Focus on Pancreatic Cancer Microenvironment

Abstract

Pancreatic ductal adenocarcinoma remains one of the most lethal solid tumors due to its local aggressiveness and metastatic potential, with a 5-year survival rate of only 13%. A robust connection between pancreatic cancer microenvironment and tumor progression exists, as well as resistance to current anticancer treatments. Pancreatic cancer has a complex tumor microenvironment, characterized by an intricate crosstalk between cancer cells, cancer-associated fibroblasts and immune cells. The complex composition of the tumor microenvironment is also reflected in the diversity of its acellular components, such as the extracellular matrix, cytokines, growth factors and secreted ligands involved in signaling pathways. Desmoplasia, the hallmark of the pancreatic cancer microenvironment, contributes by creating a dense and hypoxic environment that promotes further tumorigenesis, provides innate systemic resistance and suppresses anti-tumor immune invasion. We discuss the complex crosstalk among tumor microenvironment components and explore therapeutic strategies and opportunities in pancreatic cancer research. Better understanding of the tumor microenvironment and its influence on pancreatic cancer progression could lead to potential novel therapeutic options, such as integration of immunotherapy and cytokine-targeted treatments.

Keywords: cancer therapy; cancer-associated fibroblasts; cytokines; desmoplasia; immune cells; immunotherapy; pancreatic ductal adenocarcinoma; tumor microenvironment.

Figure 1

Pancreatic cancer tumor microenvironment (TME). Pancreatic ductal adenocarcinoma TME composition. PDA stroma is comprised of cellular and acellular components, such as fibroblasts, myofibroblasts, pancreatic stellate cells, immune cells, blood vessels, extracellular matrix and soluble proteins, such as cytokines and growth factors. Interactions between these elements promote the desmoplastic structure, creating a physical barrier responsible for PDAC treatment resistance.

Figure 2

Role of Tumor-associated macrophages (TAMs). TAMs inactivate cytotoxic T cells through PD-L1 expression, produce cytokines to recruit regulatory T cells and create an inflammatory environment. These macrophages are involved in extracellular matrix remodeling by producing proteases, such as metalloproteinases, that degrade collagen fibers, and cross-linking enzymes, which contribute to the stiffness of the extracellular matrix. Furthermore, TAMs secrete VEGF and promote angiogenesis, which is involved in tumor progression and metastasis. Tumor-associated macrophages migrate with cancer cells to blood vessels and create TMEM (tumor microenvironment of metastasis) doorways, permitting cancer cells to disseminate in the circulation. Lastly, TAMs play a role in epithelia to mesenchymal transition by producing TGF-β and CCL18, allowing cancer cells to migrate.