|Role of Chemokines and Chemokine Receptors in Prostate
Cancer Development and Progression
|Rajendra K. Singh1,2*, Akulapalli Sudhakar3,4,5 and Bal L. Lokeshwar1,2
|1Department of Urology, Miller School of Medicine, University of Miami, Miami, FL 33136, USA
|2Veterans Administration Miami Hospital, Miami, Florida, USA
|3Cell Signaling and Tumor Angiogenesis Laboratory, Department of Genetics, Boys Town National Research Hospital, Omaha, NE 68131, USA
|4Department of Biomedical Sciences, Creighton University School of Medicine, Omaha, NE 68131, USA
|5Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, 68198, USA
||Dr. Rajendra K Singh,
Department of Urology, Miller School of Medicine,
University of Miami, Miami,
FL 33136 USA,
Tel: (305) 243-1017,
Fax: (305) 243-9724,
|Received May 11, 2010; Accepted June 02, 2010; Published July 02, 2010
|Citation: Singh RK, Sudhakar A, Lokeshwar BL (2010) Role of Chemokines
and Chemokine Receptors in Prostate Cancer Development and Progression. J
Cancer Sci Ther 2: 094-099. doi:10.4172/1948-5956.1000031
|Copyright: © 2010 Singh RK, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
|Prostate cancer (PC) is the second leading cause of cancer deaths in men in America and Western Europe.
Epidemiological studies suggest that prostate cancer incidence increased in last few years in Asian population.
The causes or consequences of increasing trend of prostate cancer incidence are not completely known. Emerging
evidences suggest that among the many risk factors, inflammation is the major risk factor for developing prostate
cancer and its progression to metastasis. It is proposed that exposure to environmental factors such as infectious
agents, dietary agents and saturated lipids leads to injury of the prostate due to chronic inflammation and regenerative risk factor lesions
referred to as proliferative inflammatory atrophy (PIA). These phenomena predominantly control by a number of proinflammatory macro molecules such as chemokines, and their receptors. Some recent studies suggest that many of these
pro-inflammatory chemokines and their receptors are the products of protooncogenes or tumor suppressor pathways
in many cancers including that of the prostate. This review article will focus on the current biology of chemokines and chemokine
receptors pathways in genesis of prostate cancer. An understanding of this axis may enable researchers to develop
targeted strategies for prostate cancer.
|Prostate cancer (PC) represents the second leading cause of death
among all cancer types in men in Europe and North America (Collin
et al., 2008). Emerging evidences suggest that among the many risk
factors, inflammation is a major risk factor for developing prostate
cancer and its progression to metastasis (De Marzo et al., 2007). The
pro-inflammatory regulators such as chemokines and their receptors
network seem to play crucial functions in prostate tumorigenesis,
although chemokines have been thought of primarily as leukocyte
attractants. In general, the function of chemokines is to arrest
leukocytes at inflamed blood vessels and guide to lead them to
specific sites of inflammation. Due to specific function of site-specific
homing for leukocytes from inflammatory sites, these mediators
may play several key steps of prostate carcinogenesis including
production of inflammatory cells. Chronic inflammation predisposes
cells to produce dysregulated amounts of chemokines for malignant transformation and
progression. The accumulating evidence also points to a direct effect
of chemokines on cancer cells that express chemokine receptors. In
particular, some chemokines can activate anti-apoptotic pathways
in cancer cells (Singh and Lokeshwar, 2009). By either mechanism,
tumor cells that secrete and/or respond to chemokines would have
a selective advantage. It is extensively documented in number of
studies that they contribute to a number of tumor-related processes,
such as tumor cell growth, Araki
et al., 2007angiogenesis/angiostasis, local invasion,
and metastasis in many tumor types including prostate (Singh and
Lokeshwar, 2009; Bingle et al., 2006; Papetti and Herman, 2002).
