PDAC, the Influencer Cancer: Cross-Talk with Tumor Microenvironment and Connected Potential Therapy Strategies

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is among the leading causes of death by cancer in the world. What makes this pathological condition particularly lethal is a combination of clinical and molecular heterogeneity, lack of early diagnostic indexes, and underwhelming results from current therapeutic protocols. A major cause of PDAC chemoresistance seems to lie in the ability of cancer cells to spread out and fill the pancreatic parenchyma, exchanging nutrients, substrates, and even genetic material with cells from the surrounding tumor microenvironment (TME). Several components can be found in the TME ultrastructure, including collagen fibers, cancer-associated fibroblasts, macrophages, neutrophils, mast cells, and lymphocytes. Cross-talk between PDAC and TME cells results in the latter being converted into cancer-favoring phenotypes; this behavior could be compared to an influencer guiding followers into supporting his activity. Moreover, TME could be a potential target for some of the newest therapeutic strategies; these include the use of pegvorhyaluronidase-α and CAR-T lymphocytes against HER2, FAP, CEA, MLSN, PSCA, and CD133. Other experimental therapy options are being currently studied, aiming to interfere with the KRAS pathway, DNA-repairing proteins, and apoptosis resistance in PDAC cells. Hopefully these new approaches will grant better clinical outcomes in future patients.

Keywords: PDAC new therapeutic strategies; PDAC treatments; PDAC tumor microenvironment; pancreatic ductal adenocarcinoma.

Figure 1

Flow chart of literature selection. Created with BioRender.com.

Figure 2

Cross-talk between PDAC cells and TME. PDAC cells have been shown to interact with other cells in the TME. Healthy cells (A) are influenced by PDAC towards carcinogenesis; stellate cells and fibroblasts (B) are redirected towards an ECM-deposing phenotype through the action of SHH/HH and SAA1 pathways, while also providing PDAC cells with nutrients; immune cells (C) receive tumoral exosomes (TEXs) containing miRNAs which will stimulate pro-carcinogenic and pro-metastatic pathways. PSC: pancreas stellate cell; CAF: cancer-associated fibroblast; TAM: tumor-associated macrophage; CTL: cytotoxic T lymphocyte; TH: helper T lymphocyte; NK: natural killer lymphocyte; T-reg: regulatory lymphocyte; EV: extracellular vesicle; Black circle in panel B: cross-link. Created with BioRender.com.

Figure 3

Development and progression of PDAC. Visualization of TME role during the natural evolution of PDAC. PSC: pancreas stellate cell; CAF: cancer-associated fibroblast; ECM: extracellular matrix; PanIN: pancreatic intraepithelial neoplasia; EMT: epithelial–mesenchymal transition; arrow represents an increase. Created with BioRender.com.

Figure 4

Graphical overview of PDAC therapeutic options. The image above shows currently used protocols (dotted blue line) alongside newer, experimental methods (full purple line). Created with BioRender.com.

Figure 5

CAR-T and CAR-M are among the latest most relevant therapeutic approaches for PDAC. Once the engineered T lymphocytes or macrophages interact with the target cells (in this case PCCs and CAFs), they induce their death in various ways. MSLN: mesothelin; CD133: promin 1; CEA: carcinoembryonic antigen; HER2: human epidermal growth factor 2; FAP: fibroblast activation protein; PSCA: prostate stem cell antigen. Created with BioRender.com.