich mesenchymal stroma niches101, 104, 105 to initiate metastasis (Figure 3).

Figure 3
figure3

CXCL12 can induce CXCR4-positive (CXCR4 (+)) cancer cells and CXCR4 (+) stromal cells to secrete growth factors and cytokines and recruit CXCR4 (+) cancer cells to initiate distant metastasis. CXCL12 can induce CXCR4 (+) cancer cells to secrete IL-8, macrophages to secrete EGF and stem cells to secrete VEGF and many other growth factors and cytokines. CXCL12 is physiologically expressed mainly by mesenchymal stromal cells in various organs, such as the liver, lungs and BM. CXCR4 (+) cancer cells can be recruited to these CXCL12-rich mesenchymal stroma niches to initiate metastasis.

Furthermore, CXCL12 can attract CXCR4-positive immune cells or fibroblasts to the tumor sites to assist tumor development. High CXCL12 levels in tumors attract CXCR4-positive inflammatory, vascular and stromal cells into the tumor mass; together, these cells support tumor growth by secreting growth factors, cytokines, chemokines and pro-angiogenic factors.106 A recent study reported that CXCL12 secreted by multiple myeloma (MM) cells can attract CXCR4-expressing monocytes to the MM niche. These monocytes undergo differentiation and become macrophages that significantly increase the proliferation of MM cell lines and protect MM cells from chemotherapy- and immunotherapy-induced cell death.107 In addition, macrophages strongly induce the expression of CCL2, CCL5, IL-1β and IL-8 in MM cells, establishing a tumor-favorable microenvironment.107

CXCL12 can also induce mononuclear phagocytes to release EGF, which activates HER1 and triggers anti-apoptotic and proliferative signals in cancer cells.108 Ping et al.109 found that CXCL12 attracted CD133 (+) glioma stem-like cells and induced vascular EGF (VEGF) production by CD133 (+) glioma stem-like cells. These results indicate that CXCL12/CXCR4 promotes cancer growth and angiogenesis by inducing stromal cells to secrete growth factors. Preclinical studies support the use of CXCR4 antagonists in tumors to sensitize tumor cells to chemotherapeutic agents by disrupting CXCR4-dependent tumor–stroma interactions.110 Thus, strategies targeting CXCL12/CXCR4 may lead to promising cancer treatments.

CXCL12/CXCR4 promotes angiogenesis in cancer

Increasing evidence suggests that the CXCR4 expression level in cancer cells is positively correlated with microvessel density in many cancer types, including breast cancer, prostate cancer and glioma. Furthermore, researchers have detected CXCR4 expression in tumor-infiltrating plasma cells and the endothelial cells of large vessels in tumor stroma,29 demonstrating that the CXCL12/ CXCR4 interaction has an important role in tumor angiogenesis.

There are four possible mechanisms of the effects of CXCL12/CXCR4 on tumor angiogenesis: (1) CXCL12 upregulates VEGF expression in tumor tissue by activating the PI3K/Akt signaling pathway in cancer cells, promoting vascularization.111 VEGF facilitates cancer cells’ migration to CXCL12 via inducing CXCR4 expression.112 In ovarian cancer, pathologic concentrations of VEGF and CXCL12 efficiently and synergistically induce in vivo angiogenesis.113 Thus, there may be a regenerative feedback loop between CXCL12/CXCR4 and VEGF that facilitates angiogenesis. (2) CXCL12 reduces glycolytic enzyme phosphorglycerate kinase 1 (PGK1) expression, which leads to the increased secretion of VEGF and thus an angiogenic response in cancer.114 PGK1 is a glycolytic enzyme that catalyses the conversion of 1, 3-diphosphoglycerate to 3-phosphoglycerate. PGK1 can reduce disulfide bonds in the serine protease, which leads to the release of the tumor blood vessel inhibitor, angiostatin. Overexpression of PGK1 can reduce the secretion of VEGF and IL-8 and increases the generation of angiostatin, restraining angiogenesis. CXCL12 can inhibit PGK1 expression and promote angiogenesis. (3) CXCL12 significantly upregulates several angiogenesis-associated genes, such as interferon-α-inducible protein 27, IL-6, bone morphogenetic protein-6, SOCS2 and cyclooxygenase-2, in cancer cells. Among them, IL-6 is the earliest and highest upregulated gene. The transcriptional regulation of IL-6 by CXCL12 was found to be mediated by phosphorylation of ERK1/2 and activation of the NF-κB complex.115 IL-6 may induce angiogenesis indirectly by inducing the expression of VEGF, fibroblast growth factor, or cyclooxygenase-2.116, 117 Thus, CXCL12 may enhance angiogenesis via inducing IL-6. (4) CXCL12 can recruit endothelial progenitor cells to the vicinity of neovascularization (Figure 4). Orimo et al.106 showed that the CXCL12 released by carcinoma-associated fibroblasts is responsible for recruiting endothelial progenitor cells into tumor masses, thereby boosting tumor angiogenesis. Meanwhile, another study118 showed that the retention of recruited BM-derived circulating cells in close proximity to angiogenic vessels is mediated by CXCL12. Together, these data suggest that CXCL12 contributes to tumor angiogenesis through multiple signals. Interrupting these pathways will be a novel and efficient anti-angiogenesis strategy to treat cancer.