Specifically members of the chemoattractant chemokines, more
popularly known as CXC chemokines, and their receptors are
significant players in several of the critical steps in tumorigenesis
and/or metastasis (Singh et al., 2007; Vicari and Caux, 2002; Zlotnik,
2004; Murakami et al., 2004). Many studies mentioned that they
have been shown to play potentially important roles in many of the
critical steps of the androgen independent and metastasis process.
For example CXC chemokine CXCL-8 (IL-8) plays multiple roles in
transition of androgen sensitive tumor cells to androgen insensitive, drug resistance in prostate cancer cells (Tanaka et al., 2005; ). A recent report indicates that inhibition of IL-8 in vitro inhibits cell survival signaling of Akt and bcl2 in prostate cancer cells
(Singh and Lokeshwar, 2009). Several other chemokines produced
by primary prostate tumor site and in distant metastasis locations are
shown to play significant role in prostate tumorigenesis (Waugh et
al., 2008). These wide and differential distributions of chemokines
and their receptors particularly account for the pleiotropic actions of
chemokines in PC, including the modulation of growth, angiogenesis,
invasion, and metastasis (Vindrieux et al., 2009; Tanaka et al., 2005; Singh et al., 2007; Ben-Baruch, 2008).
|The known function of chemokines in other aspects of biology
or human diseases, apart from cancer, has been detailed in several
other reviews (Rossi and Zlotnik, 2000; Gerard and Rollins, 2001; Aragon-Ching et al., 2010). This review will emphasize what
we believe are striking about the roles of selected chemokines in the
inflammatory responses to prostate cancer initiation to metastasis
process. This review will also highlight some of the similarities
between the functions of chemokine receptors in physiologic
homing of leukocytes and purposed roles for these receptors in
prostate cancer progression and metastasis. Therefore, this review
will include descriptions of possible concurrent roles in inflammation
and prostate tumorigenesis. Within the space of this review, it is not
possible to discuss all the available evidence regarding roles for a specific chemokine and chemokine receptors networks in details.
Thus, a referenced summary of possible roles for some important
chemokine receptors in prostate cancer is discussed. With the
development of specific chemokine receptor antagonists, it may
be possible to exploit the vulnerability of cancer cells by disrupting
chemokine receptor-mediated signaling and directly inhibit prostate
tumor growth or render tumor cells more susceptible to traditional
anticancer treatment modalities. This review will focus on the roles
and the mechanisms of action and regulation of chemokines in the
different steps of PC development and will discuss present literature
on the novel strategies that are currently envisioned to target
chemokines in PC.
|Adenocarcinoma of the prostate is the most common malignancy
of the male genitourinary tract and is a significant health problem. The 2.4 million people living with PC, 214000 new
cases per year and estimated 27000 death occurred in the United
States in 2008 (Jemal et al., 2008). Localized prostate carcinomas
exist in most of elderly males at the time of diagonosis, but the most
of those carcinomas are asymptomatic and are medically important
(Denberg et al., 2006; Giovannucci et al., 2007; Mazur and Merz,
1996; Pienta and Loberg, 2005). For this reason, the research of
tumor proliferation and dissemination are even more important of
this disease than of other cancers.
