The Desmoplastic Barrier in Pancreatic Neoplasia: Established Roles in PDAC and Emerging Evidence in Pancreatic Neuroendocrine Neoplasms

Pancreatic ductal adenocarcinoma (PDAC) is defined by significant desmoplastic reaction composed of cancer-associated fibroblasts (CAFs), pancreatic stellate cells (PSCs), extracellular matrix (ECM), immune cells, and abnormal vascularization. This stromal compartment is by no means a passive fibrotic reaction; rather, it contributes to tumor progression and treatment resistance through physical and biological mechanisms. The accumulation and remodeling of collagen, hyaluronic acid, and other ECM components lead to tissue stiffness and increased tissue pressure, compress intratumoral vessels, impair blood flow, promote hypoxia, and limit homogeneous drug delivery. Simultaneously, heterogeneous CAF populations send out paracrine, metabolic, and immunomodulatory signals that can either promote or inhibit tumor growth. Such opposing features may contribute to the inconsistent or unfavorable outcomes observed in attempts to comprehensively reduce the PDAC stroma. Pancreatic neuroendocrine neoplasms (PanNENs), especially well-differentiated pancreatic neuroendocrine tumors (PanNETs), have typically been considered highly vascularized tumors with a relatively limited stromal component. New findings challenge this simplified view. In subgroups of clinically aggressive PanNETs, fibrosis, reduced microvascular density, and CAF-rich stromal phenotypes have been observed. Recent findings also suggest spatially organized interactions between CAFs and the tumor that may promote epithelial–mesenchymal plasticity, invasion, and metastasis. Nonetheless, it remains unknown whether fibrosis in PanNETs constitutes a mechanically relevant barrier to drug delivery comparable to that observed in PDAC. This mini-review explores the desmoplastic barrier in PDAC as a frame of reference, evaluates new findings on stromal and vascular remodeling in PanNETs, and underscores the need to define tumor-specific stromal and vascular phenotypes rather than assuming a common desmoplastic mechanism across all malignant pancreatic tumors.