Figure 4
figure4

CXCL12/CXCR4 promotes angiogenesis in tumors. CXCL12 can induce CXCR4 (+) cancer cells to secrete VEGF and IL-6 to promote angiogenesis in tumors. In addition, CXCL12 can recruit endothelial progenitor cells to sites of neovascularization in tumors to promote angiogenesis.

The CXCL12/CXCR4 axis induces EMT and promotes metastasis

Cancer infiltration and metastasis is a multistep and complex process. Epithelial-to-mesenchymal transition (EMT) has been recognized as an important process that is associated with cancer metastasis. Recent studies have demonstrated that CXCL12/CXCR4 signaling promotes EMT by activating the MEK/ERK, PI3K/AKT or Wnt/β-catenin pathway in chondrosarcoma,119 glioblastoma,120 colorectal cancer,121 hepatocellular carcinoma122 and pancreatic cancer.123 Thus, therapies that target CXCL12/CXCR4 may be effective by suppressing EMT in cancer.

Muller et al.124 reported that the liver, BM, lungs and lymph nodes exhibit peak expression levels of CXCL12 and represent the most common organs for homing of breast cancer metastasis, indicating that the organ-specific metastasis of cancer cells is dependent on chemokines (Figure 3). Tumor cells ultimately metastasize to distant organs by the specific binding of chemokines and their receptors. CXCR4/CXCL12 has been implicated in the metastasis of various types of cancer.125 For example, Kim et al.126 verified that CXCR4 is expressed and functional on colorectal cancer cells, and CXCL12 is highly expressed in the liver and may specifically attract colorectal cancer CXCR4 (+) cells. Thus, the liver may be a specific target for CXCR4-expressing colorectal cancer cells because of its relative abundance of CXCL12. In vivo, researchers have demonstrated that CXCL12/CXCR4 has a role in metastasis. Gelmini et al.127 reported that endometrial cancer cells (HEC1A) generated diffuse metastases in the peritoneum, lungs and liver of CD-1 nude mice; however, simultaneous treatment with a neutralizing anti-CXCR4 monoclonal antibody dramatically reduced the number and size of the metastases in these animals. All these findings indicate that after being activated by its ligand CXCL12, CXCR4 initiates the signaling pathway in tumor cells, which can promote metastasis.

At present, the most widely studied and accepted metastasis pathways include the PI3K/Akt, ERK and NF-κB pathways (Figure 2). In hematologic malignancies128 and melanoma,129 CXCL12/CXCR4 can stimulate PI3K and modulate the adhesion and migration of cancer cells through diverse downstream signals. Tsukamoto et al.130 also found that CXCL12/CXCR4 has important roles in the muscular infiltration of endometrial cancer by activating the PI3K/Akt signaling pathway. PI3K/Akt activation might promote the invasion and metastasis of cancer95, 131, 132 by regulating the integrins β1(ref. 96) and β3,21 VEGF-C96 and αvβ6 integrin-mediated uPA expression.133 We conclude that tumor infiltration and metastasis, mediated by CXCL12, is partially PI3K/Akt-dependent.