|The most commonly used method to diagnose and evaluate
prostate cancer is the PSA (Prostate Specific Antigen) test though it is
far from perfect. The only test which can fully confirm the diagnosis
of prostate cancer is a biopsy. The recent European Randomized
Study of Screening for Prostate Cancer suggests that risks incurred
by screening, diagnosis (Schröder et al., 2009; Koukourakis et al.,
2009; Aus et al., 1996) and resulting treatment (Rietbergen et al.,
1997; Yao and Lu-Yao, 1999; Alibhai et al., 2005; Potosky et al.,
2004; Lim et al., 1995; Hamilton et al., 2001; Fowler et al., 2002)
of prostate cancer are both substantial and well documented in the
literature. To the extent that over diagnosis occurs with prostatecancer
screening, many of these risks occur in men in whom prostate
cancer would not have been detected in their lifetime and were
clinically irrelevant (Tsai et al., 2007). Treatment for prostate cancer
includes surgery, radiation therapy, cryosurgery and total androgen
deprivation (hormonal) therapy. Surgical removal of the prostate (also
called prostatectomy) is a common treatment mainly for early stage
prostate cancer. Radiotherapy is also widely used in prostate cancer
treatment. However, once the tumor has spread, such local tumor
removal has little impact on the overall outcome or course of disease
(Jongsma et al., 2002). Thus, the disseminated tumors need innovative
and systemic approaches. Early in the prostate carcinoma, such
physical or chemical castration (anti-androgen) leads to regression
of the tumor masses (Jin et al., 2004). However, this rarely cures prostate
cancer as androgen independence develops within a year or two (Nacusi and Tindall, 2009). Thus, focus on the tumor-intrinsic events,
predominantly mediated by chemokines and chemokine-receptors
in androgen-independent prostate carcinomas, as novel approaches
to halting the progression of this disease. In the following sections
we will discuss the importance of these molecular pathways in the
development and progression of PC and the therapeutic significance
of the inhibition of these of pro-inflammatory signals.
|The chemokines represent a large group of small secreted
proteins (8–11 kDa in size), which are grouped into four families (C,
CC, CXC, and CX3C) based on the spacing of key cysteine residues near the N-terminus of these proteins. The CC and CXC families
represent the bulk of known chemokines (currently 53) (Zlotnik and
Yoshie, 2000). Most of the chemokines are divided between the CC
and CXC classes. There are only two known C chemokines, and one
known CX3C chemokine. Several CC chemokines with six cysteines
have been discovered, defining a structural subclass relative to the
more numerous group of CC chemokines with four cysteines. The
CXC class can also be divided into two subclasses, ELR+ and ELR-,
depending on whether the tripeptide signature glu-leu-arg is found
N-terminal to the first cysteine (Zlotnik and Yoshie, 2000).
|Chemokines are primarily known in the regulation of the motility
of hematopoietic cells (immune system cells) and their ability to
stimulate directional migration of nearly all classes of leukocytes
during inflammation through the activation of a group of cell
surface receptors belongs to G-protein receptors family (Ruffini et
al., 2007). Neutrophils, for example, migrate strongly in response
to chemokines such as CXCL8 (interleukin-8) and eosinophils to
CC chemokine ligand 11 (CCL11; eotaxin). Some chemokines have
been expressed to specific cell types (Zlotnik and Yoshie, 2000).
Many epithelial cell types and macrophages for examples, produce
significant levels of chemokines. These cell populations can have an
immediate impact on the environment tumor. The
CXC chemokines mostly ELR+ are angiogenic. These include CXCL8
(IL-8), epithelial-neutrophil activating protein (ENA-78) and growthrelated
genes (GRO-α, GRO-β, GRO-γ and GCP-2), and several other
neutrophil activating proteins (Brat et al., 2005). The second group
of CXC chemokines, which lack the ELR motif, include interferon-γ-
inducible protein (IP-10), monokine induced by γ-interferon (MIG) and
stromal derived factor (SDF-1) (Ogawa et al., 2002) Most of these
ELR-negative CXC chemokines, have been shown to antagonize the
angiogenic activities of the ELR-positive CXC chemokines as well as
basic fibroblast growth factor (bFGF) and vascular endothelial growth
factor (VEGF) (Moore et al., 1999). It is still not clear, however, whether
all of these chemokines contribute cancer related chemotaxis, or
whether a specific chemokine mediates the bulk of the chemotactic
activity and can be targeted for therapy. Chemokine biology is
also central to the immunologic anti-tumor response through the
recruitment of effector lymphocytes and the subsequent regulation
of their effector function within tumor environments (Homey et al.,
2002). Data from breast carcinoma studies have suggested that the
specific effects mediated through chemokines could be significantly
different depending on the source of ligand or receptor expression
(Azenshtein et al., 2002).
