Pancreatic Cancer: The Role of Pancreatic Stellate Cells in Tumor Progression

Abstract

Pancreatic ductal adenocarcinoma is an aggressive and highly lethal disease frequently characterized by a dense stromal or desmoplastic response. Accumulating evidence exists that tumor desmoplasia plays a central role in disease progression and that e.g. activated pancreatic stellate cells (PSCs) are responsible for the excess matrix production. The mechanisms underlying the tumor versus stroma interplay are complex. Pancreatic cancer cells release mitogenic and fibrogenic stimulants, such as transforming growth factor β₁, platelet-derived growth factor (PDGF), sonic hedgehog, galectin 3, endothelin 1 and serine protease inhibitor nexin 2, all of which may promote the activated PSC phenotype. Stellate cells in turn secrete various factors, including PDGF, stromal-derived factor 1, epidermal growth factor, insulin-like growth factor 1, fibroblast growth factor, secreted protein acidic and rich in cysteine, matrix metalloproteinases, small leucine-rich proteoglycans, periostin and collagen type I that mediate effects on tumor growth, invasion, metastasis and resistance to chemotherapy. This review intends to shed light on the mechanisms by which PSCs in the stroma influence pancreatic cancer development. The increased understanding of this interaction will be of potential value in designing new modalities of targeted therapy.

The Importance of Controlling the TGF-β Signaling Pathway in the Gastric Cancer Microenvironment

“…CAFs secrete factors such as EGF, IGF-1, PDGF, FGF, MMP, and type I collagen that favor malignant progression [49][50][51], which lead to the deposition of the ECM, the promotion of angiogenesis and the EMT, and the enhancement of proliferation, immunotolerance, and resistance to chemotherapy (Figure 2) [52,53]. These CAF functions play important roles in cancer progression and promote tumor cell invasion and metastasis.…”

Exosomes: Navigating a New Route in Pancreatic Cancer

“…Activated PSCs play key roles in the development of a fibrotic pancreatic stroma by increasing the synthesis of extracellular matrix proteins, such as collagen and enzymes responsible for matrix remodeling. Furthermore, several factors secreted from PSCs, such as platelet-derived growth factor (PDGF), galectin-1, stromal-derived factor 1, epidermal growth factor, insulinlike growth factor 1, and fibroblast growth factor, contribute to the increased invasiveness and proliferation of PDAC cells in vitro and in vivo [45,46]. PSCs have been shown to promote epithelial-tomesenchymal transition (EMT) [47,48] and a stem cell-like phenotype in pancreatic cancer cells [49], which are key features in enhancing tumorigenicity, cell migration, and resistance to chemotherapy.…”

Pancreatic Cancer Fostered Immunosuppression Privileges Tumor Growth and Progression

“…Based on the composition of the immune infiltrates surrounding PanINs, it has been shown that the stromal constituents surrounding PanINs form an inflammatory and immune suppressive environment thereby allowing the precursor lesions to escape immune surveillance [136]. The main pancreatic cancer-associated stromal fibroblasts, PSCs, are key players in the development of desmoplasia [137], and predominantly secrete gelatinases (MMP2, MMP9), which degrade the basement membrane collagen (type IV) and are associated with inflammation, fibrosis, angiogenesis, and cancer invasion. In various cancers including PDAC, basement membrane breaching, a critical step in cancer progression, brings malignant cells into direct contact with ECM proteins such as collagen type-1, thus supporting their growth, contributing to their chemo-resistance, and paving the way for invasion and metastasis.…”