Abstract
Schwann cells (SCs), the glial component of peripheral nerves, have been identified as promoters of pancreatic cancer (PC) progression, but the molecular mechanisms are unclear. In the present study, we aimed to identify proteins released by SCs that could stimulate PC growth and invasion. Proteomic analysis of human primary SC secretome was performed using liquid chromatography–tandem mass spectrometry, and a total of 13,796 unique peptides corresponding to 1,470 individual proteins were identified. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway enrichment were conducted using the Database for Annotation, Visualization, and Integrated Discovery. Metabolic and cell–cell adhesion pathways showed the highest levels of enrichment, a finding in line with the supportive role of SCs in peripheral nerves. We identified seven SC-secreted proteins that were validated by western blot. The involvement of these SC-secreted proteins was further demonstrated by using blocking antibodies. PC cell proliferation and invasion induced by SC-conditioned media were decreased using blocking antibodies against the matrix metalloproteinase-2, cathepsin D, plasminogen activator inhibitor-1, and galectin-1. Blocking antibodies against the proteoglycan biglycan, galectin-3 binding protein, and tissue inhibitor of metalloproteinases-2 decreased only the proliferation but not the invasion of PC cells. Together, this study delineates the secretome of human SCs and identifies proteins that can stimulate PC cell growth and invasion and therefore constitute potential therapeutic targets.
Highlights
Pancreatic cancer (PC) is one of the most lethal malignancies [1] and is predicted to become the second leading cause of cancerrelated death by 2030 [2]
Exploration of potential associations of the identified proteins with diseases using Genetic Association Database (GAD) resources revealed that approximately 21% (226 proteins) of the Schwann cell (SC)-secreted proteins were associated with cancer followed initially picked those proteins because they were known to be involved in tumor progression
The present study has used proteomic analysis to define the secretome of SCs and has identified several proteins that can be targeted in vitro to inhibit growth and invasion of PC cells
Summary
Pancreatic cancer (PC) is one of the most lethal malignancies [1] and is predicted to become the second leading cause of cancerrelated death by 2030 [2]. SCs maintain neuronal homeostasis through the regulation of cell growth, survival, and repair [7, 8]. The primordial role of SCs is myelination [9], SCs have recently been implicated in several malignancies including pancreatic [10,11,12], prostate [13], lung [14], oral [15], and cervical [16] cancers. In PC, SCs are involved in the initiation of disease, and their presence is associated with increased perineural invasion, the process by which cancer cells invade nerves [10]. SCs guide cancer cells toward nerves via the production of neural cell adhesion molecule 1 (NCAM 1) that promotes perineural invasion [11]. Few SC-secreted cytokines [19] and adhesion molecules [20] have been described, the secretome of SC and its impact in PC remain largely unknown
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