Cancer

Review Article

CXCR4 and cancerpin_2548 497..505

Bungo Furusato,1,2* Ahmed Mohamed,1* Mathias Uhlén3 and Johng S. Rhim1

1Center for Prostate Disease Research, Department of Surgery, Uniformed Service University of the Health Science,

Bethesda, Maryland, 2Department of Genitourinary Pathology, Armed Forces Institute of Pathology, Washington, DC,

USA, and 3Department of Biotechnology, AlbaNova University Center, Royal Institute of Technology (KTH),

Stockholm, Sweden

The chemokine receptor CXCR4 belongs to the large superfamily

of G protein-coupled receptors and has been identified

to play a crucial role in a number of biological processes,

including the trafficking and homeostasis of immune cells

such as T lymphocytes. CXCR4 has also been found to be a

prognostic marker in various types of cancer, including leukemia

and breast cancer, and recent evidence has highlighted

the role of CXCR4 in prostate cancer. Furthermore,

CXCR4 expression is upregulated in cancer metastasis,

leading to enhanced signaling. These observations suggest

that CXCR4 is important for the progression of cancer. The

CXCR4-CXCL12 (stromal cell-derived factor 1 (SDF-1)) axis

has additionally been identified to have a role in normal stem

cell homing. Interestingly, cancer stem cells also express

CXCR4, indicating that the CXCR4-SDF-1 axis may direct the

trafficking and metastasis of these cells to organs that

express high levels of SDF-1, such as the lymph nodes,

lungs, liver, and bone. This review focuses on the current

knowledge of CXCR4 regulation and how deregulation of this

protein may contribute to the progression of cancer.

Key words: cancer, cancer stem cell, CXCR4, gene fusion

THE CHEMOKINE RECEPTOR CXCR4 AND CANCER

The human chemokine system is currently known to include

more than 40 chemokines and 18 chemokine receptors.

Chemokine receptors are defined by their ability to induce

the directional migration of cells toward a gradient of a

chemotactic cytokine (a process known as chemotaxis).

Chemokine receptors are a family of seven transmembrane

G protein-coupled cell surface receptors (GPCR) that are

classified into four groups (CXC, CC, C, and CX3C) based

on the position of the first two cysteines.1,2 While chemokine

receptors have been found in many different cell types,

these receptors were initially identified on leukocytes and

were found to play an important role in the homing of such

cells to sites of inflammation.3

During the past several years, other types of nonhematopoietic

cells have been found to express receptors for

various chemokines found in their distinct tissue microenvironments.

The interactions between such receptors and their

respective chemokines are thought to help coordinate the

trafficking and organization of cells within various tissue

compartments.4,5

CXCR4 is one of the best studied chemokine receptors,

primarily due to its role as a co-receptor for HIV entry6 and its

ability to mediate the metastasis of a variety of cancers,

including prostate cancer.7–11

CXCR4 is a 352-amino acid rhodopsin-like GPCR that

selectively binds the CXC chemokine stromal cell-derived

factor 1 (SDF-1), also known as CXCL12.1,12

In an animal model, lack of either SDF-1 or CXCR4

resulted in a phenotype almost identical to that of late gestational

lethality with defects in B cell lymphopoiesis, bone

marrow colonization, and cardiac septal formation.13,14

These studies indicated that CXCR4 is essential for development,

hematopoiesis, organogenesis, as well as

vascularization13–18 and that it functions as a classical

chemokine receptor in adults.5,19

A growing body of evidence now shows that CXCR4 has a

role not only in cancer metastasis but also in cancer stem

cells. The physiological mechanism of tissue-specific recruitment

(i.e. a homing system for normal tissue replacement)

also seems to be functional for cancer stem cells.

Correspondence: Johng S. Rhim, MD, Department of Surgery, Uniformed

Services University of the Health Sciences, 1530 E. Jefferson

Street, Rockville, MD 20852, USA. Email: [e-mail]

*These authors equally contributed to this work.

Conflicts of interest: None declared.

The views expressed in this article are those of the authors and do

not reflect the official policy of the Department of the Army, Department

of Defense, or the U.S. Government.

Received 1 February 2010. Accepted for publication 9 March

2010.

© 2010 The Authors

Journal compilation © 2010 Japanese Society of Pathology and

Blackwell Publishing Asia Pty Ltd

Pathology International 2010; 60: 497–505 doi:10.1111/j.1440-1827.2010.02548.x

This review will focus on the role of CXCR4 in cancer,

including its potential involvement in the cancer stem cell

concept. We will discuss the factors involved in CXCR4

expression and regulation as well as how deregulation of

these pathways may contribute to disease progression. We

will also discuss the potential options for targeted therapy for

cancer.

