In a recent study, the expression profiles of the six CXCL12 isoforms and both receptors have been investigated in a large clinical cohort and common breast cancer cell lines. The interactions of CXCL12/CXCR4 seems to have a critical role in determining the metastatic destination of breast cancer metastasis (Muller et al., 2001 Hinton et al., 2011), while the CXCR7 expression has been linked to the ability of tumor cells to produce lung and brain metastasis (Sun et al., 2010). Moreover, a CXCL12 gene variant CXCL12-A (CXCL12-G801A, a single nucleotide polymorphism in the 3 untranslated region) was associated with an increased susceptibility to breast cancer (Dimberg et al., 2007). The CXCL12 expression has been shown to stimulate breast cancer cells proliferation and promote tumor growth (Allinen et al., 2004 Duda et al., 2011). Many others cellular functions depend on CXCL12 activity, including embryogenesis, apoptosis and survival, immune response, tissue homeostasis, angiogenesis, calcium ion homeostasis, clathrin-mediated endocytosis, cytoskeletal rearrangement, cell proliferation and migration, tumor growth and metastasis (Vlahakis et al., 2002 Goda et al., 2006 Petit et al., 2007 Khan et al., 2008 Agle et al., 2010 Drury et al.,2010 Karin, 2010 Kremer, 2010 Sun et al., 2010 Zhu et al., 2012). For example, dimeric CXCL12 form induces calcium mobilization but fails to promote chemotaxis, which is induced by the monomer-based interactions (Ray et al., 2012 Sanchez-Martin et al., 2013). In fact, whereas CXCR4 binds both monomeric and dimeric forms, CXCR7 binds preferentially the dimeric one (Sanchez-Martin et al., 2013). CXCL12 is secreted in the extracellular space as monomeric and dimeric forms, which can trigger different effects on cell signaling (Ray et al., 2012). In particular, CXCL12 has a higher affinity of binding to CXCR7 than to CXCR4 (Zhu et al., 2012), even if its affinity to CXCR7 seems to be reduced by the expression of CXCR4 at the membrane (Sanchez-Martin et al., 2013). The first one is the chemokine (C-X-C motif) receptor 4 (CXCR4), a monogamous receptor that signals through heterotrimeric G proteins and beta-arrestin the second one is the chemokine (C-X-C motif) receptor 7 (CXCR7), a non-monogamous receptor that does not activate G-protein-mediated signal transduction but signals only through beta-arrestin (Oberlin et al., 1996 Rajagopal et al., 2010 Sun et al., 2010 Zhu et al., 2012 Sanchez-Martin et al., 2013). The CXCL12 protein functions as a ligand for two seven-transmembrane receptors (7-TMRs). In the developmental stage, the isoform Alpha is ubiquitously expressed in fetal tissues, Beta and Delta isoforms in fetal spleen and liver, while Gamma and Theta isoforms are weakly detected in fetal kidney (Yu et al., 2006). The Gamma Isoform is mainly expressed in heart, while the isoforms Delta, Epsilon and Theta are mainly expressed in pancreas. The Beta isoform has been chosen as the canonical sequence and, together with Alpha isoform, is ubiquitously expressed in liver, pancreas and spleen. In particular Alpha and Beta isoforms, secreted as full-length molecules, undergo to post-translational modifications by a proteolytic cleavage, becoming respectively processed forms SDF-1-alpha(3-67) and SDF-1-beta(3-72)(De la Luz Sierra et al., 2004). Six protein isoforms have been identified in human: Alpha, Beta, Gamma, Delta, Epsilon and Theta (Table 2 Figure 2), produced by alternative splicing events (Yu et al., 2006). This family is defined by the location of the first two cysteine residues in the sequence, which are separated by one amino acid (C-X-C chemokine)(Hromas, 1997). CXCL12 gene encodes a stromal cell-derived alpha chemokine, also known as SDF1, a member of the intercrine family.
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