Early pancreatic cancer lesions suppress pain through CXCL12-mediated chemoattraction of Schwann cells.
Proc Natl Acad Sci U S A
; 114(1): E85-E94, 2017 01 03.
Article
en En
| MEDLINE
| ID: mdl-27986950
ABSTRACT
Pancreatic ductal adenocarcinoma (PDAC) cells (PCC) have an exceptional propensity to metastasize early into intratumoral, chemokine-secreting nerves. However, we hypothesized the opposite process, that precancerous pancreatic cells secrete chemokines that chemoattract Schwann cells (SC) of nerves and thus induce ready-to-use routes of dissemination in early carcinogenesis. Here we show a peculiar role for the chemokine CXCL12 secreted in early PDAC and for its receptors CXCR4/CXCR7 on SC in the initiation of neural invasion in the cancer precursor stage and the resulting delay in the onset of PDAC-associated pain. SC exhibited cancer- or hypoxia-induced CXCR4/CXCR7 expression in vivo and in vitro and migrated toward CXCL12-expressing PCC. Glia-specific depletion of CXCR4/CXCR7 in mice abrogated the chemoattraction of SC to PCC. PDAC mice with pancreas-specific CXCL12 depletion exhibited diminished SC chemoattraction to pancreatic intraepithelial neoplasia and increased abdominal hypersensitivity caused by augmented spinal astroglial and microglial activity. In PDAC patients, reduced CXCR4/CXCR7 expression in nerves correlated with increased pain. Mechanistically, upon CXCL12 exposure, SC down-regulated the expression of several pain-associated targets. Therefore, PDAC-derived CXCL12 seems to induce tumor infiltration by SC during early carcinogenesis and to attenuate pain, possibly resulting in delayed diagnosis in PDAC.
Palabras clave
Texto completo:
1
Banco de datos:
MEDLINE
Asunto principal:
Dolor
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Neoplasias Pancreáticas
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Células de Schwann
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Quimiotaxis
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Receptores CXCR4
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Carcinoma Ductal Pancreático
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Quimiocina CXCL12
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Receptores CXCR
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Animals
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En
Año:
2017
Tipo del documento:
Article