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: jrhim@verizon.net

*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.

REFERENCES

1 Murphy PM, Baggiolini M, Charo IF et al. International union of

pharmacology. XXII. Nomenclature for chemokine receptors.

Pharmacol Rev 2000; 52: 145–76.

2 Zlotnik A, Yoshie O. Chemokines: A new classification system

and their role in immunity. Immunity 2000; 12: 121–7.

3 Loetscher P, Moser B, Baggiolini M. Chemokines and their

receptors in lymphocyte traffic and HIV infection. Adv Immunol

2000; 74: 127–80.

4 Baggiolini M. Chemokines and leukocyte traffic. Nature 1998;

392: 565–8.

5 Moser B, Loetscher P. Lymphocyte traffic control by chemokines.

Nat Immunol 2001; 2: 123–8.

6 Feng Y, Broder CC, Kennedy PE, Berger EA. HIV-1 entry

cofactor: Functional cDNA cloning of a seven-transmembrane,

G protein-coupled receptor. Science 1996; 272: 872–7.

7 Zlotnik A. Involvement of chemokine receptors in organspecific

metastasis. Contrib Microbiol 2006; 13: 191–9.

8 Burger JA, Kipps TJ. CXCR4: A key receptor in the crosstalk

between tumor cells and their microenvironment. Blood 2006;

107: 1761–7.

9 Kucia M, Reca R, Miekus K et al. Trafficking of normal stem

cells and metastasis of cancer stem cells involve similar

mechanisms: Pivotal role of the SDF-1-CXCR4 axis. Stem

Cells 2005; 23: 879–94.

10 Zlotnik A. Chemokines and cancer. Int J Cancer 2006; 119:

2026–9.

11 Sun YX, Wang J, Shelburne CE et al. Expression of CXCR4

and CXCL12 (SDF-1) in human prostate cancers (PCa) in vivo.

J Cell Biochem 2003; 89: 462–73.

12 Fredriksson R, Lagerstrom MC, Lundin LG, Schioth HB. The

G-protein-coupled receptors in the human genome form five

main families. Phylogenetic analysis, paralogon groups, and

fingerprints. Mol Pharmacol 2003; 63: 1256–72.

13 Nagasawa T, Hirota S, Tachibana K et al. Defects of B-cell

lymphopoiesis and bone-marrow myelopoiesis in mice lacking

the CXC chemokine PBSF/SDF-1. Nature 1996; 382: 635–8.

14 Zou YR, Kottmann AH, Kuroda M, Taniuchi I, Littman DR.

Function of the chemokine receptor CXCR4 in haematopoiesis

and in cerebellar development. Nature 1998; 393: 595–9.

15 Ma Q, Jones D, Borghesani PR et al. Impaired

B-lymphopoiesis, myelopoiesis, and derailed cerebellar

neuron migration in CXCR4- and SDF-1-deficient mice. Proc

Natl Acad Sci USA 1998; 95: 9448–53.

16 McGrath KE, Koniski AD, Maltby KM, McGann JK, Palis J.

Embryonic expression and function of the chemokine SDF-1

and its receptor, CXCR4. Dev Biol 1999; 213: 442–56.

17 Nagasawa T, Tachibana K, Kishimoto T. A novel CXC chemokine

PBSF/SDF-1 and its receptor CXCR4: Their functions in

development, hematopoiesis and HIV infection. Semin

Immunol 1998; 10: 179–85.

18 Tachibana K, Hirota S, Iizasa H et al. The chemokine receptor

CXCR4 is essential for vascularization of the gastrointestinal

tract. Nature 1998; 393: 591–4.

19 Murphy PM. The molecular biology of leukocyte chemoattractant

receptors. Annu Rev Immunol 1994; 12: 593–633.

20 Lapidot T, Pflumio F, Doedens M, Murdoch B, Williams DE,

Dick JE. Cytokine stimulation of multilineage hematopoiesis

from immature human cells engrafted in SCID mice. Science

1992; 255: 1137–41.

21 Tavor S, Petit I, Porozov S et al. CXCR4 regulates migration

and development of human acute myelogenous leukemia stem

cells in transplanted NOD/SCID mice. Cancer Res 2004; 64:

2817–24.

22 Pardal R, Clarke MF, Morrison SJ. Applying the principles of

stem-cell biology to cancer. Nat Rev Cancer 2003; 3: 895–902.

23 Reya T, Morrison SJ, Clarke MF, Weissman IL. Stem cells,

cancer, and cancer stem cells. Nature 2001; 414: 105–11.

