Abstract
Perineural invasion (PNI) is one of the major pathological characteristics of pancreatic ductal adeno-carcinoma (PDAC), which is mediated by invading cancer cells into nerve cells. Herein, we identify the overexpression of Interleukin-13 Receptor alpha2 (IL-13Rα2) in the PNI from 236 PDAC samples by studying its expression at the protein levels by immunohistochemistry (IHC) and the RNA level by in situ hybridization (ISH). We observe that ≥75% samples overexpressed IL-13Rα2 by IHC and ISH in grade 2 and 3 tumors, while ≥64% stage II and III tumors overexpressed IL-13Rα2 (≥2+). Interestingly, ≥36 % peripancreatic neural plexus (PL) and ≥70% nerve endings (Ne) among PNI in PDAC samples showed higher levels of IL-13Rα2 (≥2+). IL-13Rα2 +ve PL and Ne subjects survived significantly less than IL-13Rα2 –ve subjects, suggesting that IL-13Rα2 may have a unique role as a biomarker of PNI-aggressiveness. Importantly, IL-13Rα2 may be a therapeutic target for intervention, which might not only prolong patient survival but also help alleviate pain attributed to perineural invasion. Our study uncovers a novel role of IL-13Rα2 in PNI as a key factor of the disease severity, thus revealing a therapeutically targetable option for PDAC and to facilitate PNI-associated pain management.
Highlights
Pancreatic ductal adenocarcinoma (PDAC) is identified as one of the highly aggressive cancers, with increased mortality among gastrointestinal cancer patients [1]
We have demonstrated that IL-13Rα2 is overexpressed in numerous solid human cancers such as malignant glioma, squamous cell carcinoma of head and neck, Kaposi’s sarcoma, kidney cancer, adrenocortical cancer, and ovarian carcinoma [15,16] and that IL-13Rα2 can be efficiently targeted by a chimeric recombinant protein, which consists of IL-13 and truncated Pseudomonas exotoxin [17,18]
Among ten clinicopathological factors of pancreatic ductal adeno-carcinoma (PDAC), our findings uniquely demonstrate that IL-13Rα2 is significantly overexpressed in the peripancreatic neural plexus and nerve endings, which is correlated with the poor survival of patients
Summary
Pancreatic ductal adenocarcinoma (PDAC) is identified as one of the highly aggressive cancers, with increased mortality among gastrointestinal cancer patients [1]. It is commonly seen that the pancreatic cancer is characterized by the local spread to adjacent tissues or organs, with early metastatic lesions to the nearest lymph nodes, liver, and surrounding nerves within the pancreas and the peripheral nerve plexus [2]. It has been demonstrated that nerve growth factors (NGF) produced by tumor-associated immune cells and fibroblasts can be causative factors for pain generation through binding with tropomyosin receptor kinase A (TrkA) and neurotrophin receptor p75(P75NTR ) to trigger neurogenic inflammation [8,9], which are overexpressed in pancreatic cancer cells and adjacent nerves and not typically seen in normal exocrine pancreas [10,11]. Like NGF, the nerve-released glial cell line-derived neutrotrophic factor (GDNF) family receptor (GFR) α1 is identified as one of the key factors involved in PNI through GDNF-Ret proto-oncogene (RET) signal transduction [12]
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