CONCEPT OF CANCER STEM CELLS

Growing evidence suggests that quiescent tissue-committed

stem cells (TCSC), which are cells that are closely related to

the development of each organ, may be the cells from which

cancer development begins. This phenomenon was initially

demonstrated in experiments in human leukemia20 and

several investigators subsequently postulated the existence

of cancer stem cells. Stem cells are long-lived and thus can

become targets for cell damage. Because of their longevity,

these cells are able to accumulate mutations over time; such

mutations are a crucial part of the initiation and progression

of cancer. Several studies have shown that mutations occurring

in normal stem cells can lead to malignant transformation

and tumor initiation.21–23

Recent studies on solid tumors, such as brain, breast, and

prostate cancers, have demonstrated the important role that

cancer stem cells play in the development of some

tumors.24–26

Cancer stem cells have features similar to those of normal

stem cells and are known to be very difficult to eradicate with

treatments such as chemotherapy. Since cancer stem cells

may exist in a quiescent state, they are thought to be relatively

resistant to most drugs that only target dividing cells.

Cancer stem cells only represent a subpopulation of cells in

a growing tumor but are capable of initiating metastasis,

additionally, they can regroup (or function as ‘seeds’) to form

new tumors after unsuccessful treatment.

CXCR4 is expressed on normal stem cells of various

organs and tissues; this may explain why some tumor cells

express CXCR4 and why many researchers suggest that

malignant cells may be derived from CXCR4-expressing

normal stem cells (Table 1).

THE ROLE OF THE CXCR4-SDF-1 (CXCL12) AXIS IN

THE MOBILIZATION, TRAFFICKING AND HOMING OF

CANCER STEM CELLS

The CXCR4-SDF-1 axis seems to have a large influence on

the biology of tumors. High levels of SDF-1 in organs and

tissue structures such as the lymph nodes, lungs, liver, and

bones are believed to direct the metastasis of CXCR4-

expressing tumor cells.

In support of this hypothesis, several researchers have

shown that multiple cancers expressing CXCR4 (e.g. breast,

ovarian, and prostate cancers, as well as rhabdomyosarcoma

and neuroblastoma) metastasize to the bones through

the bloodstream in an SDF-1 (CXCL12)-dependent

manner.11,25,27–32

The CXCR4-SDF-1-mediated trafficking/homing of tumor

cells during metastasis seems to share some molecular

mechanisms with normal stem cell processes. Additionally,

the mobilization, trafficking and homing of both cancer and

normal stem cells seem to be multistep processes, as

described in several studies9,33–35 (Fig. 1).

CXCR4 RECEPTOR EXPRESSION, REGULATION

AND PATHWAY

CXCR4 is normally expressed in a wide variety of tissues and

organs. Among these, the bone marrow, blood, spleen,

thymus, lymph node, pituitary gland, and adrenal glands

seem to express the highest levels of CXCR4. However, the

interaction between CXCR4 and cancer appears to be quite

complex. Interestingly, when CXCR4 is expressed in a

variety of cancers, its expression in adjacent normal tissue is

minimal or absent.11,27,36 This may result from changes within

the vasculature or in the O2-carrying capacity of cells that

lead to hypoxic conditions during tumor progression.37

Hypoxia induces the activation of hypoxia-inducible

factor-1 (HIF-1), which may also promote the expression of a

number of target genes, including CXCR4.37–40

The function of HIF-1 was discovered during studies on the

von Hippel Lindau (VHL) tumor suppressor gene. Inactivating

mutations of VHL, which normally targets HIF-1 for degradation,

result in increased CXCR4 expression in renal cell

carcinomas.38–40

Increased levels of vascular endothelial growth factor and

the activation of nuclear factor kappa B (NF-kB) both have

the ability to increase CXCR4 expression, specifically during

Table 1 Examples of CXCR4-expressing tumors that may be

derived from normal stem cells expressing CXCR4. [Adapted and

modified from Kucia et al.9]

Normal cells Corresponding tumor

Prostate gland epithelial stem cells Prostate cancer

Hematopoietic stem cells Leukemia

Neural stem cells Brain tumors

Mammary gland epithelial stem cells Breast cancer

Skeletal muscle satellite cells Rhabdomyosarcoma

Neuroectodermal stem cells Neuroblastoma

Renal tubular epithelium stem cells Wilms’ tumor

Retina pigment epithelium stem cells Retinoblastoma

Liver oval stem cells Hepatoblastoma

Ovarian epithelium stem cells Ovarian cancer

Cervical epithelium stem cells Cervical cancer

498 B. Furusato et al.

© 2010 The Authors

Journal compilation © 2010 Japanese Society of Pathology and Blackwell Publishing Asia Pty Ltd

cancer progression.41,42 These genes enhance CXCR4

expression in breast cancer, promoting invasion and

metastasis.