|Chemokines interact with cell-surface receptors, which are
members of a large superfamily their of seven-transmembrane domain,
G protein-coupled receptors. The
receptor nomenclature system is based on the observation that
ligand selectivity of promiscuous chemokine receptors is restricted
by chemokine class. Some chemokine
receptors bind to multiple chemokines and vice versa, suggesting
that certain redundancies exist in chemokine function. There are 18 human chemokine receptors (Zaballos et al.,
1999; Homey et al., 2000; Schweickart et al., 2000; Yoshida et al.,
1998) and over fifty distinct chemokines identified at present .They
play very distinct role in normal cells and cancer (Zlotnik and Yoshie,
2000). The molecular mechanism of signaling function has still not
been demonstrated for Duffy, D6, CCX CKR, and CXCR7 which are all
7TM proteins that bind large subsets of chemokines (Homey et al., 2000) The ten human chemokine receptors such as CXCR1, CXCR4,
CXCR5, CXCR6, CCR6, CCR8, CCR9, CCR10, XCR1 and CX3CR1 are
highly selective for one main high affinity endogenous chemokine
ligand. On the other hand, other chemokine receptors (CXCR2,
CXCR3 and CXCR7) are typically highly promiscuous. For example
CXCR7 is member of chemokine receptors, CXC family, it
has been later shown to bind a new two chemokines, CXCL12/SDF-1 and
CXCL11 (Burns et al., 2006). The exact function of CXCR7 how it is
regulated in prostate and other cancer is not known.
|The major function of chemokines is to regulate leukocyte
trafficking in hematopoiesis and in innate and adaptive immunity
in many cell types. Other functions include angiogenic activity,
apoptosis, T-cell differentiation and phagocyte activation (Kim, 2004).
Inadvertent activation of chemokine receptors leads to autoimmunity
by inappropriately targeting self antigens for destruction by cytotoxic
T-cells and macrophages (Christopherson and Hromas, 2001). They
are sub classified according to their function such as homeostatic
leukocyte homing molecules (CXCR4, CXCR5, CCR7, CCR9) versus
inflammatory/inducible molecules (CXCR1, CXCR2, CXCR3, CCR1-6,
CX3CR1), and substantial progress has been made, in part through
the study of knock-out mice, in identifying specific phenotypes
in development and disease. Phenotypes are concentrated in
hematopoietic development, innate and adaptive immune responses
and susceptibility to infectious agents (Cyster, 1999). Chemokine
receptors preferentially expressed on important functional subsets
of epithelial cells, dendritic cells, monocytes and lymphocytes have
been defined in many studies (Charbonnier et al., 1999; Sallusto et
|Chemokines and chemokine receptors in inflammation,
prostate cancer development and progression
|Prostate Cancer (PC) progression is a complex physiological
and pathological event. Several multidisciplinary studies have been
suggesting a link between chronic inflammation and PC. Several
studies suggest a link between bacterial infections, inflammation
and pre-deposition of pro-inflammatory proteins in the prostate
gland. Such self-perpetuating mechanism can be triggered with
the age of men and may increase the risk of malignancy of prostate
(Yanamandra et al., 2009; Hermani et al., 2006; Xie et al., 2010).
Studies have also found an increased in relative risk of PC in men with
a prior history of certain sexually transmitted infections or prostatitis
diseases (Sadeghi-Nejad et al., 2010; Cheng et al., 2010). Significant
association between prostatitis, sexually transmitted diseases (STDs),
and prostate cancer among African American, Asian American, Latino,
were found in participants of the California Men’s Health Study
(Robert et al., 2009). Furthermore, several studies suggested genetic
or germline defect or variants of several genes associated with the
immunological aspects of inflammation in modulating PC risk (Vasto
et al., 2008). Somatic alterations of genes are shown to be involved
in defenses against inflammatory damage and in tissue recovery.