24 Singh SK, Hawkins C, Clarke ID et al. Identification of human

brain tumour initiating cells. Nature 2004; 432: 396–401.

25 Dontu G, Al-Hajj M, Abdallah WM, Clarke MF, Wicha MS.

Stem cells in normal breast development and breast cancer.

Cell Prolif 2003; 36 (Suppl 1): 59–72.

26 Collins AT, Maitland NJ. Prostate cancer stem cells. Eur J

Cancer 2006; 42: 1213–18.

27 Muller A, Homey B, Soto H et al. Involvement of chemokine

receptors in breast cancer metastasis. Nature 2001; 410:

50–56.

28 Geminder H, Sagi-Assif O, Goldberg L et al. A possible role for

CXCR4 and its ligand, the CXC chemokine stromal cellderived

factor-1, in the development of bone marrow

metastases in neuroblastoma. J Immunol 2001; 167: 4747–

57.

29 Porcile C, Bajetto A, Barbero S, Pirani P, Schettini G. CXCR4

activation induces epidermal growth factor receptor transactivation

in an ovarian cancer cell line. Ann N Y Acad Sci 2004;

1030: 162–9.

30 Hall JM, Korach KS. Stromal cell-derived factor 1, a novel

target of estrogen receptor action, mediates the mitogenic

effects of estradiol in ovarian and breast cancer cells. Mol

Endocrinol 2003; 17: 792–803.

Table 2 CXCR4 expression in various cancers

Cancer expressing

CXCR4 Reference

Colon cancer 82–84

Breast cancer 85–89

Lung cancer 91–96

Ovarian cancer 97–102

Prostate cancer 68,75,103–106

Kidney cancer 107–111

Brain cancer 112–118

Thyroid cancer 44,59,119,120

Liver cancer 61

Pancreatic cancer 121–126

Esophageal cancer 127–129

Cervical cancer 130–132

Oral cancer 133–136

Melanoma 137–144

Leukemia 145–151

CXCR4 and cancer 501

© 2010 The Authors

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

31 Libura J, Drukala J, Majka M et al. CXCR4-SDF-1 signaling is

active in rhabdomyosarcoma cells and regulates locomotion,

chemotaxis, and adhesion. Blood 2002; 100: 2597–606.

32 Jankowski K, Kucia M, Wysoczynski M et al. Both hepatocyte

growth factor (HGF) and stromal-derived factor-1 regulate the

metastatic behavior of human rhabdomyosarcoma cells, but

only HGF enhances their resistance to radiochemotherapy.

Cancer Res 2003; 63: 7926–35.

33 Petit I, Szyper-Kravitz M, Nagler A et al. G-CSF induces stem

cell mobilization by decreasing bone marrow SDF-1 and

up-regulating CXCR4. Nat Immunol 2002; 3: 687–94.

34 Lapidot T, Petit I. Current understanding of stem cell mobilization:

The roles of chemokines, proteolytic enzymes, adhesion

molecules, cytokines, and stromal cells. Exp Hematol 2002;

30: 973–81.

35 Hattori K, Heissig B, Tashiro K et al. Plasma elevation of

stromal cell-derived factor-1 induces mobilization of mature

and immature hematopoietic progenitor and stem cells. Blood

2001; 97: 3354–60.

36 Scotton CJ, Wilson JL, Milliken D, Stamp G, Balkwill FR.

Epithelial cancer cell migration: A role for chemokine receptors?

Cancer Res 2001; 61: 4961–5.

37 Hirota K, Semenza GL. Regulation of angiogenesis by

hypoxia-inducible factor 1. Crit Rev Oncol Hematol 2006; 59:

15–26.

38 Schioppa T, Uranchimeg B, Saccani A et al. Regulation of the

chemokine receptor CXCR4 by hypoxia. J Exp Med 2003; 198:

1391–402.

39 Staller P, Sulitkova J, Lisztwan J, Moch H, Oakeley EJ, Krek

W. Chemokine receptor CXCR4 downregulated by von Hippel-

Lindau tumour suppressor pVHL. Nature 2003; 425: 307–11.

40 Zagzag D, Krishnamachary B, Yee H et al. Stromal cellderived

factor-1alpha and CXCR4 expression in hemangioblastoma

and clear cell-renal cell carcinoma: Von Hippel-

Lindau loss-of-function induces expression of a ligand and its

receptor. Cancer Res 2005; 65: 6178–88.

41 Bachelder RE, Wendt MA, Mercurio AM. Vascular endothelial

growth factor promotes breast carcinoma invasion in an autocrine

manner by regulating the chemokine receptor CXCR4.

