Accumulation in the Tumor Microenvironment

Accumulation of hyaluronan (HA) in the tumor microenvironment (TME) has been reported in a number of solid tumors, including:

  • Pancreatic cancer1,2
  • Gastric cancer1
  • Lung cancer3,4
  • Breast cancer3,4

Furthermore, in these and other cancers, elevated tumor HA levels serve as an indicator for poor survival.1,2,5-11

Effects of HA accumulation

The accumulation of HA and associated water molecules in the TME can cause swelling and increased tumor interstitial pressure.12 These changes can limit tumoral access by constricting blood vessels.12,13 The HA gel-like barrier may also hinder the ability of immune cells to reach cancer cells.1

Potential impact of HA accumulation

  • Increased tumor interstitial pressure1,12,14
  • Constricted vasculature12,15
  • Reduced tumoral access for anticancer therapeutics and immune cells14,16
  • Hypoxia12,17
  • Tumor cell proliferation, invasion, and metastasis3,18
  • Poor survival1,2,5-11
HA—an unbranched, negatively charged disaccharide polymer—has hydrodynamic properties.13

Tumor-promoting interactions in the TME

While biophysical properties of HA can contribute toward tumorigenesis, malignancy can also be promoted via signaling through cell surface receptors.13 High levels of HA in the TME can also enhance tumorigenesis by recruiting and activating stromal cells.4

For example, binding of HA to the CD44 receptor activates downstream signaling pathways that can play key roles in tumor cell survival and proliferation, such as19:

  • Mitogen-activated protein kinase (MAPK)
  • Rac
  • Phosphoinositide 3-kinase (PI3K)

Mechanism of HA accumulation

The balance of synthesis and degradation of HA is regulated via homeostatic mechanisms.19,20 HA can be synthesized by both stromal and malignant cells.4 Synthesis can result in HA binding at the cell surface or accumulating in the extracellular space of the TME.13

The accumulation of HA in the TME may be attributable to:

  • Increased expression of HA synthase19,20
  • Dysregulation of hyaluronidase enzymes1