Hyaluronic Acid Binding to TLR4 Promotes Proliferation and Blocks Apoptosis in Colon Cancer

Area of Science:

• Oncology
• Molecular Biology
• Immunology

Background:

• Hyaluronic acid (HA), an extracellular matrix component, promotes colorectal cancer (CRC) growth.
• CD44 is a known HA receptor, but HA also binds to Toll-like receptor 4 (TLR4), implicated in CRC.

Purpose of the Study:

• To investigate the distinct roles of HA binding to CD44 versus TLR4 in colon tumorigenesis.
• To evaluate the therapeutic potential of blocking HA-receptor interactions in CRC models.

Main Methods:

• Utilized Apc^Min/+ mice, azoxymethane/dextran sodium sulfate (AOM-DSS), and CT26 tumor isografts.
• Employed knockout mice and CRISPR-mediated knockdown of CD44 and TLR4 in CT26 cells.
• Modulated HA activity using PEP1 (HA binding inhibitor), hyaluronidase (degradation), and 4-MU (synthesis inhibitor).

Main Results:

• PEP1 blockade of HA binding significantly reduced tumor growth across all models and in vitro.
• CD44 deletion or TLR4 deletion reduced tumor burden and slowed tumor growth, with decreased proliferation and increased apoptosis.
• Endogenous HA was shown to inhibit lipopolysaccharide (LPS) binding to TLR4 in vitro.
• PEP1 treatment enhanced tumor radiation sensitivity in isograft models.

Conclusions:

• Both CD44 and TLR4 are critical receptors for HA's pro-tumorigenic effects in colorectal cancer.
• Targeting HA-receptor interactions, specifically with agents like PEP1, shows promise as an adjuvant therapy for colon cancer.