Chemokines and Receptors Proteins

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Chemokines and Receptors Proteins

Chemokines and Receptors Proteins Background

Chemokines are small chemo-attractant cytokines that contain over 50 members. They are classified into four subgroups C, CC, CXC, and CX3C, based on the location of the first two cysteine residues at the N-terminal region of the sequence. These chemokines function through their seven transmembrane G protein couple receptors (GPCRs). While the CC and CXC families have multiple members, the C family has only two chemokines (XCL1, 2) and one receptor (XCR1), and the CX3C family has one chemokine (CX3CR1) and one receptor (CX3CL1). In the CXC family, the ligands are further divided into two groups, according to the presence or absence of a Glu-Leu-Arg (ELR) motif. This ELR motif is located at the N-terminus adjacent to the first cysteine amino acid residue. ELR+ CXC chemokines have opposite functions to ELR- CXC chemokines regarding angiogenesis. The ELR+ chemokines promote angiogenesis by regulating neutrophil migration. On the other hand, ELR- chemokines are angiostatic peptides. Most chemokines are secreted with the exception of CX3CL1 and CXCL16. The relationship between chemokines and their receptors are promiscuous as some chemokines bind to multiple receptors and some receptors in turn bind multiple chemokines, whereas certain chemokines interact with single receptor and some receptors bind only one chemokine. As a result, there is a high degree of redundancy in their binding specificity and in the activation of downstream signaling pathways regulated by chemokine systems. First discovered as critical factors that regulate leukocyte homing, chemokines and their receptors are commonly known for their functions not only in homeostasis but also in inflammatory responses during pathological processes.


Chemokine Systems in Cancers

Because of their contribution in inflammation, it is not surprising that chemokine systems have roles in cancer biology. Due to their chemoattractant property, chemokines and chemokine receptors are well-known for guiding the migration of cells and thus regulating metastasis. In this pivotal characteristic of cancer, chemokine receptors may potentially facilitate tumor dissemination at each of the key steps of metastasis, including adherence of tumor cells to endothelium, extravasation from blood vessels, metastatic colonization, and protection from the host response via activation of key survival pathways such as extracellular signal-regulated kinase (ERK)/motigen-activated protein kinase (MAPK), phosphatidylinositol 3-and 4-kinase (PI-3K)/(v-akt murine thymoma viral oncogene homolog 1(AKT)/mammalian target of rapamycin (mTOR), or Janus kinase (JAK)/signal transducer and activator of transcription (STAT). Moreover, during tumorigenesis, chemokine networks play important roles in many processes required for tumor development, such as tumor growth, proliferation, invasion, angiogenesis, and recruitment of immune cells to tumor microenvironment.

CCL5/CCR1/CCR3/CCR5 Another member of the CC family, CCL5 (alternatively named regulated on activation normal T cell expressed and secreted, or RANTES) also promotes macrophage and lymphocyte infiltration in various types of human cancers. In a transplantable model of breast carcinoma, CCL5 was determined to be expressed by tumor cells, while its receptor, CCR5, was localized to infiltrating macrophages and lymphocytes. Furthermore, the dual CCR1/CCR5 antagonist, Met-CCL5, was able to reduce tumor growth and inhibit the migration of macrophages and lymphocytes into 410.4 tumors, suggesting a potential role of CCL5 in tumor-promoting macrophage/lymphocyte infiltration.

CXCL11/CXCL12 and CXCR4/CXCR7 CXCR4 and its ligand CXCL12 (SDF-1α) is one of the common chemokine receptor/chemokine pairs studied in the tumorigenesis. Present in different types of cancer, including but not limited to pancreatic cancer, colon cancer, ovarian cancer, lymphoma, medulloblastoma and glioma, CXCL12 and CXCR4 are best known for their roles in metastasis, angiogenesis, and tumor growth. Evidence for CXCL12/CXCR4 function in metastasis has been described. These investigators showed that CXCR4 was expressed by primary breast cancer cells while the ligand CXCL12 was highly detected in the lymph nodes, lungs, liver, and bone, all of which are frequent metastatic sites of breast cancer. Moreover, blocking CXCL12/CXCR4 interactions with a neutralizing anti-CXCR4 antibody impaired the metastasis of breast cancer cells to regional lymph nodes and lung in a xenograft model. In the context of glioma, CXCR4 is elevated in GBM and grade III glioma compared with grade II glioma. Like other cancers, the CXCL12/CXCR4 axis also contributes diverse roles in the malignancy of gliomas. CXCR4 is overexpressed in GBM- derived sphere cultures when compared with the differentiated tumor cells and the coexpression of CXCR4 with the progenitor-cell marker CD133 was detected within cancerous populations in specimens of human GBM. Moreover, studies from our group demonstrated the expression of CXCR4 was increased in the slow cycling population of primary patient-derived GBM cells, which are enriched in GSLC markers. The presence of both CXCL12 and CXCR4 in the tumor regions characterized by necrosis and angiogenesis suggests the possibility for their involvement in angiogenic regulation. CXCR4 expression is primarily under the control of HIF-1 in hypoxic pseudopalisading cells in and around areas of necrosis, whereas VEGF released by these cells is responsible for CXCR4 upregulation in microvessels. The activation of CXCR4 by CXCL12 also promoted mobilization of bone marrow cells, which were then recruited to form new vessels. The fact that CXCL12 is strongly expressed in neurons, blood vessels, subpial regions, and white-matter tracts that form the basis of Scherer’s secondary structures, and that CXCR4 is dominant in invading glioma cells implies additional function of CXCL12/CXCR4 in tumor invasion and growth, possibly through the activation of metalloproteinases MMP-2 and MMP-9.

Besides CXCR4, CXCL12 was recently found to have additional interactions with another chemokine receptor, named CXCR7. The presence of this receptor was discovered when murine fetal liver cells from CXCR4 knockout mice could still bind CXCL12 and discrepancies were observed between CXCR4 expression and CXCL12 binding affinity in several human cancer cell lines. The expression of CXCR7 was reported in many tumor cell lines, in tumor associated endothelial cells, as well as in vascular endothelium. Unlike CXCR4, the property of CXCR7 in GPCR mediated signaling transduction is not understood. Several mechanisms underlying CXCR7 function have been proposed. One role that CXCR7 may play is to scavenge or sequester CXCL12, thereby generating gradients of CXCL12 that lead to differential signaling by CXCR4. Another role for the receptor is that it may serve as a co-receptor for CXCR4 and enhancing CXCL12-mediated Gi/o protein signaling via CXCR4, as the two receptors form heterodimers in the context of overexpression in transiently transfected cells. These observations suggest that ligand binding to CXCR7 results in crosstalk with CXCR4 mediated by intracellular signaling molecules. More recently, it has been demonstrated that CXCR7 interacts with β-arrestin in a ligand dependent manner. CXCR7 can signal through β-arrestin and act as an endogenous β- arrestin-biased receptor.

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