CXCL12 acts through CXCR4 to activate the MEK/ERK/NF-κB pathway, contributing to the migration of human osteosarcoma cells. The results of a recent study indicated that CXCL12/CXCR4 promote metastasis in oral squamous cell carcinoma by activating ERK1/2, Akt/PKB134 and NF-kB.135 Activation of the ERK1/2 signaling pathway can increase the activity of matrix metallopeptidase 2 and matrix metallopeptidase 9, increasing the adhesion capability of cancer cells and metastasis.136, 137

The basal lamina of endothelial venules is rich in CXCL12,138 which may attract CXCR4-positive cancer cells to blood vessels from the primary tumor and thus support hematogenous metastasis. In addition, CXCL12 in peripheral vessels can support and maintain stem cells in stem cell niches. Tumors are often under hypoxic conditions, and CXCL12 expression can be upregulated in endothelial cells by hypoxia-inducible factor-1α.139 Thus, CXCL12 may recruit CXCR4-positive cancer stem cells to the peripheral vessels as a pool for metastasis.140

These data emphasize the importance of CXCL12/CXCR4 in cancer metastasis and suggest that targeting the molecular components of the signaling pathways described above will provide several important therapeutic opportunities for controlling the progression and metastasis of cancer mediated by CXCL12/CXCR4.

CXCR7 may have a different role from CXCR4 in cancer cells

Although CXCL12 can have roles in cancer through binding CXCR4 and CXCR7, CXCR7 may have different roles from CXCR4. First, CXCR7 may be differentially regulated in cancer. For example, E2 enhanced CXCR4 expression but repressed CXCR7 expression in breast cancer cells. A recent study demonstrated that CXCR4 expression was induced by hypoxia-inducible factor-1α, whereas CXCR7 expression was independent of hypoxia.141 Second, CXCR7 may activate different genes from CXCR4 in cancer. A recent study reported that CXCR4 and CXCR7 are disparate twins in colon cancer. The expression of AXL, C5, IGFBP7, IL-24 and EGFR was increased after exposure to CXCL12 in CXCR4-overexpressing cancer cells, whereas the expression of AKR1C3 and TNNC1 was increased after stimulation with CXCL12 in CXCR7-overexpressing cancer cells. AXL, C5, IGFBP7, IL-24 and EGFR were assigned to the positive regulation of cell migration, and proliferation, whereas AKR1C3 and TNNC1 were assigned to fatty acid, lipid and cellular lipid metabolic processes.142 Furthermore, CXCR4-overexpressing cells showed increased sensitivity against 5-fluorouracil, whereas CXCR7-overexpressing cells were more chemoresistant, indicating that CXCR7 may have different roles from CXCR4 in cancer cells. Thus, further studies may be required to elucidate the exact role of CXCR7 in cancer.

Several reports have shown that CXCR7 can activate intracellular signaling pathways, including AKT, MAPK and JAK2/STAT3, promoting cancer development and progression143 (Figure 2). In addition, CXCL12/CXCR7 enhanced ovarian cancer cell invasion by upregulating matrix metallopeptidase 9 expression through the p38 MAPK pathway.40 Thus, targeting CXCR7 may provide a new treatment for cancer.

CXCL12 in tumor immunosuppression and immunotherapy

As a pleiotropic chemokine, CXCL12 participates in the regulation of tissue homeostasis, immune surveillance, autoimmunity and cancer. First, the constitutive expression of CXCL12 in the BM and other tissues is responsible for regulating the trafficking and localization of immature and maturing leukocytes to these tissues, holding tissue homeostasis.144 Moreover, CXCL12, through CXCR4, has an important role in maintaining neutrophil homeostasis. CXCL12 can direct the migration of neutrophils to organs, particularly immune-privileged organs, as part of immune surveillance of the body.144

CXCR7 is expressed by lymphocytes and granulocytes in the BM, whereas it is expressed by monocytes, granulocytes and platelets among peripheral blood cells.13 In the immune system, CXCR7 is expressed in B cells and dendritic cells. Studies demonstrated that CXCR7 is required for mature B-cell function and for the survival and differentiation of the switch memory cohort145 and that it may be important at the beginning of the innate immune response.13

