Tumor Microenvironment Features and Chemoresistance in Pancreatic Ductal Adenocarcinoma: Insights into Targeting Physicochemical Barriers and Metabolism as Therapeutic Approaches

Abstract

Currently, the median overall survival of PDAC patients rarely exceeds 1 year and has an overall 5-year survival rate of about 9%. These numbers are anticipated to worsen in the future due to the lack of understanding of the factors involved in its strong chemoresistance. Chemotherapy remains the only treatment option for most PDAC patients; however, the available therapeutic strategies are insufficient. The factors involved in chemoresistance include the development of a desmoplastic stroma which reprograms cellular metabolism, and both contribute to an impaired response to therapy. PDAC stroma is composed of immune cells, endothelial cells, and cancer-associated fibroblasts embedded in a prominent, dense extracellular matrix associated with areas of hypoxia and acidic extracellular pH. While multiple gene mutations are involved in PDAC initiation, this desmoplastic stroma plays an important role in driving progression, metastasis, and chemoresistance. Elucidating the mechanisms underlying PDAC resistance are a prerequisite for designing novel approaches to increase patient survival. In this review, we provide an overview of the stromal features and how they contribute to the chemoresistance in PDAC treatment. By highlighting new paradigms in the role of the stromal compartment in PDAC therapy, we hope to stimulate new concepts aimed at improving patient outcomes.

Keywords: acidic pH; chemoresistance; desmoplasia; extracellular matrix; hypoxia; metabolism; pancreatic ductal adenocarcinoma; treatment; tumor microenvironment.

Figure 1

Role of hyaluronan in increasing tissue interstitial pressure. Hyaluronan forms long chains creating a highly osmotic environment that produces edema and increased interstitial pressure. Despite the fact that the diagram only shows a tetrasacharide, hyaluronan is a very lengthy unbranched chain of repeating disaccharides. Red arrows indicate the hydrophilic parts of glucuronic acid and N-acetyl glucosamine, proving the highly hydrophilic ability of hyaluronan. Increased hyaluronan in tumors is an early event occurring in TME, which leads to increased interstitial pressure due to its hygroscopic properties, causing an obstacle to the adequate delivery of chemotherapeutic drugs.

Figure 2

Binding of hyaluronan to CD44 unleashes a pro-tumoral intracellular signaling. The intracellular signaling functions of hyaluronan are triggered after its binding with CD44. This interaction results in the increased expression of the multi-drug resistance protein 1 (MDR1) through STAT3 activation and in the activation of phosphatidylinositol-3-kinase (PI3K/AkT) signaling pathway, causing phosphorylation of Bad, and the subsequent downregulation of apoptosis. The hyaluronan synthesis inhibitor, 4-methylumbelliferone (4-MU), inhibits cell migration, proliferation, and invasion by blocking the interaction between hyaluronan and CD44.

Figure 3

Activity of the proton extruders NHE1 ATPase proton pump. On the left side in green, it is represented the active secretion of cellular protons into the extracellular space by NHE1. On the other side in red, the active extrusion of cellular protons into the extracellular space by V-ATPase proton exporter is shown. Interestingly, both extrude protons against the gradient; however, while proton pumps need energy (ATP) for their activity, NHE1 does not need ATP to achieve the same purpose.

Figure 4

Contribution of carbonic anhydrases to tumor acidification. The cellular metabolism produces an excess of CO₂ that diffuses from the cell into the extracellular space. Membrane carbonic anhydrases IX and XII convert it in carbonic acid (CO₃H₂) through hydration. CO₃H₂ spontaneously ionizes into a molecule of ionized hydrogen (proton) that remains in the matrix, contributing to its acidification. The bicarbonate ion is reintroduced into the cell through the activity of the sodium bicarbonate cotransporter (NBC) contributing to cytoplasmic alkalinity.

Figure 5

The “fate” of the HIF-1α protein with the oxygen tissue level. Upper panel: HIF-1α is unstable in normoxia because due its binding to the VHL protein, it is carried to proteasomal degradation. Lower panel: The situation changes under hypoxic conditions. When HIF-1α is released from VHL (stabilization) and translocates to the nucleus, it dimerizes with the constitutional HIF-1β. This dimer acts as a transcription factor for a set of genes that contain a Hypoxia Responsive Element (HRE) sequence in their promoter region. On the right side there are some of the genes that are promoted by the dimer.

Figure 6

Schematic representation of the relationship between hypoxia and desmoplasia.

Figure 7

Schematic representation of the discussed metabolic pathways in PDAC. The glycolytic pathway (yellow shade), glutaminolysis (orange shade), and the fatty acid metabolism (blue shade) are represented. The enzymes and transporters (bold) are the key intermediated targets which can be envisaged for new promising therapeutic strategies. Dashed arrows indicate more reactions not explored in the review. Legend: glucose transporters (GLUT1 and GLUT3), hexokinase (HK), phosphofructokinase 1 (PFK1), pyruvate dehydrogenase (PHD), lactate dehydrogenase (LDH), monocarboxylate transporters (MCT4 and MCT1), fatty acid transporter CD36, fatty-acid synthase (FASN), acetyl-CoA carboxylase (ACC), carnitine palmitoyl transferase (CPT), citrate synthetase (CS), ASCT2 (glutamine transporter) and glutaminase (GLS).