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.

Thermomagnetic Resonance Effect of the Extremely Low Frequency Electromagnetic Field on Three-Dimensional Cancer Models

“…Pancreatic ductal adenocarcinoma is characterized by a desmoplastic hypoxic stroma that plays an important role in driving progression, metastasis and chemoresistance; it is believed that hypoxia can mediate chemotherapy resistance through mechanisms, such as extrinsic resistance, regulation of drug efflux, metabolic reprogramming, alterations in apoptosis and cell survival, and induction of stemness [ 15 ].…”

“…The existence of a dense tumor microenvironment (TME) may be the main reason why therapies specifically targeting only cancer-associated molecular pathways have not given satisfactory results [ 14 ]. Indeed, the TME of PDAC is characterized by abundant stroma, associated with areas of hypoxia with a significant reduction in oxygen tissue levels and acidic extracellular pH, a deficient blood supply, a reprogrammed metabolism and elevated immunosuppression [ 15 ]. Glioblastoma (GBM), the most common and aggressive central nervous system (CNS) malignancy with a 5-year overall survival of 5.6%, represents 47.7% of all primary malignant tumors of the CNS [ 16 ].…”

Next Generation of Cancer Drug Repurposing: Therapeutic Combination of Aspirin and Oseltamivir Phosphate Potentiates Gemcitabine to Disable Key Survival Pathways Critical for Pancreatic Cancer Progression

“…Cancer metabolic activity is significantly related to chemoresistance [40,41]. The specific metabolic alterations in cancer development may be a metabolic functional driver of tumor growth and progression, and as a result, dysregulated metabolic pathways have become attractive targets for cancer therapeutics [42].…”

Effects of TP53 Mutations and miRs on Immune Responses in the Tumor Microenvironment Important in Pancreatic Cancer Progression

“…TGF-β1 was determined to be a negative regulator of miR-29 in PSCs. It increased the expression of collagens, laminin and fibronectin, all components of the ECM [ 33 ]. Regulatory loops between TP53 and miR-29 exist, as TP53 can activate miR-29 expression and miR-29 can negatively regulate MDM2 expression, resulting in increased stability of TP53 [ 34 ].…”