Editors' ChoiceCancer

Tumors block pain with CXCL12

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Sci. Signal.  10 Jan 2017:
Vol. 10, Issue 461,
DOI: 10.1126/scisignal.aam7233

The chemokine CXCL12 released from early stage pancreatic cancer recruits Schwann cells and suppresses pain signaling.

Pancreatic cancer is known as one of the most painful cancers, yet detection typically occurs long after metastasis. Demir et al. found that Schwann cells present in human pancreatic ductal adenocarcinoma (PDAC) were positive for the receptor proteins CXCR4 and CXCR7, which are activated by the chemokine CXCL12. In normal pancreatic tissue, CXCL12 was predominantly present in intrapancreatic ducts, whereas in PDAC this chemokine was found in the stroma surrounding the tumors. Hypoxia triggered an increase in the mRNA for CXCL12 and the secretion of this chemokine from pancreatic cancer cell lines, and conditioned medium from these cells stimulated migration of human Schwann cells in culture. Experiments with three-dimensional cultures and pharmacological or genetic inhibition of CXCR4 or CXCR7 showed that these receptors contributed to the migration of Schwann cells toward cancer cells. In the KC mouse model of PDAC, conditional knockout of CXCL12 in pancreatic cells reduced the number of Schwann cells in both the tumors and precancerous lesions but increased the number of activated astrocytes and microglia. Consistent with this increase in reactive glial cells, the CXCL12-deficient KC mice exhibited increased abdominal mechanosensitivity compared with that of the KC mice, even though both mouse models developed PDAC. Furthermore, PDAC patients stratified by pain scores exhibited a negative correlation between the abundance of CXCR4 and CXCR7 and pain: Less receptor abundance in the tumor-associated neural tissue correlated with increased pain. Targeted transcriptomic analysis of pain-associated genes showed that human Schwann cells exposed to CXCL12 indicated that 6 of 17 pain-associated transcripts were increased and 11 of 17 were decreased, including several pain-mediating receptors and ligands. These data suggest that hypoxia stimulates an increase in the production and release of CXCL12 from both precancerous lesions and PDAC cells, resulting in the recruitment of Schwann cells and suppression of pain responsiveness. This may explain why pain is not a reliable indicator of pancreatic cancer until late in the disease when the cancer cells have invaded the neural tissue to metastasize.

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