Cancer Res 2002; 62: 7203–6.

42 Helbig G, Christopherson KW 2nd, Bhat-Nakshatri P et al.

NF-kappaB promotes breast cancer cell migration and

metastasis by inducing the expression of the chemokine

receptor CXCR4. J Biol Chem 2003; 278: 21631–8.

43 Tomescu O, Xia SJ, Strezlecki D et al. Inducible short-term and

stable long-term cell culture systems reveal that the PAX3-

FKHR fusion oncoprotein regulates CXCR4, PAX3, and PAX7

expression. Lab Invest 2004; 84: 1060–70.

44 Castellone MD, Guarino V, De Falco V et al. Functional

expression of the CXCR4 chemokine receptor is induced by

RET/PTC oncogenes and is a common event in human papillary

thyroid carcinomas. Oncogene 2004; 23: 5958–67.

45 Hartmann TN, Burger JA, Glodek A, Fujii N, Burger M. CXCR4

chemokine receptor and integrin signaling co-operate in mediating

adhesion and chemoresistance in small cell lung cancer

(SCLC) cells. Oncogene 2005; 24: 4462–71.

46 Fernandis AZ, Prasad A, Band H, Klosel R, Ganju RK. Regulation

of CXCR4-mediated chemotaxis and chemoinvasion of

breast cancer cells. Oncogene 2004; 23: 157–67.

47 Janowska-Wieczorek A, Marquez LA, Dobrowsky A, Ratajczak

MZ, Cabuhat ML. Differential MMP and TIMP production by

human marrow and peripheral blood CD34(+) cells in response

to chemokines. Exp Hematol 2000; 28: 1274–85.

48 Samara GJ, Lawrence DM, Chiarelli CJ et al. CXCR4-

mediated adhesion and MMP-9 secretion in head and neck

squamous cell carcinoma. Cancer Lett 2004; 214: 231–41.

49 Spiegel A, Kollet O, Peled A et al. Unique SDF-1-induced

activation of human precursor-B ALL cells as a result of altered

CXCR4 expression and signaling. Blood 2004; 103: 2900–907.

50 Campbell JJ, Hedrick J, Zlotnik A, Siani MA, Thompson DA,

Butcher EC. Chemokines and the arrest of lymphocytes rolling

under flow conditions. Science 1998; 279: 381–4.

51 Glodek AM, Honczarenko M, Le Y, Campbell JJ, Silberstein

LE. Sustained activation of cell adhesion is a differentially

regulated process in B lymphopoiesis. J Exp Med 2003; 197:

461–73.

52 Wright N, Hidalgo A, Rodriguez-Frade JM et al. The chemokine

stromal cell-derived factor-1 alpha modulates alpha 4 beta

7 integrin-mediated lymphocyte adhesion to mucosal

addressin cell adhesion molecule-1 and fibronectin. J Immunol

2002; 168: 5268–77.

53 Allinen M, Beroukhim R, Cai L et al. Molecular characterization

of the tumor microenvironment in breast cancer. Cancer Cell

2004; 6: 17–32.

54 Gladson CL,Welch DR. New insights into the role of CXCR4 in

prostate cancer metastasis. Cancer Biol Ther 2008; 7: 1849–

51.

55 Lapteva N, Yang AG, Sanders DE, Strube RW, Chen SY.

CXCR4 knockdown by small interfering RNA abrogates breast

tumor growth in vivo. Cancer Gene Ther 2005; 12: 84–9.

56 Liang Z, Yoon Y, Votaw J, Goodman MM, Williams L, Shim H.

Silencing of CXCR4 blocks breast cancer metastasis. Cancer

Res 2005; 65: 967–71.

57 Du YF, Shi Y, Xing YF, Zeng FQ. Establishment of CXCR4-

small interfering RNA retrovirus vector driven by human

prostate-specific antigen promoter and its biological effects on

prostate cancer in vitro and in vivo. J Cancer Res Clin Oncol

2008; 134: 1255–64.

58 Burger M, Glodek A, Hartmann T et al. Functional expression

of CXCR4 (CD184) on small-cell lung cancer cells mediates

migration, integrin activation, and adhesion to stromal cells.

Oncogene 2003; 22: 8093–101.

59 Hwang JH, Chung HK, Kim DWet al. CXC chemokine receptor

4 expression and function in human anaplastic thyroid cancer

cells. J Clin Endocrinol Metab 2003; 88: 408–16.

