Abstract PR1: The role of the microenvironment protein cathelicidin LL-37 in pancreatic ductal adenocarcinoma

Abstract

Abstract The tumor-associated microenvironment does not only provide structural support for tumor development, but more importantly the microenvironment provides cues to cancer initiating cells [i.e. cancer stem cells (CSC)] that regulate their self-renewal capacity and metastatic potential. Recent evidence also suggests that inflammatory molecules at the tumor-stroma interface may also play critical roles in the development and progression of numerous tumors, such as pancreatic cancer, and their effects may also be paracrine-mediated. Along these lines, we have discovered that the immuno-modulatory cationic antimicrobial protein 18 (hCAP-18 or LL-37) is highly expressed in microenvironment resident cells (cancer-associated fibroblasts, infiltrating immune cells, and pancreatic stellate cells) of patients with pancreatic cancer. It is also secreted by primary human macrophages co-cultured with pancreatic CSCs. Intriguingly, LL-37 was not detectable in tissue from patients with chronic pancreatitis or pancreatic intraepithelial neoplasia (PanIN) suggesting a bilateral crosstalk between LL-37 producing cells and fully transformed cancer (stem) cells. As we have recently shown a strong role for the tumor stroma and microenvironment-secreted factors in pancreatic CSC self-renewal and invasiveness, LL-37 may represent a new and uncharacterized PDAC microenvironment factor that may play a critical role in pancreatic cancer progression and metastasis. Indeed, treatment of pancreatic CSCs with LL-37 increased CSC pluripotency-associated gene expression, self-renewal, and invasion in vitro as well as tumorigenicity and metastasis in vivo. LL-37 exerted its biological functions through interaction with the G protein—coupled receptor, formyl peptide receptor—like 1, P2X(7) purinergic receptor. In addition, receptor independent activity was mediated by stabilization of the CXCR4 receptor in the cell membrane. Taken together, our data expands our understanding of the tumor microenvironment and the tumor host interactions that perpetuate pancreatic ductal adenocarcinoma. Even more importantly, these studies identify a new tumor-specific factor for identifying malignant lesions in the pancreas and predicting patient outcome. Targeting of LL-37 could improve our therapeutic armamentarium against this deadly disease. This abstract is also presented as Poster A18. Citation Format: Bruno Sainz, Jr., Javier Frias, Michele Cioffi, Sonia Alcala, Christopher Heeschen. The role of the microenvironment protein cathelicidin LL-37 in pancreatic ductal adenocarcinoma. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Invasion and Metastasis; Jan 20-23, 2013; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2013;73(3 Suppl):Abstract nr PR1.