Multifaced roles of desmoplastic reaction and fibrosis in pancreatic cancer progression: Current understanding and future directions

Abstract

Desmoplastic reaction is a fibrosis reaction that is characterized by a large amount of dense extracellular matrix (ECM) and dense fibrous stroma. Fibrotic stroma around the tumor has several different components, including myofibroblasts, collagen, and other ECM molecules. This stromal reaction is a natural response to the tissue injury process, and fibrosis formation is a key factor in pancreatic cancer development. The fibrotic stroma of pancreatic cancer is associated with tumor progression, metastasis, and poor prognosis. Reportedly, multiple processes are involved in fibrosis, which is largely associated with the upregulation of various cytokines, chemokines, matrix metalloproteinases, and other growth factors that promote tumor growth and metastasis. Fibrosis is also associated with immunosuppressive cell recruitment, such as regulatory T cells (Tregs) with suppressing function to antitumor immunity. Further, dense fibrosis restricts the flow of nutrients and oxygen to the tumor cells, which can contribute to drug resistance. Furthermore, the dense collagen matrix can act as a physical barrier to block the entry of drugs into the tumor, thereby further contributing to drug resistance. Thus, understanding the mechanism of desmoplastic reaction and fibrosis in pancreatic cancer will open an avenue to innovative medicine and improve the prognosis of patients suffering from this disease.

Keywords: cancer; desmoplastic reaction; fibroblasts; fibrosis; pancreas.

FIGURE 1

Desmoplastic reaction is a phenomenon seen in many cancers, including pancreatic cancer, and it occurs when the tumor invades the surrounding tissues, inducing an inflammatory response that causes fibrosis and scar tissue formation. This reaction is believed to be responsible for limiting tumor spread, but dense scar tissue can limit the effectiveness of chemotherapy and radiation therapy.

FIGURE 2

The process of demyelination and fibrosis is governed by multiple factors, including (1) inflammation, (2) growth factors such as fibroblast growth factors (FGFs), transforming growth factor beta (TGFB), hepatocyte growth factor (HGF), and platelet‐derived growth factor (PDGF), (3) cytokines such as tumor necrosis factor alpha (TNF‐α and interleukin‐1 (IL‐1), (4) oxidative stress, and (5) matrix metalloproteinases (MMPs).

FIGURE 3

Desmoplastic reaction results in increased deposition of extracellular matrix components such as collagen, fibronectin, and laminin. The process by which tumor cells secrete a variety of cytokines and growth factors, leading to increased fibrosis, is called epithelial‐mesenchymal transition (EMT) and causes an increased risk of metastasis.

FIGURE 4

Fibrosis regulatory T cell (Tregs) are involved in suppressing fibrosis in pancreatic cancer and may play a role in reducing inflammation and metastasis of pancreatic cancer cells.