Explore the Tumor Microenvironment

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The tumor microenvironment is a rich, dynamic milieu around tumor cells that can serve as a tumorigenic space between the tumor and surrounding tissues.1,2

Tumor growth and the tumor microenvironment

The tumor microenvironment is a highly dynamic space—changing to serve the needs of the tumor over time. Within the tumor microenvironment, numerous biological processes are coordinated to promote tumorigenesis and metastasis, including3:

Tumor microenvironment composition

Communications between malignant and normal cells produce the complex tumor microenvironment, which is composed of a mixture of cellular and noncellular components4-6:

  • Cellular:
    • Immune cells
    • Pericytes
    • Fibroblasts
    • Vasculature
    • Lymphatics
  • Noncellular:
    • Signaling molecules (eg, growth factors and other cytokines)
    • Structural elements that make up the ECM, including hyaluronan (HA)

HA in the tumor microenvironment

HA is an important component of the tumor extracellular matrix, providing both a scaffolding for tumor-promoting molecules to crosslink and a viscous medium capable of sequestering growth factors and cytokines required for tumor cell survival.6-9 Furthermore, this gel-like framework may also hinder the ability of immune cells to reach tumor cells.6

HA also accumulates in the tumor microenvironment of numerous solid tumors, including:

  • Pancreatic ductal adenocarcinoma6,10
  • Gastric cancer6
  • Lung cancer7,11
  • Breast cancer7,11
HA is a polysaccharide composed of 2 repeating disaccharide subunits: glucuronic acid and N-acetylglucosamine.12

Functional roles of HA are dependent upon disease state, with different functions ascribed to HA during homeostasis versus disease progression.12

HOMEOSTASIS PATHOLOGICAL ACCUMULATION IN THE TUMOR MICROENVIRONMENT
Structural role
Interacts with water molecules to form a viscous, gel-like substance1,13,14
Structural role
Increased tumor interstitial pressure, compressed vasculature, and compromised delivery of anticancer therapeutics and immune cells6,13,14,16,17
Signaling role
Regulation of cell adhesion, motility, and proliferation via signaling through the receptor CD44 and the receptor for HA-mediated motility (RHAMM)9,15
Signaling role
Binding to CD44 has demonstrated activation of downstream signaling pathways mitogen-activated protein kinase (MAPK), Rac, and phosphoinositide 3-kinase (PI3K), which can play key roles in tumor cell survival and proliferation18,19