ArticleProceedings of the National Academy of Sciences of the United States of America2017
Early pancreatic cancer lesions suppress pain through CXCL12-mediated chemoattraction of Schwann cells.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 51 papers.
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Who cites it
51 citing papers in PubMed, 82 citations in OpenAlex.
- Molecular mechanisms and therapeutic targets in lung cancer-nerve crosstalk.Chinese medical journal pulmonary and critical care medicine · 2026Review
- Immunological and molecular insights into acinar-ductal metaplasia and atypical flat lesions as precursor lesions of pancreatic ductal adenocarcinoma.Journal of experimental & clinical cancer research : CR · 2026Article
- The substance P/ Neurokinin-1 receptor signaling drives perineural invasion in pancreatic ductal adenocarcinoma (PDAC).Frontiers in cell and developmental biology · 2026Article
- Vitamin D Binding Protein, a Ligand of Integrin beta 1, Motivates Both Tumor Cells and Schwann Cells to Promote Perineural Invasion in Pancreatic Ductal Adenocarcinoma.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2025Article
- Tumor-infiltrating nerves: unraveling the role of cancer neuroscience in tumorigenesis, disease progression, and emerging therapies.Discover oncology · 2025Review
- Review
- Stromal Cells in Early Inflammation-Related Pancreatic Carcinogenesis-Biology and Its Potential Role in Therapeutic Targeting.Cancers · 2025Review
- Extracellular vesicles from pancreatic cancer and its tumour microenvironment promote increased Schwann cell migration.British journal of cancer · 2025Article
- Sympathetic nerve signaling rewires the tumor microenvironment: a shift in "microenvironmental-ity".Cancer metastasis reviews · 2025Review
- The CXCL12/CXCR4 Axis: An Emerging Therapeutic Target for Chronic Pain.Journal of pain research · 2025Review
- The supporting role of Schwann cells in perineural invasion of pancreatic ductal adenocarcinoma.Frontiers in pharmacology · 2025Review
- Benign non-immune cells in tumor microenvironment.Frontiers in immunology · 2025Review
- Perineural invasion in colorectal cancer: mechanisms of action and clinical relevance.Cellular oncology (Dordrecht, Netherlands) · 2024Review
- Construction of a preoperative nomogram model for predicting perineural invasion in advanced gastric cancer.Frontiers in medicine · 2024Article
- Review
- Dynamics and cytokinic regulation of immune cell infiltration in genetically engineered mouse models of pancreatic cancer dictate the sensitivity to immunotherapy.Cancer communications (London, England) · 2024Article
- Glial cell-derived soluble factors increase the metastatic potential of pancreatic adenocarcinoma cells and induce epithelial-to-mesenchymal transition.Journal of cancer research and clinical oncology · 2023Article
- Phenotype screens of murine pancreatic cancer identify a Tgf-α-Ccl2-paxillin axis driving human-like neural invasion.The Journal of clinical investigation · 2023Article
- Important Cells and Factors from Tumor Microenvironment Participated in Perineural Invasion.Cancers · 2023Review
- Tumor-associated nonmyelinating Schwann cell-expressedScience advances · 2023Article
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Authors and funding
19 authors at 3 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
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.
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