Neutrophil-Derived Proteases in the Microenvironment of Pancreatic Cancer -Active Players in Tumor Progression

Abstract

A hallmark of pancreatic ductal adenocarcinoma (PDAC) is the fibro-inflammatory microenvironment, consisting of activated pancreatic stellate cells, extracellular matrix proteins, and a variety of inflammatory cells, such as T cells, macrophages, or neutrophils. Tumor-infiltrating immune cells, which are found in nearly all cancers, including PDAC, often fail to eliminate the tumor, but conversely can promote its progression by altering the tumor microenvironment. Pancreatic cancer cells are able to attract polymorphonuclear neutrophils (PMN) via tumor secreted chemokines and in human PDAC, PMN infiltrates can be observed in the vicinity of tumor cells and in the desmoplastic tumor stroma, which correlate with undifferentiated tumor growth and poor prognosis. The behavior of tumor-infiltrating neutrophils in the tumor micromilieu is not yet understood at a mechanistic level. It has been shown that PMN have the potential to kill tumor cells, either directly or by antibody-dependent cell-mediated cytotoxicity, but on the other side various adverse effects of PMN, such as promotion of aggressive tumor growth with epithelial-to-mesenchymal transition and increased metastatic potential, have been described. Recent therapeutic approaches for PDAC focus not only the tumor cell itself, but also elements of the tumor microenvironment. Therefore, the role of PMN and their derived products (e.g. cytokines, proteases) as a new vein for a therapeutic target should be critically evaluated in this context. This review summarizes the current understanding of the interplay between proteases of tumor-infiltrating neutrophils and pancreatic tumor cells and elements of the desmoplastic stroma.

Obesity-Induced Inflammation and Desmoplasia Promote Pancreatic Cancer Progression and Resistance to Chemotherapy

“…This is in agreement with previous reports showing that in the pancreas of mice fed a high-fat diet, fibrosis is also accompanied by inflammation in early-stage neoplastic lesions (43, 44); and with our previous observation that metformin reduces IL-1β and desmoplasia in tumors implanted in obese mice (50). It was shown before that neutrophil infiltrates can be observed in the vicinity of tumor cells and in the desmoplastic tumor stroma, which correlates with undifferentiated tumor growth and poor prognosis (51). We found that TAN specific depletion reduces PSC activation and the number of αSMA-positive cells associated with collagen I.…”

Synthesis and functionalization of protease-activated nanoparticles with tissue plasminogen activator peptides as targeting moiety and diagnostic tool for pancreatic cancer

“…Elevated expression of MMP-9 is associated with cancerous and inflammatory microenvironments, including PDAC [26]. We aimed to use the presence of active MMP-9 in the tumor microenvironment to potentiate targeted delivery and infiltration of NPs into the tumor tissue of pancreatic cancer patients.…”

Mouse versus Human Neutrophils in Cancer: A Major Knowledge Gap

“…Hence, the concept of a predominantly pro-tumoral role of neutrophils and their derived products in tumor biology may be drawn from a small slice of the total physiologic functions of neutrophils, leaving other equally important aspects to be overlooked. For example, the pro-tumoral functions of neutrophil-derived proteases, including neutrophil elastase, have been attributed to their ability to degrade cytokines, chemokines, and their receptors, remodel the extracellular matrix, increase angiogenesis, and promote metastasis [30–32]. A study by Houghton and colleagues showed neutrophil elastase uptake by lung adenocarcinoma cells, where it localized to endosomes and induced tumor cell proliferation by cleaving insulin receptor substrate-1, inducing hyperactivity of the phosphatidylinositol-3-kinase (PI3K) pathway and uncontrolled proliferation [33].…”