A novel role of low molecular weight hyaluronan in breast cancer metastasis.

Low molecular weight hyaluronan (LMW-HA), a degradation fragment of the extracellular matrix component hyaluronan (HA), has been proven to play a crucial role in cancer progression. However, no systematic clinical study of breast cancer has been performed to correlate LMW-HA levels with metastasis. In the present study, we analyzed 176 serum specimens and found for the first time that the serum LMW-HA (but not total HA) level significantly correlated with lymph node metastasis, suggesting that serum LMW-HA represents a better prognostic indicator of breast cancer progression than HA. Similarly, we found that breast cancer cell lines displaying higher invasive potential had a higher LMW-HA concentration than less-invasive cell lines. This higher LMW-HA level was accompanied by the overexpression of hyaluronan synthase (HAS2) and hyaluronidase (both HYAL1 and HYAL2). Of great importance, decreasing LMW-HA production significantly inhibited breast cancer cell migration and invasion. Overall, our results suggest that during cancer progression, cancer cells may actively remodel their microenvironment via an autocrine/paracrine-like process, resulting in elevated LMW-HA levels, which in turn may facilitate cancer progression by promoting the migration and invasion of cancer cells. Therefore, cancer-associated LMW-HA may be a more promising molecular biomarker than total HA for detecting metastasis and may have further applications in breast cancer treatment.