Journal
PANCREAS
Volume 44, Issue 4, Pages 528-534Publisher
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1097/MPA.0000000000000298
Keywords
CXCR4; CXCR7; CXCL12; damage-associated molecular pattern molecules; HMGB1; pancreatic cancer
Categories
Funding
- Division of Surgical Oncology, University of Pittsburgh Medical Center
- American Association for Cancer Research-Pancreatic Cancer Action Network
- [1 R01 MH094564-01]
- [1R21CA180211]
- [3P30CA047904-22S1]
- [R01 CA160417-01]
- [1 R01 CA181450-01]
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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.
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