60 Kijima T, Maulik G, Ma PC et al. Regulation of cellular proliferation,

cytoskeletal function, and signal transduction through

CXCR4 and c-Kit in small cell lung cancer cells. Cancer Res

2002; 62: 6304–11.

61 Schimanski CC, Bahre R, Gockel I et al. Dissemination of

hepatocellular carcinoma is mediated via chemokine receptor

CXCR4. Br J Cancer 2006; 95: 210–17.

62 Jones PA, Baylin SB. The fundamental role of epigenetic

events in cancer. Nat Rev Genet 2002; 3: 415–28.

63 Wendt MK, Johanesen PA, Kang-Decker N, Binion DG, Shah

V, Dwinell MB. Silencing of epithelial CXCL12 expression by

DNA hypermethylation promotes colonic carcinoma metastasis.

Oncogene 2006; 25: 4986–97.

64 Sato N, Matsubayashi H, Fukushima N, Goggins M. The

chemokine receptor CXCR4 is regulated by DNA methylation

in pancreatic cancer. Cancer Biol Ther 2005; 4: 70–76.

65 Hernandez PA, Gorlin RJ, Lukens JN et al. Mutations in the

chemokine receptor gene CXCR4 are associated with WHIM

syndrome, a combined immunodeficiency disease. Nat Genet

2003; 34: 70–74.

66 Ueda Y, Neel NF, Schutyser E, Raman D, Richmond A. Deletion

of the COOH-terminal domain of CXC chemokine receptor

4 leads to the down-regulation of cell-to-cell contact, enhanced

motility and proliferation in breast carcinoma cells. Cancer Res

2006; 66: 5665–75.

67 Geldof AA. Models for cancer skeletal metastasis: A reappraisal

of Batson’s plexus. Anticancer Res 1997; 17: 1535–9.

502 B. Furusato et al.

© 2010 The Authors

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

68 Taichman RS, Cooper C, Keller ET, Pienta KJ, Taichman NS,

McCauley LK. Use of the stromal cell-derived factor-1/CXCR4

pathway in prostate cancer metastasis to bone. Cancer Res

2002; 62: 1832–7.

69 Havens AM, Jung Y, Sun YX et al. The role of sialomucin

CD164 (MGC-24v or endolyn) in prostate cancer metastasis.

BMC Cancer 2006; 6: 195.

70 Andela VB, Schwarz EM, Puzas JE, O’Keefe RJ, Rosier RN.

Tumor metastasis and the reciprocal regulation of prometastatic

and antimetastatic factors by nuclear factor kappaB.

Cancer Res 2000; 60: 6557–62.

71 Kukreja P, Abdel-Mageed AB, Mondal D, Liu K, Agrawal KC.

Up-regulation of CXCR4 expression in PC-3 cells by stromalderived

factor-1alpha (CXCL12) increases endothelial adhesion

and transendothelial migration: Role of MEK/ERK

signaling pathway-dependent NF-kappaB activation. Cancer

Res 2005; 65: 9891–8.

72 Carver BS, Tran J, Gopalan A et al. Aberrant ERG expression

cooperates with loss of PTEN to promote cancer progression

in the prostate. Nat Genet 2009; 41: 619–24.

73 Han B, Mehra R, Lonigro RJ et al. Fluorescence in situ hybridization

study shows association of PTEN deletion with ERG

rearrangement during prostate cancer progression. Mod

Pathol 2009; 22: 1083–93.

74 Darash-Yahana M, Pikarsky E, Abramovitch R et al. Role of

high expression levels of CXCR4 in tumor growth, vascularization,

and metastasis. FASEB J 2004; 18: 1240–42.

75 Engl T, Relja B, Marian D et al. CXCR4 chemokine receptor

mediates prostate tumor cell adhesion through alpha5 and

beta3 integrins. Neoplasia 2006; 8: 290–301.

76 Suzuki Y, Rahman M, Mitsuya H. Diverse transcriptional

response of CD4(+) T cells to stromal cell-derived factor

(SDF)-1: Cell survival promotion and priming effects of SDF-1

on CD4(+) T cells. J Immunol 2001; 167: 3064–73.

77 Sun YX, Schneider A, Jung Y et al. Skeletal localization and

neutralization of the SDF-1(CXCL12)/CXCR4 axis blocks prostate

cancer metastasis and growth in osseous sites in vivo. J

Bone Miner Res 2005; 20: 318–29.

78 Singh S, Singh UP, Grizzle WE, Lillard JW, Jr. CXCL12-

CXCR4 interactions modulate prostate cancer cell migration,

metalloproteinase expression and invasion. Lab Invest 2004;

84: 1666–76.

