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THE
ROLE OF CHEMOKINES AND CHEMOKINE RECEPTORS IN BREAST CANCER
K.T. Papazisis1,
T. Kalemi2,3, A Lambropoulos3,
A. H. Kortsaris4
1Breast
Cancer Biology Group, Cancer Research UK, London SE1 9RT, UK
2Research Dpt, Theagenion Cancer Institute,
Thessaloniki Greece
3Laboratory of Gen Biology, School of Medicine,
Aristotle University of Thessaloniki, Greece
4Laboratory of Biochemistry, School of Medicine,
Democritus University of Thrace, Alexandroupolis, Greece
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Keywords:
Fullerene; Cell line; Cell cycle; DNA synthesis; Mitosis; Cytotoxicity;
Antitumor drug |
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Chemokines
are small (8-14 kDa), cytokine-like proteins that regulate the transport
of leucocytes. They were found to mediate the adhesion to endothelial
cells, transendothelial migration and tissue invasion. They act
through stimulation of specific receptors that are expressed in
target cells and belong to the seven transmembrane domain G-protein-coupled
receptors (GPCRs). The downstream message induces cytoskeletal rearrangement,
changes in adhesion molecule expression and migration responses.
Depending on the location of the first two cysteines in the protein
sequence (N-terminal) they are classified into four major subgroups
: The CXC (or CXCL - CXC-Ligand), the CC (CCL), the C and the CX3C
chemokines. The old nomenclature for their characterization was
SCY (small secreted cytokines) and were designated as SCYa, SCYb,
SCYc and SCYd respectively. Currently there are 15 known human CXC
chemokines and 24 CC, but only one C (lymphotaktine) and one CX3C
(fractalkine). The chemokine receptors are classified according
to the subgroup of the chemokine ligands as CXCRs (6), CCRs (10),
CR (1) and CX3R (1). There are chemokines that bind to more than
one receptor and receptors that bind more than one chemokines into
the same subgroup.
The swift between chemokine receptor patterns of expression enables
antigen-presenting cells (like dendritic cells) to travel across
the human body, encounter antigens in the primary invasion site,
migrate to lymphoid tissues to "present" the processed antigenic
peptides and recruit specific T or B-cells . This highly-specified
system for leucocyte trafficking is however believed to be adopted
by tumor cells and to facilitate tumor-cell proliferation and metastasis.
The first observation was that though lymphoid infiltration has
a positive correlation with a more favorable prognosis in young
women with breast cancer, monocyte infiltration correlated with
a worse prognosis and depth of invasion. It was recently found that
agents like chemokines that are secreted by macrophages in the vicinity
of the tumor induce cancer cell proliferation, because tumor cells
express the corresponding chemokine receptors. On the basis of such
observations the link between inflammation and cancer is reevaluated.
One of the most known chemokines, IL-8 (CXCL8) acts as a direct
autocrine growth factor for malignant melanoma, liver, pancreatic,
colon and ovarian cancer. Receptors for CXCL8 (CXCR1 and CXCR2)
activate MAPK (mitogen-activated protein kinase) cascade and cross-talk
with EGFR in induction of cellular proliferation . CXCR2 is a receptor
for CXCL1, 2 and 5 also and all these chemokines have been reported
to act as autocrine (and/or paracrine) growth factors. Other chemokines,
like CXCL12 are direct angiogenic factors, facilitating invasion
and metastasis. It was recently found that CCR7 expression is associated
with lymph node metastasis of gastric carcinoma . The ligand for
CCR7, CCL21, is a powerful chemokine expressed by lymph nodes and
attracts naive T-cells and mature (antigen-encountered) dendritic
cells. It is possible that cancer cells have adopted this way of
trafficking to lymph nodes and other organs as well. CXCR4 is overexpressed
in many tumors (myeloma, astroglioma, lymphomas, CLL, CML, pancreatic
cancer , ovarian cancer kidney cancer and breast cancer).
In a recent paper in Nature, Müller et al have reported that human
CXCR4 and CCR7 are overexpressed in breast cancer cells, malignant
breast tumors and metastases . Their respective ligands (CXCL12
and CCL21) are highly expressed in organs that breast cancer tends
to metastasise (lymph node, lung, liver, bone marrow) . Signalling
through these receptors induces actin polymerisation, pseudopodia
formation and invasion. Inhibition of the CXCL12-CXCR4 interaction
greatly reduces lung metastases in vivo. Other chemokines have been
implicated in breast cancer invasion (RANTES - CCR5 , ) linking
inflammatory responses and breast cancer progression.
CXCR2 was reported by Müller et al to be downregulated in breast
cancer. However its expression correlates with aggressiveness in
colon cancer , induces proliferation in ovarian cancer cells3 and
it is possibly one of the most powerful chemokine inductors of proliferation.
We have seen that CXCR2 is overexpressed in the majority of human
breast cancer tissues (non-metastatic), it is inversely correlated
with expression of some of the HER family receptors and regulates
cellular proliferation (preliminary data). The expression, regulation
and function of CXCR2 in breast cancer tissue is currently under
investigation.
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