Furthermore, oncoproteins such as PAX3-FKHR and RET/

PTC have also been shown to induce CXCR4 expression.

31,43,44 The PAX3-FKHR fusion leads to the enhanced

migration and adhesion of rhabdomyosarcoma cells, while

the RET/PTC-induced expression of CXCR4 enhances the

transforming ability of breast cancer cells.31,44

Tumor progression, especially in tumor metastasis, is also

affected by CXCR4-SDF-1 signaling through the induction of

tumor-associated integrin activation and signaling.45 Additionally,

CXCR4 stimulates the production of matrixmetalloproteases.

46–49 SDF signaling is also able to increase

integrin activity,50–52 thus enhancing cell adhesion under flow

conditions.

If CXCR4 truly mediated metastasis, then tumor cells

entering the blood or lymphatic systems would preferentially

migrate and adhere to areas with high expression of SDF-1.

Breast cancer cells follow this pattern of metastasis, migrating

primarily to the lymph nodes, lung, liver, and bone marrow

tissue, all of which have high levels of SDF-1 expression.

Prostate cancer also seems to follow this pattern.30,53,54

In vivo application of CXCR4-neutralizing antibodies or

siRNA targeting the CXCR4 gene inhibits the metastasis and

growth of breast and prostate cancer cells.30,55–57 Other

cancers such as small cell lung cancer, thyroid cancer, neuroblastoma,

as well as hematological and hepatic malignancies,

also metastasize to areas with high SDF-1

expression.28,58–61 Previous studies suggest that the expression

of CXCR4 in hepatocellular carcinoma correlates to local

tumor progression, lymphatic and distant metastasis, and

decreased three-year survival rates in liver cancer patients.61

Some studies indicate that epigenetic mechanisms that

negatively regulate the expression of SDF-1 or CXCR4 may

be necessary for tumor metastasis. One example of an epigenetic

mechanism is DNA methylation, which is a modification

typically associated with the inactivation of tumor

Figure 1 The role of the SDF-1-CXCR4 axis in the migration and

circulation of normal stem cells and metastasis of cancer stem cells.

The migration of normal stem cells and metastasis of malignant stem

cells are multistep processes in which cells: (i) leave their stem cell

niches (normal stem cells) or primary tumor (cancer stem cells) and

enter the circulation; (ii) arrive at the site of homing (normal stem

cells) or metastasis (malignant stem cells) via the peripheral blood or

lymph; (iii) adhere to the endothelium; and (iv) invade tissues, proliferate,

and expand at a location that provides a supportive environment.

We hypothesize that CXCL12/SDF-1 plays a crucial role in this

process, chemoattracting CXCR4+ normal or tumor stem cells. SC,

stem cell; SDF, stromal-derived factor. [Adapted and modified from

Kucia et al.9]

Figure 2 Expression of CXCR4 in various cancers. Most cancer

shows moderate cytoplasmic and/or membranous staining. (a)

Breast cancer. (b) Cervical cancer. (c) Colorectal cancer. (d) Ovarian

cancer. (e) Pancreatic cancer. (f) Prostate cancer.

CXCR4 and cancer 499

© 2010 The Authors

Journal compilation © 2010 Japanese Society of Pathology and Blackwell Publishing Asia Pty Ltd

suppressors. There is evidence that methylation of the SDF

promoter in the colonic epithelium promotes metastasis of

tumors in the colon.62,63 Additionally, in pancreatic cancer, the

CXCR4 promoter has been found to be regulated by DNA

methylation, resulting in lower CXCR4 mRNA and protein

levels.64

Furthermore, the CXCR4 COOH-terminal domain also

seems to play a major role in receptor regulation, particularly

during the process of epithelial-to-mesenchymal transition

(EMT).65,66 Previous studies suggested that there are

C-terminal truncation mutations in the chemokine receptor

CXCR4 in warts, hypogammaglobulinemia, immunodeficiency,

and myelokathexis syndrome; these findings suggest

that aberrant chemokine receptor function can cause human

disease.65 It has also been shown in MCF-7 mammary carcinoma

cells that expression of the C-tail truncated mutant of

CXCR4 results in a higher growth rate and altered morphology,

as indicated by EMT.66

In addition to this complex picture of molecular interactions

that include the mechanisms that account for prostate

cancer, the behavior of cells homing to the bone and lymph

nodes may not rely solely on molecular mechanisms. It has

also been suggested that the behavior of cells homing to the

bone may include a direct vascular pathway, highly permeable

marrow sinusoids, chemotactic factors produced by

marrow stromal cells such as SDF-1, and the synthesis of

growth factors by resident cells within the bone and bone

marrow that support the survival, growth, and proliferation of

cancer cells.67 Several studies have demonstrated that some

of the most widely used prostate cancer cell lines, such as

PC3, DU145, LNCaP, and LNCaP C4-2B, as well as malignant

prostate cancer cells, express functional CXCR4 receptors

and that SDF-1 alters the adherence, migration, and

invasion of human prostate cancer cell lines.68–71 Prostate

cancer cells may use CXCR4 receptors as cellular adhesion

components and/or as extracellular matrix components in the

bone marrow.