79 Sun YX, Pedersen EA, Shiozawa Y et al. CD26/dipeptidyl

peptidase IV regulates prostate cancer metastasis by

degrading SDF-1/CXCL12. Clin Exp Metastasis 2008; 25:

765–76.

80 Xing Y, Liu M, Du Y et al. Tumor cell-specific blockade of

CXCR4/SDF-1 interactions in prostate cancer cells by hTERT

promoter induced CXCR4 knockdown: A possible metastasis

preventing and minimizing approach. Cancer Biol Ther 2008;

7: 1839–48.

81 Porvasnik S, Sakamoto N, Kusmartsev S et al. Effects of

CXCR4 antagonist CTCE-9908 on prostate tumor growth.

Prostate 2009; 69: 1460–69.

82 Mitra P, Shibuta K, Mathai J et al. CXCR4 mRNAexpression in

colon, esophageal and gastric cancers and hepatitis C infected

liver. Int J Oncol 1999; 14: 917–25.

83 Zeelenberg IS, Ruuls-Van Stalle L, Roos E. The chemokine

receptor CXCR4 is required for outgrowth of colon carcinoma

micrometastases. Cancer Res 2003; 63: 3833–9.

84 Ottaiano A, di Palma A, Napolitano M et al. Inhibitory effects of

anti-CXCR4 antibodies on human colon cancer cells. Cancer

Immunol Immunother 2005; 54: 781–91.

85 Chen Y, Stamatoyannopoulos G, Song CZ. Down-regulation of

CXCR4 by inducible small interfering RNA inhibits breast

cancer cell invasion in vitro. Cancer Res 2003; 63: 4801–4.

86 Benovic JL, Marchese A. A new key in breast cancer metastasis.

Cancer Cell 2004; 6: 429–30.

87 Epstein RJ. The CXCL12-CXCR4 chemotactic pathway as a

target of adjuvant breast cancer therapies. Nat Rev Cancer

2004; 4: 901–9.

88 Cabioglu N, Yazici MS, Arun B et al. CCR7 and CXCR4 as

novel biomarkers predicting axillary lymph node metastasis in

T1 breast cancer. Clin Cancer Res 2005; 11: 5686–93.

89 Orimo A, Gupta PB, Sgroi DC et al. Stromal fibroblasts present

in invasive human breast carcinomas promote tumor growth

and angiogenesis through elevated SDF-1/CXCL12 secretion.

Cell 2005; 121: 335–48.

90 Phillips RJ, Burdick MD, Lutz M, Belperio JA, Keane MP,

Strieter RM. The stromal derived factor-1/CXCL12-CXC

chemokine receptor 4 biological axis in non-small cell lung

cancer metastases. Am J Respir Crit Care Med 2003; 167:

1676–86.

91 Oonakahara K, Matsuyama W, Higashimoto I, Kawabata M,

Arimura K, Osame M. Stromal-derived factor-1alpha/CXCL12-

CXCR 4 axis is involved in the dissemination of NSCLC

cells into pleural space. Am J Respir Cell Mol Biol 2004; 30:

671–7.

92 Spano JP, Andre F, Morat L et al. Chemokine receptor CXCR4

and early-stage non-small cell lung cancer: Pattern of expression

and correlation with outcome. Ann Oncol 2004; 15: 613–

17.

93 Belperio JA, Phillips RJ, Burdick MD, Lutz M, Keane M, Strieter

R. The SDF-1/CXCL 12/CXCR4 biological axis in non-small

cell lung cancer metastases. Chest 2004; 125: 156S.

94 Hartmann TN, Burger M, Burger JA. The role of adhesion

molecules and chemokine receptor CXCR4 (CD184) in small

cell lung cancer. J Biol Regul Homeost Agents 2004; 18:

126–30.

95 Phillips RJ, Mestas J, Gharaee-Kermani M et al. Epidermal

growth factor and hypoxia-induced expression of CXC

chemokine receptor 4 on non-small cell lung cancer cells is

regulated by the phosphatidylinositol 3-kinase/PTEN/AKT/

mammalian target of rapamycin signaling pathway and activation

of hypoxia inducible factor-1alpha. J Biol Chem 2005; 280:

22473–81.

96 Huang YC, Hsiao YC, Chen YJ, Wei YY, Lai TH, Tang CH.

Stromal cell-derived factor-1 enhances motility and integrin

up-regulation through CXCR4, ERK and NF-kappaBdependent

pathway in human lung cancer cells. Biochem

Pharmacol 2007; 74: 1702–12.

