Tumor Microenvironment Role in Pancreatic Cancer Stem Cells

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal malignancy with a majority of patients presenting with unresectable or metastatic disease, resulting in a poor 5-year survival rate. This, in turn, is due to a highly complex tumor microenvironment and the presence of cancer stem cells, both of which induce therapy resistance and tumor relapse. Therefore, understanding and targeting the tumor microenvironment and cancer stem cells may be key strategies for designing effective PDAC therapies. In the present review, we summarized recent advances in the role of tumor microenvironment in pancreatic neoplastic progression.

Keywords: PDAC; cancer stem cells; tumor microenvironment (TME).

Figure 1

Cancer heterogeneity can be explained by two different models. The first model is the clonal evolution model (A), where stochastic mutations give rise to the tumor, and every tumor cell has the potential to generate a new tumor. The second model is the cancer stem cell model (B), in which tumors arise from mutations in stem cells or progenitor stem-like cells, and only the cancer stem cells can sustain and form new tumors.

Figure 2

Representative scheme of the different markers found in pancreatic CSCs. ATP-binding cassette (ABC); Epithelial cell adhesion molecule (EpCAM); Aldehyde dehydrogenase 1 (ALDH); C-X-C chemokine receptor 4 (CXCR4). Different combinations of cell surface markers provide the possibility of isolating clones with higher or lower aggressiveness.

Figure 3

Schematic representation of the different cellular and acellular components of the TME. The interplay between the tumor and surrounding environment, known as the tumor microenvironment (TME), involves a myriad of cellular and acellular components, constantly interacting and influencing each other. The crosstalk between malignant and non-malignant cells plays a significant role in cancer progression and treatment response.

Figure 4

Within the TME, there are various specialized microenvironments, including the hypoxic, acid, immune, and metabolic niches. These niches continuously interact and communicate with cellular and acellular components, influencing the efficacy of therapies, as well as the progression, evolution, and prognosis of various cancer types.

Figure 5

PDAC TME. Schematic representation of the microenvironment in the normal pancreas (left) with a regular tissue architecture and the tumor microenvironment in PDAC (right) in which we can observe high desmoplastic zones, unrecognizable pancreatic architecture, immune infiltration, and a large number of stromal cells, increased amounts of ECM and the lack of organized blood vessels (which causes hypoxic conditions).