The Chemokine Receptors CXCR4/CXCR7 and Their Primary Heterodimeric Ligands CXCL12 and CXCL12/High Mobility Group Box 1 in Pancreatic Cancer Growth and Development

Abstract

Novel therapies need to be developed for patients with pancreatic cancer because of the poor outcomes of current regimens. Pancreatic cancer cells respond to the C-X-C chemokine receptor type 4 (CXCR4)/C-X-C chemokine receptor type 7 (CXCR7)/C-X-C motif chemokine 12 (CXCL12)/high-mobility group box 1 signaling axis and this axis presents a novel target for therapy. C-X-C motif chemokine 12 stimulates CXCR4/CXCR7-bearing cells in a paracrine manner. C-X-C chemokine receptor type 4 and CXCR7 are transmembrane G protein-coupled receptors that, upon interaction with ligand CXCL12, activate downstream protein kinases that promote a more aggressive behavior. C-X-C chemokine receptor type 4 is expressed on most pancreatic cancer cells, whereas CXCR7 is primarily expressed on tumor-associated endothelium. High-mobility group box 1 promotes the CXCR4 and CXCL12 interaction, promoting angiogenesis and lymphangiogenesis. Hypoxia-inducible factor 1 is a potent stimulator of CXCR4 and CXCL12 expression, promoting more aggressive behavior. This receptor/ligand interaction can be disrupted by CXCR4 antagonists available and in clinical use to harvest bone marrow stem cells. Novel imaging strategies are now being developed at several centers to evaluate response to therapy and identify early recurrence. Thus, the CXCR4/CXCR7/CXCL12 interaction plays a critical role in cancer cell progression, proliferation, invasion, as well as metastasis and is a suitable target for therapy, imaging, as well as development of novel diagnostics.

Soluble factors from stellate cells induce pancreatic cancer cell proliferation via Nrf2-activated metabolic reprogramming and ROS detoxification

“…SDF-1α has been implicated in proliferation, invasion, metastasis and chemoresistance of PDAC [47–49]. Nrf2 can directly bind to the promoter of the receptor, CXCR4, and activate its transcription [50].…”

BH3 mimetics suppress CXCL12 expression in human malignant peripheral nerve sheath tumor cells

“…Targeting tumor-specific growth promoting pathways is important for successful cancer therapy, and the CXCL12/CXCR4 signaling axis is involved in tumor progression and migration in multiple tumor types [12, 39, 40]. The physiological role for chemotactic cytokines is to direct the homing of hematopoietic cells to specific sites within the body via interaction with cell-surface receptors [41–47].…”

The CXCR4-CXCL12-Axis is of Prognostic Relevance in DLBCL and Its Antagonists Exert Pro-Apoptotic Effects in Vitro

“…We determined the expression levels of CXCR4, CXCR7 and their ligand CXCL12 [19] in NGCB-and GCB-DLCBLs consisting of primary and transformed follicular lymphomas (n=77 in total) and germinal centre B cells (GC-B, n=5) serving as non-neoplastic controls by using RQ-PCR. We observed an average of 140-fold higher CXCR4 expression in DLBCL and all investigated DLBCL subgroups in comparison to GC-Bs (Figure 1a, p<0.001), whereas no differential expression was found for CXCR7 and CXCL12 (Figure 1a and Figure S1a).…”