97 Scotton CJ, Wilson JL, Scott K et al. Multiple actions of the

chemokine CXCL12 on epithelial tumor cells in human ovarian

cancer. Cancer Res 2002; 62: 5930–38.

98 Kulbe H, Hagemann T, Szlosarek PW, Balkwill FR, Wilson JL.

The inflammatory cytokine tumor necrosis factor-alpha regulates

chemokine receptor expression on ovarian cancer cells.

Cancer Res 2005; 65: 10355–62.

99 Kryczek I, Lange A, Mottram P et al. CXCL12 and vascular

endothelial growth factor synergistically induce neoangiogenesis

in human ovarian cancers. Cancer Res 2005; 65: 465–72.

100 Furuya M, Suyama T, Usui H et al. Up-regulation of CXC

chemokines and their receptors: Implications for proinflammatory

microenvironments of ovarian carcinomas and

endometriosis. Hum Pathol 2007; 38: 1676–87.

101 Oda Y, Ohishi Y, Basaki Y et al. Prognostic implications of the

nuclear localization of Y-box-binding protein-1 and CXCR4

expression in ovarian cancer: Their correlation with activated

Akt, LRP/MVP and P-glycoprotein expression. Cancer Sci

2007; 98: 1020–26.

102 Kajiyama H, Shibata K, Terauchi M, Ino K, Nawa A, Kikkawa F.

Involvement of SDF-1alpha/CXCR4 axis in the enhanced

CXCR4 and cancer 503

© 2010 The Authors

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

peritoneal metastasis of epithelial ovarian carcinoma. Int J

Cancer 2008; 122: 91–9.

103 Miwa S, Mizokami A, Keller ET, Taichman R, Zhang J, Namiki

M. The bisphosphonate YM529 inhibits osteolytic and osteoblastic

changes and CXCR-4-induced invasion in prostate

cancer. Cancer Res 2005; 65: 8818–25.

104 Chinni SR, Sivalogan S, Dong Z et al. CXCL12/CXCR4 signaling

activates Akt-1 and MMP-9 expression in prostate

cancer cells: The role of bone microenvironment-associated

CXCL12. Prostate 2006; 66: 32–48.

105 Miki J, Furusato B, Li H et al. Identification of putative stem cell

markers, CD133 and CXCR4, in hTERT-immortalized primary

nonmalignant and malignant tumor-derived human prostate

epithelial cell lines and in prostate cancer specimens. Cancer

Res 2007; 67: 3153–61.

106 Hirata H, Hinoda Y, Kikuno N et al. CXCL12 G801A polymorphism

is a risk factor for sporadic prostate cancer susceptibility.

Clin Cancer Res 2007; 13: 5056–62.

107 Gerritsen ME, Peale FV, Jr, Wu T. Gene expression profiling in

silico: Relative expression of candidate angiogenesis associated

genes in renal cell carcinomas. Exp Nephrol 2002; 10:

114–19.

108 Schrader AJ, Lechner O, Templin M et al. CXCR4/CXCL12

expression and signalling in kidney cancer. Br J Cancer 2002;

86: 1250–56.

109 Haviv YS, van Houdt WJ, Lu B, Curiel DT, Zhu ZB. Transcriptional

targeting in renal cancer cell lines via the human CXCR4

promoter. Mol Cancer Ther 2004; 3: 687–91.

110 Pan J, Mestas J, Burdick MD et al. Stromal derived factor-1

(SDF-1/CXCL12) and CXCR4 in renal cell carcinoma metastasis.

Mol Cancer 2006; 5: 56.

111 Jones J, Marian D, Weich E et al. CXCR4 chemokine receptor

engagement modifies integrin dependent adhesion of renal

carcinoma cells. Exp Cell Res 2007; 313: 4051–65.

112 Sehgal A, Keener C, Boynton AL, Warrick J, Murphy GP.

CXCR-4, a chemokine receptor, is overexpressed in and

required for proliferation of glioblastoma tumor cells. J Surg

Oncol 1998; 69: 99–104.

113 Rempel SA, Dudas S, Ge S, Gutierrez JA. Identification and

localization of the cytokine SDF1 and its receptor, CXC

chemokine receptor 4, to regions of necrosis and angiogenesis

in human glioblastoma. Clin Cancer Res 2000; 6: 102–11.

114 Rubin JB, Kung AL, Klein RS et al. A small-molecule antagonist

of CXCR4 inhibits intracranial growth of primary brain

tumors. Proc Natl Acad Sci USA 2003; 100: 13513–18.

