Pancreatic cancer tumor microenvironment is a major therapeutic barrier and target

Abstract

Pancreatic Ductal Adenocarcinoma (PDAC) is projected to become the 2nd leading cause of cancer-related deaths in the United States. Limitations in early detection and treatment barriers contribute to the lack of substantial success in the treatment of this challenging-to-treat malignancy. Desmoplasia is the hallmark of PDAC microenvironment that creates a physical and immunologic barrier. Stromal support cells and immunomodulatory cells face aberrant signaling by pancreatic cancer cells that shifts the complex balance of proper repair mechanisms into a state of dysregulation. The product of this dysregulation is the desmoplastic environment that encases the malignant cells leading to a dense, hypoxic environment that promotes further tumorigenesis, provides innate systemic resistance, and suppresses anti-tumor immune invasion. This desmoplastic environment combined with the immunoregulatory events that allow it to persist serve as the primary focus of this review. The physical barrier and immune counterbalance in the tumor microenvironment (TME) make PDAC an immunologically cold tumor. To convert PDAC into an immunologically hot tumor, tumor microenvironment could be considered alongside the tumor cells. We discuss the complex network of microenvironment molecular and cellular composition and explore how they can be targeted to overcome immuno-therapeutic challenges.

Pancreatic Cancer and Venous Thromboembolism

“…Notably, PDAC is commonly characterized by numerous and severe hypoxic regions, with a median tissue partial oxygen pressure (pO2) of 0–5.3 mmHg (0–0.7%) compared to the adjacent normal pancreas pO2 at 24.3–92.7 mmHg (3.2–12.3%) [ 58 ]. One hallmark of PDAC tumors is the presence of desmoplastic fibrotic stroma that creates a physical and immunological barrier and promotes hypoxia and tumor progression [ 2 ]. Hypoxia is considered as one of the independent prognostic factors for PC [ 59 ].…”

“…Pancreatic ductal adenocarcinoma (PDAC) is currently the fourth leading cause of cancer-related deaths in the United States [ 1 , 2 ]. It is projected that, by 2030, it will become the second leading cause of cancer-related deaths [ 3 ].…”

Targeted Therapy for Highly Desmoplastic and Immunosuppressive Tumor Microenvironment of Pancreatic Ductal Adenocarcinoma

“…One of the reasons for failed therapeutic intervention in PDAC is the prominence of a stromal microenvironment with striking cellular and material heterogeneity, which constitutes a mechanical barrier that impedes successful drug delivery [3]. Consequent to desmoplasia, immunomodulatory cells and stromal support cells are incessantly challenged by the aberrant signaling of pancreatic cancer cells, leading to a hypoxic tumor microenvironment (TME), ECM deposition, the suppression of antitumor immunity, and the advancement of tumorigenesis [4]. These counterbalances in immune and cellular architectures underline the highly resistant TME of PDAC.…”