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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.
Highlights
Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal gastrointestinal tumors; it is characterized by poor prognosis and the survival rate is only 8%
To understand the tumor onset, behavior, and drug resistance, it is important to study the stromal component of PDAC. This component consists of several cell types: cancer-associated fibroblasts (CAFs), T cells, pancreatic stellate cells (PSCs), macrophages, endothelial cells, and others [4, 5]
Data show that CXCL12/CXCR4/ACKR3 axis is involved in keeping the communication between pancreatic cancer and its microenvironment
Summary
Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal gastrointestinal tumors; it is characterized by poor prognosis and the survival rate is only 8%. PSCs produce extracellular matrix molecules (i.e., laminin, fibronectin, and periostin) [7,8,9,10] while macrophages release matrix metalloproteinases (e.g., MMP-9) [11] Both tumor and stromal cells release growth factors, including FGF, EGF, VEGF, HGF, and TGF-β and the inflammatory messenger IL-6. The activation of one or more of these pathways supports the tumor growth and invasion, promotes resistance to drug therapy, provides possible niches for the metastasis development, and protects tumor cells from the host’s immune system [17, 18] Regarding the latter, it is known that CXCL12 exerts a predominant immunosuppression effect by sequestering CD8+ T cells and preventing them from attacking the cancer cells [19]. By depleting fibroblast activation protein (FAP)expressing CAFs, it was possible to attain immune control of the PDAC development and to restore the antitumor effects of anti-CTLA-4 and anti-PD-L1 immune checkpoint antagonists [20,21,22]
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