115 Salmaggi A, Gelati M, Pollo B et al. CXCL12 in malignant glial

tumors: A possible role in angiogenesis and cross-talk between

endothelial and tumoral cells. J Neurooncol 2004; 67: 305–17.

116 Schuller U, Koch A, Hartmann W et al. Subtype-specific

expression and genetic alterations of the chemokinereceptor

gene CXCR4 in medulloblastomas. Int J Cancer 2005; 117:

82–9.

117 Ping YF, Yao XH, Chen JH et al. The anti-cancer compound

Nordy inhibits CXCR4-mediated production of IL-8 and VEGF

by malignant human glioma cells. J Neurooncol 2007; 84: 21–9.

118 Bian XW, Yang SX, Chen JH et al. Preferential expression of

chemokine receptor CXCR4 by highly malignant human

gliomas and its association with poor patient survival. Neurosurgery

2007; 61: 570–8; discussion 78–9.

119 Borrello MG, Alberti L, Fischer A et al. Induction of a proinflammatory

program in normal human thyrocytes by the RET/PTC1

oncogene. Proc Natl Acad Sci USA 2005; 102: 14825–30.

120 De Falco V, Guarino V, Avilla E et al. Biological role and

potential therapeutic targeting of the chemokine receptor

CXCR4 in undifferentiated thyroid cancer. Cancer Res 2007;

67: 11821–9.

121 Koshiba T, Hosotani R, Miyamoto Y et al. Expression of

stromal cell-derived factor 1 and CXCR4 ligand receptor

system in pancreatic cancer: A possible role for tumor progression.

Clin Cancer Res 2000; 6: 3530–35.

122 Mori T, Doi R, Koizumi M et al. CXCR4 antagonist inhibits

stromal cell-derived factor 1-induced migration and invasion

of human pancreatic cancer. Mol Cancer Ther 2004; 3: 29–

37.

123 Sato N, Fukushima N, Maitra A et al. Gene expression profiling

identifies genes associated with invasive intraductal papillary

mucinous neoplasms of the pancreas. Am J Pathol 2004; 164:

903–14.

124 Marchesi F, Monti P, Leone BE et al. Increased survival, proliferation,

and migration in metastatic human pancreatic tumor

cells expressing functional CXCR4. Cancer Res 2004; 64:

8420–27.

125 Wehler T, Wolfert F, Schimanski CC et al. Strong expression

of chemokine receptor CXCR4 by pancreatic cancer correlates

with advanced disease. Oncol Rep 2006; 16: 1159–64.

126 Billadeau DD, Chatterjee S, Bramati P et al. Characterization

of the CXCR4 signaling in pancreatic cancer cells. Int J Gastrointest

Cancer 2006; 37: 110–19.

127 Kaifi JT, Yekebas EF, Schurr P et al. Tumor-cell homing

to lymph nodes and bone marrow and CXCR4 expression

in esophageal cancer. J Natl Cancer Inst 2005; 97: 1840–

47.

128 Koishi K, Yoshikawa R, Tsujimura T et al. Persistent CXCR4

expression after preoperative chemoradiotherapy predicts

early recurrence and poor prognosis in esophageal cancer.

World J Gastroenterol 2006; 12: 7585–90.

129 Gockel I, Schimanski CC, Heinrich C et al. Expression of

chemokine receptor CXCR4 in esophageal squamous cell and

adenocarcinoma. BMC Cancer 2006; 6: 290.

130 Kodama J, Hasengaowa, Kusumoto T et al. Association of

CXCR4 and CCR7 chemokine receptor expression and lymph

node metastasis in human cervical cancer. Ann Oncol 2007;

18: 70–76.

131 Zhang JP, Lu WG, Ye F, Chen HZ, Zhou CY, Xie X. Study on

CXCR4/SDF-1alpha axis in lymph node metastasis of cervical

squamous cell carcinoma. Int J Gynecol Cancer 2007; 17:

478–83.

132 Yang YC, Lee ZY, Wu CC, Chen TC, Chang CL, Chen CP.

CXCR4 expression is associated with pelvic lymph node

metastasis in cervical adenocarcinoma. Int J Gynecol Cancer

2007; 17: 676–86.

133 Almofti A, Uchida D, Begum NM et al. The clinicopathological

significance of the expression of CXCR4 protein in oral squamous

cell carcinoma. Int J Oncol 2004; 25: 65–71.

134 Uchida D, Begum NM, Tomizuka Y et al. Acquisition of lymph

node, but not distant metastatic potentials, by the overexpression

of CXCR4 in human oral squamous cell carcinoma. Lab

Invest 2004; 84: 1538–46.

