Hyal2 Expression in Tumor-Associated Myeloid Cells Mediates Cancer-Related Inflammation in Bladder Cancer

Area of Science:

• Oncology
• Immunology
• Biochemistry

Background:

• Myeloid-derived suppressor cells (MDSC) and tumor-associated macrophages (TAM) are prevalent in tumors.
• The role of these myeloid cells in hyaluronan (HA) metabolism within the tumor microenvironment remains unclear.

Purpose of the Study:

• To investigate the function of tumor-associated myeloid cells in regulating HA metabolism in human bladder cancer.
• To identify the mechanisms and consequences of HA fragmentation in the tumor microenvironment.

Main Methods:

• Analysis of HA fragments and myeloid cell populations (Hyal2+, CD11b+, CD33+) in bladder cancer tissue and blood.
• Investigation of Hyal2 activity regulation by tumor-conditioned medium and cytokines (IL1β).
• Assessment of CD44-mediated signaling in Hyal2-expressing myeloid cells.

Main Results:

• Tumor-associated myeloid cells enhance extracellular HA breakdown, producing low molecular weight HA (LMW-HA) fragments (<20 kDa).
• LMW-HA accumulation correlates with increased inflammatory cytokines, chemokines, and angiogenic factors.
• Hyaluronidase 2 (Hyal2) mediates HA fragmentation by Hyal2+CD11b+ myeloid cells, identified as monocytic MDSCs.
• IL1β stimulates Hyal2 activity, and CD44 signaling regulates Hyal2 translocation and IL1β secretion.

Conclusions:

• Hyal2-expressing myeloid cells are key drivers of LMW-HA accumulation in bladder cancer.
• This process contributes to cancer-related inflammation and angiogenesis.
• Targeting Hyal2 or CD44 signaling may offer therapeutic strategies for bladder cancer.