Recently, immunotherapy has emerged as a promising treatment strategy. Recent studies showed that CXCL12 contributes to tumor immune suppression by recruiting specific immune cell populations.146 Thus, blocking CXCL12/CXCR4 may decrease immune suppression in cancer. The delivery of a CXCR4 antagonist-expressing oncolytic vaccinia virus could decrease immune suppression by decreasing the numbers of endothelial cells, myeloid cells, plasmacytoid dendritic cells and T-regulatory cells, leading to the reduced metastatic spread of tumors and improved overall survival in a mouse model.147 Similar findings were reported in breast cancer mouse model.148 Thus, the application of CXCR4 antagonist represents a potent therapy for cancer.

In pancreatic ductal adenocarcinoma, depleting carcinoma-associated fibroblasts that express fibroblast activation protein could help to achieve immune control of PDA growth. Fibroblast activation protein (+) carcinoma-associated fibroblasts were the principal source of CXCL12 in pancreatic ductal adenocarcinoma, and cancer cells were coated with CXCL12, leading to the absence of T cells from regions of tumor-containing cancer cells. Administering AMD3100, a CXCR4 inhibitor, induced rapid T-cell accumulation among cancer cells and diminished cancer cells.149 AMD3100 is a kind of CXCR4 antagonist that was reported to inhibit immune suppression.150 Studies revealed that blocking CXCL12/CXCR4 with AMD3100 prevents ultraviolet (UV) radiation-induced immune suppression and skin cancer.151, 152 AMD3100 also prevented polarization toward an immune-suppressive microenvironment, inhibited tumor growth, reduced lung metastasis and improved survival in hepatocellular carcinoma models.153 CXCL12 can recruit regulatory T cells to the BM, and regulatory T cells may form an immunosuppressive niche to facilitate cancer bone metastasis and contribute to bone deposition.154 In B-cell lymphoma, AMD3100 enhances antilymphoma effects by blocking regulatory T recruitment toward the lymphoma tissue.155

CXCL12/CXCR4 in anticancer therapies

Blocking the CXCL12 pathway may be a valid strategy for targeting various components in cancer,156, 157 such as CXCR4 and CXCR7. Thus, it is urgent that we gain a deep understanding of the CXCL12/CXCR4 pathway in preclinical studies to inform the future translation of CXCL12, CXCR4 or CXCR7 inhibitors into clinical use. So far, several molecules have been developed that target CXCR4 or CXCL12 and thus interfere with tumor growth, including the anti-CXCR4 drugs AMD3100 and AMD3465, the CXCL12 analog peptide CTCE-9908, the anti-CXCL12 aptamer Nox-A12 and the CXCR7-specific inhibitor CCX2066 (Table 1).39

Table 1 CXCL12/CXCR4 inhibition in cancer

AMD3100, a CXCR4 antagonist, was demonstrated to block CXCL12-induced HER2/neu activation in vitro and inhibit tumor growth in vivo.158 The effects of CXCL12 on tumorigenesis were inhibited by AMD3100.95, 159, 160 Treatment with AMD3100 blocked ligand–receptor binding reduced the growth of ovarian cancer cells and intraperitoneal dissemination, and modestly improved the overall survival of mice with metastatic ovarian cancer.159, 161, 162 In adult T-cell leukemia, AMD3100 inhibited both the CXCL12-induced migration and phosphorylation of ERK1/2 and the infiltration of lymphomatous cells into liver and lung tissues in vivo.163

AMD3465, a monocyclam, is also a CXCR4 antagonist. AMD3465 induces the mobilization of acute myeloid leukemia cells and endothelial progenitor cells into the circulation and enhances the antileukemic activity of chemotherapy, prolonging animal survival.164 Thus, the combination of AMD3465 and chemotherapy may provide promising therapy for cancer. In addition, the cyclopentapeptide FC131, a new CXCR4 antagonist, can also bind CXCR4 and inhibit CXCL12-mediated activation on the basis of ligand modification, receptor mutagenesis and computational modeling approaches.165

