Unraveling the Connection: Pancreatic Cancer Cells and Schwann Cells

Abstract

Pancreatic ductal adenocarcinoma is one of the most lethal solid malignancies, characterized by its aggressiveness and metastatic potential, with a 5-year survival rate of only 13%. Progress in the management of metastatic disease has been modest. A robust connection between nervous system and tumor progression exists, with prominent neural alterations having been observed during pancreatic cancer's progression, including neural hypertrophy, neural density, and neural remodeling. The pancreatic tumor microenvironment includes s set of cells and structures that constantly dialogue with cancer cells, influencing its growth and behavior. The microglia is key cellular components of the tumor microenvironment, and Schwann cells are the principal glial cells in the peripheral neural system. Schwann cells can regulate changes in the tumor microenvironment and immune responses by secreting a variety of factors and can support a tumor's invasion of nerves and distant metastasis, with further pain exacerbation. Schwann cells secrete various pain-related molecules, such as the neural growth factor, to mediate the activation of primary sensory neurons, leading to pain induction. The binding of the neural growth factor to tropomyosin receptor kinase A is an important signaling mechanism for pain perception in humans. Consequently, directing efforts towards targeting neural invasion may provide an alternative strategy to improve the prognosis of and alleviate pain in patients with pancreatic cancer.

Keywords: Schwann cells; cancer pain; neural invasion; pancreatic ductal adenocarcinoma; tumor microenvironment.

Figure 1

Interplay of signaling pathways: cellular dynamics within the pancreatic ductal adenocarcinoma microenvironment. The activation of SCs from a quiescent to an active state is induced by IL6 release from cancer cells. The hypoxic tumor state upregulates GM-CSF, promoting the migration and proliferation of SCs. Reciprocal paracrine signaling is established between cancer cells and SCs, with cancer cells releasing TIMP1 and NGF to influence SCs. Conversely, SCs release TGF-b and L1CAM, impacting cancer cells and contributing to NI. SCs play a multifaceted role by recruiting macrophages through the release of IL33 and CCL2. The CCL2-CCR2 pathway prompts TAMs to emit cathepsin B, thereby promoting nerve injury. TAMs, activated by IL33, release bFGF, establishing a positive feedback loop within the microenvironment. This intricate interplay highlights the dynamic and interconnected nature of cellular communication in the context of PDAC. Abbreviations: SCs, Schwann cells; GM-CSF, granulocyte–macrophage colony-stimulating factor; TIMP1, tissue inhibitor of metalloproteinases 1; NGF, nerve growth factor; TGF-b, transforming growth factor-beta; L1CAM, L1 cell adhesion molecule; NI, neural invasion; CCL2, chemokine ligand 2; TAMs, tumor-associated macrophages; bFGF, basic fibroblast growth factor; and PDAC, pancreatic ductal adenocarcinoma.

Figure 2

Pivotal role of the NGF/TrkA signaling pathway in PDAC. NGF binds to two receptors: low-affinity p75NTR and high-affinity TrkA receptors. NGF binding to a TrkA receptor mediates proliferation, differentiation, and survival via the activation of the Ras/MAPK, PI3K/AKT, and PLCγ pathways. NGF binding to the p75NTR receptor activates JNK and NF-κB. These mediate opposing effects of survival and apoptosis, respectively. Beyond NGF, several other neurotrophic molecules such as BDNF, NT-3, and NT-4/5 play a role in nerve growth. BDNF and NT-4 bind to the TrkB receptor and NT-3 to the TrkC receptor. GDNF binds to the GFR-α1-RET receptor. Effects of NGF increase the nociceptive ion channels, receptors, and peptides, such as BR, Na, Ca, K, CGRP, SP, BDNF, TRPV1, ASIC3, and p75. The red arrows show possible sites of NGF/TrkA signaling pathway inhibition. 1: NGF antagonists; 2: inhibitors of NGF binding to TrkA, and 3: TrkA inhibitors. Abbreviations: TrkA, tropomyosin receptor kinase A; NGF, nerve growth factor; MAPK, mitogen-activated protein kinase; PI3K, phosphatidylinositol-3-kinase; PLCγ, phospholipase Cγ; JNK, c-Jun N-terminal kinase; NF-κB, nuclear factor-κB; BDNF, brain-derived neurotrophic factor; neurotrophin-3 (NT-3); neurotrophin-4/5 (NT-4/5); TrkB, tropomyosin receptor kinase B; TrkC, tropomyosin receptor kinase C; GDNF, glial-derived neurotrophic factor; BR, bradykinin receptor; Na, sodium; Ca, calcium; K, potassium; CGRP, calcitonin gene-related peptide; SP, substance P; TRPV1, transient receptor potential cation channel subfamily V member 1; and ASIC3, acid-sensing ion channel 3.