Several studies showed that chronic inflammation of prostate
area caused a novel putative PC precursor lesion called proliferative
inflammatory atrophy, which shares some molecular traits with
prostate intraepithelial neoplasia and PC (Sciarra et al., 2007). The
hypothesis associating chronic inflammation and PC wastested in a
number of animal models of prostate inflammation that should allowed
the elucidation of the mechanisms by which prostatic inflammation
could lead to the initiation and progression of PC (Nelson et al.,
2001; Hsing and Chokkalingam, 2006). These emerging insights into
chronic inflammation in the etiology of prostate carcinogenesis hold the promise of spawning new diagnostic and therapeutic modalities
for men with PC (Wagenlehner et al., 2007; Chung et al., 2005).
|Prostate tumorigenesis occurs through several steps, the first
being the transition from normal prostate to PIN in many cases
(Yanamandra et al., 2009; Hermani et al., 2006), but not all BPH
diseases establish cancer in later stage. During the transitions from
normal to PIN and from PIN to PC, a number of chemokines and
chemokine receptors display variations in their expression. It is most
important to notice that chemokines are produced by a variety of
cells such as tumor-associated fibroblasts, endothelial cells, or tumor
infiltrating cells such as macrophages and or lymphocytes have
selected advantage of progression of prostate disease. Many studies
have been suggested that chemokines CXCL8, CXCL12, and CCL2
level increased with the progression of prostate PC. Expression of
IL-8 is low levels in normal human prostate at the apical membrane
of epithelial cells (Murphy et al., 2005). The levels of proangiogenic
chemokine IL-8 is higher in PIN compared with normal prostate
tissue and cell lines represent the PIN and stroma tissue of PIN. This
suggests that a reactive stroma pattern is correlated with an increase
in CXCL8 levels in the adjacent epithelium.
|It is suggested in many studies that many CXC chemokines are
involved in prostate that tumor invasion and metastasis. This is very important mechanism of prostate tumor progression.
The ability to break matrix barriers causes the vast majority of
morbidity and mortality from prostate cancer due to metastasis to
vital organs such as bone, liver and lymph nodes. Histological analyses
in de-novo human tumor specimens and animal tumor models
showed that cancer cells invading into adjacent healthy tissues or
breaching a basement membrane to access a vessel for dissemination.
Cell motility and invasion is tightly
controlled by growth factors and cytokines during organogenesis,
inflammation and wound healing, while it appears to become
dysregulated during tumorgenesis. This lack of control and direction
results in invasion. Prostate cancer cells that becomes hormone-independent become highly invasive
with an increased incidence of skeletal/bone metastases as the
disease progresses (Gladson and Welch, 2008; Bostwick et al., 2004; Logothetis and Lin, 2005). PC shares a number of features with
benign prostatic hyperplasia (BPH) and the putative precursor of
cancer, prostatic intraepithelial neoplasia. All three stages of prostate
disease increase in prevalence with age and require androgens for
growth and development. So far, the factors responsible for PC
progression remain elusive. Among the mediators of carcinogenesis,
the significance of chemokines in PC progression has increased. In
multicellular organisms, the interactions between individual cells are
essential to ensure their correct functions in an appropriate spatial
and temporal manner. In particular, cell homing requires a fine tune
in embryonic development, inflammation, or immunity. Such events
appear to be deregulated in the neoplastic process. In the PC context
and other cancer, chemokines play diverse effects and some of them
deriving from their ability to induce cell migration and angigogenesis.
The ability of chemokines to enhance the motility of leukocytes,
endothelial cells, and by tumor cells is a key factor in determining
the cancer establishment and progression. On the other hand, some
chemokines may inhibit angogengesis and angiostatic effects.
|The expression level of chemokines is also altered with the
progression of PC. In situ hybridization experiments have shown
that CXCL8 RNA and its receptors CXCR1 and CXCR2 levels increase
with the Gleason score of prostate tumors of high-grade tumors
(Gladson and Welch, 2008). The localization of CXCL8 is somewhat
controversial as another study has reported that CXCL8 is expressed
by the neuroendocrine cells PC. This discrepancy could arise from
the use of different antibodies to detect CXCL8. The same study also
observed an increased expression of CXCR1 in epithelial cells of PC as compared with normal prostate. Moreover, CXCR2 is present in
neuroendocrine cells. CXCL8 protein can also be detected in the
serum of patients. Serum CXCL8 levels are elevated in patients Wangh et al., 2007 with
bone metastasis compared with patients with localized disease.
