Early pancreatic cancer lesions suppress pain through CXCL12-mediated chemoattraction of Schwann cells

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.Schwann cells | pancreatic cancer | CXCL12 | CXCR4 | CXCR7

Cancer Manipulation of Host Physiology: Lessons from Pancreatic Cancer

“…CCL2, CCL5, CXCL1, CXCL2, CXCL12 [19, 27–30]), and growth factors (such as GM–CSF and TGF-β [31, 32]), with profound effects on immune cell infiltration, activation status, as well as skewing towards cellular phenotypes that support tumor growth and immune escape (reviewed in the next section; Fig. 4).…”

“…Both ligand and receptor are significantly upregulated on cancer cells as well as various other stromal cell types, and have important roles in bidirectional tumor-stroma communication in human PDAC, including promotion of tumor growth and invasion, enhancement of the cancer-associated fibroblast (CAF) compartment, and maintenance of intratumoral immunosuppression [36–38]. Intriguingly, it was recently implicated in neural invasion of PDAC: specifically, human peri-pancreatic Schwann cells were found to upregulate CXCR4 and CXCR7 in response to pancreatic cancer and associated hypoxia [30]. Cancer cells secrete CXCL12 which attracts peri-pancreatic nerves to infiltrate early PDAC lesions, rendering them less-responsive to pain [30].…”

“…Intriguingly, it was recently implicated in neural invasion of PDAC: specifically, human peri-pancreatic Schwann cells were found to upregulate CXCR4 and CXCR7 in response to pancreatic cancer and associated hypoxia [30]. Cancer cells secrete CXCL12 which attracts peri-pancreatic nerves to infiltrate early PDAC lesions, rendering them less-responsive to pain [30]. Although this may be a defense mechanism to shield the patient from the intractable pain of pancreatic cancer-related neural invasion, it is clearly hijacked by cancer cells to promote loco-regional tumor dissemination [30].…”

“…Cancer cells secrete CXCL12 which attracts peri-pancreatic nerves to infiltrate early PDAC lesions, rendering them less-responsive to pain [30]. Although this may be a defense mechanism to shield the patient from the intractable pain of pancreatic cancer-related neural invasion, it is clearly hijacked by cancer cells to promote loco-regional tumor dissemination [30]. …”

Challenges and Opportunities in Modeling Pancreatic Cancer

“…Intriguingly, genes regulating axon guidance are frequently mutated in PDA, providing a possible cell-intrinsic mechanism for this process (Biankin et al 2012). It has been well-established that tumor cells can promote neural sprouting and Schwann cell recruitment (Demir et al 2016), and that neuron and Schwann cell -derived signals can regulate tumor cell invasion (Liang et al 2016). However, models faithfully recapitulating neuronal -epithelial interactions are required for understanding the mechanisms driving PNI and for screening compounds that can inhibit this process.…”