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Review
. 2019 Jun 2:2019:9681698.
doi: 10.1155/2019/9681698. eCollection 2019.

CXCL12 and Its Isoforms: Different Roles in Pancreatic Cancer?

Alessandra Righetti  1 , Matteo Giulietti  1 , Berina Šabanović  1 , Giulia Occhipinti  1 , Giovanni Principato  1 , Francesco Piva  1
Affiliations
Review

CXCL12 and Its Isoforms: Different Roles in Pancreatic Cancer?

Alessandra Righetti et al. J Oncol. .

Abstract

CXCL12 is a chemokine that acts through CXCR4 and ACKR3 receptors and plays a physiological role in embryogenesis and haematopoiesis. It has an important role also in tumor development, since it is released by stromal cells of tumor microenvironment and alters the behavior of cancer cells. Many studies investigated the roles of CXCL12 in order to understand if it has an anti- or protumor role. In particular, it seems to promote tumor invasion, proliferation, angiogenesis, epithelial to mesenchymal transition (EMT), and metastasis in pancreatic cancer. Nevertheless, some evidence shows opposite functions; therefore research on CXCL12 is still ongoing. These discrepancies could be due to the presence of at least six CXCL12 splicing isoforms, each with different roles. Interestingly, three out of six variants have the highest levels of expression in the pancreas. Here, we report the current knowledge about the functions of this chemokine and then focus on pancreatic cancer. Moreover, we discuss the methods applied in recent studies in order to understand if they took into account the existence of the CXCL12 isoforms.

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Figures

Figure 1
Figure 1
CXC chemokine structure. Chemokine presents three antiparallel β-sheets and a C-terminal α-helix; this tertiary structure is owing to the presence, starting from N-terminal region, of an “N-loop”, a single 310 helix, and then the 30s and 40s loops. The two cysteine residues at the N-terminal end allow the formation of disulphide bonds which are fundamental to the chemokine structure and receptor interaction.
Figure 2
Figure 2
CXCL12 sequence. (a) The CXCL12 immature form, the propeptide, which includes the 21 amino acids at the N-terminal end, that will be removed. (b) The mature CXCL12 form has undergone a proteolytic cut of 21 amino acids at the N-terminal end. The first 8 amino acids of the mature CXCL12 allow the receptor interaction; in particular, the first two, lysine and proline, activate the CXCR4 receptor while the other six are used for the receptor binding. Also, the “RFFESH” sequence allows the ligand-receptor binding. (c) Representations of all CXCL12 isoforms are reported. They all have the same starting sequence, but each one differs from the others in the terminal region length.
Figure 3
Figure 3
Protein multialignment of all CXCL12 isoforms.
Figure 4
Figure 4
Primary pancreatic tumor microenvironment. PDAC stromal cells, like cancer-associated fibroblasts (CAFs) and cancer stellate cells, release the different CXCL12 isoforms in the tumor microenvironment. Cancer cells, which expressed the CXCL12-receptor on their surface, can bind the ligand. This ligand-receptor binding can cause tumor invasion, cellular proliferation, angiogenesis, epithelial to mesenchymal transition (EMT), and metastasis.
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