CTCE-9908, a small analog peptide, consists of a dimer of CXCL12 and acts as a competitive inhibitor of CXCL12, which can suppress CXCL12 secretion. CTCE-9908 was found to deregulate DNA damage checkpoint proteins and spindle assembly checkpoint proteins at the G (2)–M phases of the cell cycle.166 Furthermore, combined treatment with CTCE-9908 and the drug paclitaxel led to additive cytotoxicity that also involved mitotic catastrophe.166

Blocking the CXCL12 pathway alone may not be sufficient. Several recent studies have revealed that certain chemotherapeutic agents, vascular-disrupting agents and radiation can activate the CXCL12 pathway.167, 168 Thus, therapy-induced activation of the CXCL12 pathway may havea role in resistance to cytotoxic therapy.169 The use of anti-CXCL12 therapy in combination with other anticancer therapies has shown promising efficacy in many studies. For example, combination therapy with AMD3100 and cisplatin significantly decreased the tumor burden in mice compared with either agent as monotherapy.170 In human ALL, AMD3100 increased the efficacy of the cell cycle-specific drug vincristine, resulting in extended survival of non-obese diabetes severe combined immunodeficient (NOD/SCID) mice with ALL.171 In another study, the combination of docetaxel and AMD3100 exerted a greater antitumor effect than did docetaxel alone.172 Therefore, clinical trials should be feasible with the development of novel orally available CXCR4 inhibitors combined with chemotherapy.

Moreover, CXCR4 blockade with AMD3100 may not be sufficient to block the effects of CXCL12, which can also bind to CXCR7 on cancer and stromal cells. This effect can be studied using Nox-A12, an aptamer against CXCL12, or CXCR7-specific inhibitors, such as CCX2066.39 Nox-A12 is an l-enantiomeric RNA oligonucleotide that binds and inhibits CXCL12 with high affinity. In recent studies, NOX-A12 inhibited CXCL12-induced chemotaxis of CLL cells and sensitized CLL cells to bendamustine and fludarabine.173 Furthermore, treatment with NOX-A12 prolonged the lifespans of irradiated rats with glioblastoma.174 Another study reported that NOX-A12 mobilized white blood cells and hematopoietic stem and progenitor cells into the peripheral blood. In healthy volunteers, single doses of NOX-A12 dose-dependently mobilized white blood cells and hematopoietic stem cells into the peripheral blood,175 indicating that NOX-A12 is appropriate for therapeutic use in hematological cancer cells.

Recently, researchers have found new drugs that target CXCL12, such as the high-affinity antistromal-derived factor-1 PEGylated mirror-image l-oligonucleotide (olaptesed-pegol). Using this drug in BM niches rendered the microenvironment less receptive to MM cells and reduced MM cell homing and growth, thereby inhibiting MM metastasis in the BM.176

Concluding remarks

In conclusion, an abundance of studies have shown that CXCL12 has a vital role in tumor development. CXCL12 can activate various signaling pathways of cancer cells in an autocrine or paracrine manner, provoke cancer cell multiplication and infiltration, suppress apoptosis and promote angiogenesis in cancer tissue. The ligand can also attract stromal cells and stimulate them to secrete growth factors to support tumor growth and angiogenesis. Consequently, inhibition of the CXCL12/CXCR4 axis may be a new approach to targeted therapy for cancer.

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Acknowledgements

We thank Ann Sutton from the Department of Scientific Publications at The University of Texas MD Anderson Cancer Center for editing this manuscript. This work was partially supported by funds from the Tianjin Municipal Science and Technology Commission International Cooperation Foundation (No. 15RCGFSY00108), the Natural Science Fund of Tianjin Municipal Science and Technology Commission (No. 12JCYBJC17900), and the Tianjin Medical University Science Foundation (No. 2014KYQ03).

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Guo, F., Wang, Y., Liu, J. et al. CXCL12/CXCR4: a symbiotic bridge linking cancer cells and their stromal neighbors in oncogenic communication networks. Oncogene 35, 816–826 (2016). https://doi.org/10.1038/onc.2015.139

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