Abstract
Simple SummaryPancreatic ductal adenocarcinoma (PDAC) has an extremely poor prognosis. The lack of early diagnosis and the absence of suitable biomarkers coupled with resistance to available therapeutic options has made PDAC one of the deadliest cancers. Despite advances in diagnostics and therapeutics, the prognosis of PDAC remains dismal. PDAC has a prominent desmoplastic stromal microenvironment that includes a dense extracellular matrix together with a series of activated cell types, hypoxia, and an acidic extracellular pH. This activated desmoplastic stroma compromises treatments yet, despite the recognition of its importance, it has not been comprehensively studied in this role. Moreover, PDAC metabolic reprogramming has also been found to be one of the key factors involved in treatment failure. Here, we critically review the role of the various stromal components in determining resistance to available therapeutics with the hope that its comprehensive understanding, if employed in the appropriate combination therapy, may make this recalcitrant cancer more manageable.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.
Highlights
Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer-related mortality in western countries and is projected to be the second-leading cause of cancerrelated death in the United States by 2030 [1]
While some reports have shown that total tissue hyaluronan content is not correlated with tissue elasticity and hydraulic conductivity [72], another study demonstrated that extracellular matrix (ECM) molecular selectivity is regulated by variation of the hyaluronan content, affecting molecule penetration based on charge and size [73]
Numerous studies have demonstrated that the invasive capacity of PDAC correlates with epithelial-tomesenchymal transition (EMT) [212,213] together with their increased ability to migrate while remetastasis and it is associated with a negative prognosis [206,207]
Summary
Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer-related mortality in western countries and is projected to be the second-leading cause of cancerrelated death in the United States by 2030 [1]. This enhanced interstitial edema together with the absence of an efficient lymphatic system in tumor tissue, results in a remarkable reduction in the exchange of several substances with the bloodstream, including chemotherapeutics [53] This significant deposition of hyaluronan in pancreatic cancer stroma is one of the main features of pancreatic TME responsible for decreased chemotherapeutic penetration (Figure 1) [54,55]. While some reports have shown that total tissue hyaluronan content is not correlated with tissue elasticity and hydraulic conductivity [72], another study demonstrated that ECM molecular selectivity is regulated by variation of the hyaluronan content, affecting molecule penetration based on charge and size [73] In line with this second paper, the depletion of hyaluronan in a PC3 xenograft model decreased tumor interstitial fluid pressure and increased vascular area, suggesting that hyaluronan might have an important role in blocking the penetration of chemotherapeutic agents [74]. Regarding PDAC, more studies are needed to disclose whether hyaluronan content may have a role in tissue elasticity and mechanobiology of ECM, and how this can be correlated with drug perfusion and chemoresistance
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