Tumor Stroma as a Therapeutic Target for Pancreatic Ductal Adenocarcinoma

Abstract

Pancreatic ductal adenocarcinoma (PDAC) has a poor prognosis owing to its desmoplastic stroma. Therefore, therapeutic strategies targeting this tumor stroma should be developed. In this study, we describe the heterogeneity of cancer-associated fibroblasts (CAFs) and their diverse roles in the progression, immune evasion, and resistance to treatment of PDAC. We subclassified the spatial distribution and functional activity of CAFs to highlight their effects on prognosis and drug delivery. Extracellular matrix components such as collagen and hyaluronan are described for their roles in tumor behavior and treatment outcomes, implying their potential as therapeutic targets. We also discussed the roles of extracellular matrix (ECM) including matrix metalloproteinases and tissue inhibitors in PDAC progression. Finally, we explored the role of the adaptive and innate immune systems in shaping the PDAC microenvironment and potential therapeutic strategies, with a focus on immune cell subsets, cytokines, and immunosuppressive mechanisms. These insights provide a comprehensive understanding of PDAC and pave the way for the development of prognostic markers and therapeutic interventions.

Keywords: Cancer-associated fibroblast; Extracellular matrix; Immune cells; Pancreatic cancer; Stroma.

Fig. 1

The influence of cancer-associated fibroblasts (CAFs) on the principal hallmarks of PDAC. Through dynamic interactions with the tumor stroma microenvironment, CAFs assimilate physiological roles that fundamentally influence the principal hallmarks of PDAC.

Fig. 2

Heterogeneity of cancer-associated fibroblast (CAFs) and ECM remodeling in PDAC. Pancreatic stellate cells (PSCs) and other resident tissue fibroblasts are the primary progenitors of CAFs in PDAC, and mesothelial cells, adipocytes and bone marrow-derived macrophages transform into CAFs. Epithelial and endothelial cells are also identified as potential sources of CAFs that are recruited and transformed in the tumor microenvironment. Based on the subtype of CAFs, they generally include myofibroblast CAFs, inflammatory CAFs and antigen-presenting CAFs. The ECM of PDAC is particularly dense and contributes to its desmoplastic response. It’s composed of collagen, proteoglycans, laminin, and fibronectin, etc.

Fig. 3

Cancer-associated fibroblasts (CAFs) interact with immune cells. CAFs secrete ECM components and contribute to the fibrotic tumor microenvironment. Cancer cytokines such as TGF-β, IL-1β and CXCL13 play a critical role in the activation of CAFs. Once activated, CAFs promote cancer cell growth by releasing factors that support tumor development. PDAC has dysfunctional T cells with decreased levels of CD3⁺, CD4⁺ and NK cells and increased levels of regulatory T cells. In addition to recruiting and regulating immunosuppressive cells, CAFs also interfere with the anti-tumor functions of CD8⁺ T cells.