Recently, chromosomal translocations involving the ERG

locus were found in human prostate cancer. One study indicated

that the TMPRSS2-ERG rearrangement found in prostate

cancer specimens is associated with the loss of the

tumor suppressor PTEN.72,73 In a PTEN heterozygous background

the transgenic overexpression of ERG in mouse prostate

tissues resulted in marked acceleration and progression

of high-grade prostatic intraepithelial neoplasia to prostatic

adenocarcinoma. Interestingly, two candidate genes,

ADAMTS1 and CXCR4, were strongly associated with cell

migration and were upregulated in the presence of ERG

overexpression.72

CXCR4/SDF-1 interactions trigger the activation of many

downstream pathways, including Ca2+ influx, activation of the

MAPK/ERK-1/2 pathway, activation of phosphatidylinositol

3-kinase and Akt, as well as increased NF-kB activity. These

pathways are known to play an important role in the regulation

of cell proliferation and survival.

Taken together, the current body of knowledge suggests

that CXCR4 is involved in many diverse processes, including

cancer development and metastasis. Much work has been

done to delineate the potential pathways that mediate specific

effects (e.g. pathways leading to metastasis); however,

the detailed receptor regulation process has not yet been

established. Understanding the precise mechanisms regulating

CXCR4 function at the receptor level may provide new

insights for developing attractive therapeutic targets in

cancer.

CONCLUSION AND FUTURE DIRECTIONS

The concept of a chemokine that can influence a metastasis

site is only now beginning to be understood. Expression of

chemokine receptors by cancer stem cells appears to be an

important aspect of tumorigenesis and metastasis. Although

not all chemokine receptors are well-established, expression

of CXCR4 in cancer stem cells is likely to be involved in

organ-specific metastasis, for example metastasis of prostate

cancer to bone.

There is now mounting evidence that interactions

between the CXCR4/SDF-1 signaling pathway and other

genes or pathways plays a significant role in the promotion

of cancer metastasis including prostate cancer.68,71,74–80

These studies provide valuable additions to the growing list

of potential therapeutic targets and mechanisms by which

genes may contribute to the metastatic process.75–80 Some

studies have successfully shown that blockade of CXCR4 or

CXCR4/SDF-1 interactions by siRNA and chemical or small

molecule inhibitors suppresses prostate cancer cell proliferation,

invasion and metastasis. Currently, a small molecule

inhibitor of CXCR4 (CTCE-9908, British Canadian

BioSciences Corp., Vancouver, BC, Canada) is being tested

in animal models of cancer.81 However, in reality, any therapeutic

method based on such findings (e.g. administration of

a CXCR4 antagonist to a prostate cancer patient with bone

metastasis) would probably not be used alone; combinations

with established chemotherapy protocols would be

much more likely.

From a basic science perspective, a great deal remains to

be learned about CXCR4 and its association with various

cancers (Table 2) (Fig. 2). CXCR4 involvement in cancer

metastasis suggests that CXCR4 antagonists may be a

potential option for prevention of metastasis.152 One study

indicated that transfection of tumor cells with CXCR4 greatly

enhanced their metastatic potential.153 Therefore, rather than

antagonizing this receptor, a successful antimetastasis strategy

may involve the modulation of CXCR4 expression in

tumor cells. While the role of CXCR4 in cancer stem cells

500 B. Furusato et al.

© 2010 The Authors

Journal compilation © 2010 Japanese Society of Pathology and Blackwell Publishing Asia Pty Ltd

presents exciting clinical implications, its application to

cancer care has yet to gain widespread acceptance.

We anticipate that the findings described here will be replicated

in additional tumor types and that knowledge of the

detailed biology and clinical significance of this experimentally

defined population of stem cells will provide further

support for the concept of cancer stem cells.

Ultimately, focusing research efforts on the role of CXCR4

in cancer may generate important advances in our understanding

of the biology of cancers and cancer stem cells and

may provide important advances in our understanding of

cancer biology and may provide novel treatment approaches

for devastating diseases.

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Breast cancer 85–89

Lung cancer 91–96

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Kidney cancer 107–111

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Thyroid cancer 44,59,119,120

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Oral cancer 133–136

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CXCR4 and cancer 501

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