The Tumor Stroma

The tumor stroma is the tumor-nourishing compartment of the tumor microenvironment (TME) responsible for tumor growth. Making up the tumor stroma are the nonmalignant constituents of the TME, including1-3:

  • Pericytes
  • Fibroblasts
  • Signaling molecules (eg, growth factors and other cytokines)
  • Structural elements, including hyaluronan (HA)

Dynamics of the tumor stroma

The tumor stroma is not static; rather, it is subject to change over the course of disease progression in response to cellular crosstalk.3 Changes to both stromal compartment composition and size can contribute to the role of the stroma in tumor progression.3 In cases of desmoplastic TMEs, the stroma can account for up to 90% of the tumor mass.1

One such transformative change in the tumor stroma occurs in the ECM, which provides structural support for the TME and plays a role in tumorigenesis and metastasis.4 The ECM is composed of3:

  • Structural components, such as collagen and HA
  • Tumor-promoting factors, such as TGF, FGF, and VEGF

Excess ECM deposition

Excess amounts of ECM components secreted by cancer-associated fibroblasts (CAFs) can promote disease progression.4,5 Excess ECM deposition is also a hallmark of desmoplasia, a highly fibrotic stroma that can lead to compromised vascular and lymphatic function as well as hypoxia.6-8

HA-rich stroma

Restructuring of the ECM can be associated with an abundance of the glycosaminoglycan HA, an important ECM component.3,5,9 In turn, high levels of HA in the TME can enhance tumorigenesis by recruiting and activating stromal cells. HA’s ability to recruit fibroblasts into the TME may also induce further changes to the stroma via increased synthesis of ECM components by CAFs, as this can increase rigidity of the extracellular space.9

Elevated HA levels can also impact the stroma as a result of HA’s hydrodynamic properties. The accumulation of HA and associated water molecules can cause swelling and increased tumor interstitial pressure.10 These changes can limit tumoral access by constricting blood vessels.10,11