|Some studies have suggested that chemokines and their receptors
could also contribute to the variable incidence of PC in higher in
African–American men when compared with European–American
men. A comparative microarray analysis of chemokine expression
profiles of patients with primary prostate tumors showed that CCL5,
CCR7, and CXCR4 were expressed at higher levels in African–American patients compared with European–American patients (Wallace et al.,
2008). Genetic polymorphism of some chemokine genes is altered
in PC, which could potentially correlate with the expression levels
of chemokines. A single nucleotide polymorphism of CXCL12 G801A
has been reported. It appears that the genotype GA+AA is increased
in PC patients compared with healthy controls (Hirata et al., 2007).
In addition, the genotype AA is more frequent in metastatic patients
compared with non-metastatic patients (Hendrix et al., 2000). The
growing evidence of chemokine involvement in all stages of prostate
cancer progression, manipulation of this signaling pathway may be
therapeutic benefit. Several antagonist including AMD 3100 and T22
are tested but unlikely owing to pharmacokinetic problems (Hendrix
et al., 2004; Civenni and Sommer, 2009). Apart from metastasis,
increasing evidence suggest that chemokines is implicated in
neoplastic cell transformation. Chemokines regulate proliferation
and migration of various types of normal stem and progenitor cells,
including precursor cells of neuroectodermal origin. Based on this it
is conceivable that the established role of chemokines in cancer cell
proliferation and organ-specific metastasis might also be associated
with stem cell-like cells present in the tumor. Such cancer stem cells
represent a small subpopulation of tumor cells that are thought to
initiate and sustain tumor formation (Burger et al., 1999). The IL-8
and CXCL1 have been demonstrated to continually stimulate certain
cells expressing the CXCR1 and CXCR2 by autocrine and paracine
mechanism and leading to malignant and oncogenic transformation
(Waugh et al., 2008). Clinical observations and mouse models have
suggested that inflammation can be pro-tumorigenic properties such
CXCL16 and CXCR6 arising in an inflammatory milieu and mediate
pro-tumorigenic effects of inflammation through direct effects on
cancer cell growth and by inducing the migration and proliferation
of tumor-associated leukocytes (Darash-Yahana et al., 2009). The
multi-faceted roles of chemokine and chemokine receptors in PC are
outlined in Table 1.
||Table 1: Overview of Chemokines and Chemokine Receptors in Prostate Cancer.
|Chemokines and chemokine-receptors seems to be important
factors not only play a significant role in normal cell physiology but also
regulated many tumor related mechanism such as increases cell survival
and migration associated with metastasis of several cancers including
prostate. Leukocyte infiltration is a cardinal feature of inflammation
and important in progression of prostate cancer. This mechanism of
up-regulation not only autocrine and paracrine mechanism of tumor
cells secreted chemokines to promote tumorigenesis but also they
responsible for eliciting local accumulation of inflammatory cells
that appear to play a same role in the formation of peri- and intratumoural
infiltrates. Chronic inflammation predisposes and scretion
of tumor related chemokines (CXC) are likely to be important factors
in prostate cancer formation and progression. In part, chemokines
may be a consequence of its ability to attract mononuclear cells to
cancer sites, where they provide growth or angiogenic factors that
enhance cancer development. However, accumulating evidence also
points to a direct effect of chemokines on cancer cells that express
chemokine receptors. In particular, some chemokines can activate anti-apoptotic pathways in these cells. By either mechanism, tumor
cells that secrete and/or respond to chemokines would have a
selective advantage of host systems to promote tumorigenesis.
|This work was supported by grant from VA mert Review (VAMC 5312.1 to
BLL) and Flight Attendant Medical Research Institute Young Clinical Scientist
Award Grant (#062558) and #RO1CA143128, startup funds of Cell Signaling and Tumor Angiogenesis
Laboratory at Boys Town National Research Hospital to AS.
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