135 Ishikawa T, Nakashiro K, Hara S et al. CXCR4 expression is

associated with lymph-node metastasis of oral squamous cell

carcinoma. Int J Oncol 2006; 28: 61–6.

136 Onoue T, Uchida D, Begum NM, Tomizuka Y, Yoshida H, Sato

M. Epithelial-mesenchymal transition induced by the stromal

cell-derived factor-1/CXCR4 system in oral squamous cell carcinoma

cells. Int J Oncol 2006; 29: 1133–8.

137 Robledo MM, Bartolome RA, Longo N et al. Expression of

functional chemokine receptors CXCR3 and CXCR4 on

human melanoma cells. J Biol Chem 2001; 276: 45098–

105.

138 Payne AS, Cornelius LA. The role of chemokines in melanoma

tumor growth and metastasis. J Invest Dermatol 2002; 118:

915–22.

504 B. Furusato et al.

© 2010 The Authors

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

139 Murakami T, Maki W, Cardones AR et al. Expression of CXC

chemokine receptor-4 enhances the pulmonary metastatic

potential of murine B16 melanoma cells. Cancer Res 2002; 62:

7328–34.

140 Scala S, Ottaiano A, Ascierto PA et al. Expression of CXCR4

predicts poor prognosis in patients with malignant melanoma.

Clin Cancer Res 2005; 11: 1835–41.

141 Longo-Imedio MI, Longo N, Trevino I, Lazaro P, Sanchez-

Mateos P. Clinical significance of CXCR3 and CXCR4 expression

in primary melanoma. Int J Cancer 2005; 117: 861–5.

142 Tucci MG, Lucarini G, Brancorsini D et al. Involvement of

E-cadherin, beta-catenin, Cdc42 and CXCR4 in the progression

and prognosis of cutaneous melanoma. Br J Dermatol

2007; 157: 1212–16.

143 Schutyser E, Su Y, Yu Y et al. Hypoxia enhances CXCR4

expression in human microvascular endothelial cells and

human melanoma cells. Eur Cytokine Netw 2007; 18: 59–70.

144 Li H, Alizadeh H, Niederkorn JY. Differential expression of

chemokine receptors on uveal melanoma cells and their

metastases. Invest Ophthalmol Vis Sci 2008; 49: 636–43.

145 Mohle R, Bautz F, Rafii S, Moore MA, Brugger W, Kanz L. The

chemokine receptor CXCR-4 is expressed on CD34+ hematopoietic

progenitors and leukemic cells and mediates transendothelial

migration induced by stromal cell-derived factor-1.

Blood 1998; 91: 4523–30.

146 Burger JA, Burger M, Kipps TJ. Chronic lymphocytic leukemia

B cells express functional CXCR4 chemokine receptors that

mediate spontaneous migration beneath bone marrow stromal

cells. Blood 1999; 94: 3658–67.

147 Monaco G, Belmont JW, Konopleva M et al. Correlation

between CXCR4 and homing or engraftment of acute myelogenous

leukemia. Cancer Res 2004; 64: 6832; author reply

32–3.

148 Sipkins DA, Wei X, Wu JW et al. In vivo imaging of specialized

bone marrow endothelial microdomains for tumour engraftment.

Nature 2005; 435: 969–73.

149 Dommange F, Cartron G, Espanel C et al. CXCL12 polymorphism

and malignant cell dissemination/tissue infiltration in

acute myeloid leukemia. FASEB J 2006; 20: 1913–15.

150 Kalinkovich A, Tavor S, Avigdor A et al. Functional CXCR4-

expressing microparticles and SDF-1 correlate with circulating

acute myelogenous leukemia cells. Cancer Res 2006; 66:

11013–20.

151 Konoplev S, Rassidakis GZ, Estey E et al. Overexpression of

CXCR4 predicts adverse overall and event-free survival in

patients with unmutated FLT3 acute myeloid leukemia with

normal karyotype. Cancer 2007; 109: 1152–6.

152 Zhang WB, Navenot JM, Haribabu B et al. A point mutation

that confers constitutive activity to CXCR4 reveals that T140 is

an inverse agonist and that AMD3100 and ALX40-4C are weak

partial agonists. J Biol Chem 2002; 277: 24515–21.

153 Zeelenberg IS, Ruuls-Van Stalle L, Roos E. Retention of

CXCR4 in the endoplasmic reticulum blocks dissemination of a

T cell hybridoma. J Clin Invest 2001; 108: 269–77.

CXCR4 and cancer 505

© 2010 The Authors

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

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