The tumor microenvironment (TME) of certain difficult-to-treat cancers, including pancreatic and gastric cancers, is often characterized by desmoplasia, a highly fibrotic environment that can limit drug delivery and efficacy.1-3

Desmoplasia and excess extracellular matrix deposition

Excess extracellular matrix (ECM) deposition is a hallmark of desmoplasia.4 Cell-mediated signaling may increase the synthesis of fibrotic proteins, hyaluronan (HA), and proteoglycans that comprise the ECM, thereby leading to the desmoplastic environment that can result in compromised vascular and lymphatic function as well as hypoxia.2,3

HA accumulation and desmoplasia

One ECM component that can be elevated in desmoplastic TMEs is the glycosaminoglycan HA, which is frequently observed in pancreatic ductal adenocarcinoma.2 In these HA-rich environments, HA can contribute to increased tumor interstitial pressure.5 This can limit tumoral access by constricting blood vessels.6,7 High interstitial pressure can also lead to hypoxia and serves as a physical barrier that can prevent penetration of anticancer therapies.3,7

Increased deposition of ECM components can lead to vascular and lymphatic dysfunction observed in desmoplasia.3

Features of desmoplasia3,8

  • Dense ECM
  • Increased tumor interstitial pressure
  • Vascular compression
  • Reduced perfusion
  • Hypoxia
  • Immunosuppression
  • Tumor promotion