Poster Presentation 14th International Biennial Conference on Metastasis Research 2012

Degradation products of hyaluronan produced in the context of tumors are novel regulators of lymphangiogenesis (#195)

Jonathan P Sleeman 1 2 , Anja Schmaus 2 , Jochen Bauer 2 , Melanie Rothley 1 , David Jackson 3 , Wilko Thiele 1 2
  1. University of Heidelberg, Mannheim, Baden, Germany
  2. Institute of Toxicology and Genetics, KIT, Karlsruhe, Baden, Germany
  3. University of Oxford, Oxford, Oxfordshire, United Kingdom

Tumor lymphatics attract increasing interest as a possible target for cancer therapy. During the formation of metastases, lymphatics serve as a conduit for disseminating tumor cells. The first metastases often form in regional lymph nodes and they are highly clinically significant for the prognostic evaluation of different types of tumors. Thus, it is important to understand how tumors interact with the lymphatic vasculature. A molecule involved in cancer progression is the extracellular matrix component hyaluronic acid. It exists as a high molecular weight polymer which can be degraded progressively in the tumor context by hyaluronidases or by reactive oxygen species. The resulting small fragments of HA (sHA) are highly bioactive molecules. In contrast to high molecular weight HA (HMW HA), for example, sHA can potently induce angiogenesis. Here we show that sHA is also a novel regulator of lymphangiogenesis. Low concentrations of sHA increase the proliferation rate of primary lymphatic endothelial and act additively with VEGF-C and FGF-2. In addition, sHA promotes outgrowth of lymphatic capillaries in ex-vivo lymphangiogenesis assays. The sHA induced lymphangiogenesis is dependent on Lyve-1, a hyaluronan receptor that is widely used as a marker of lymphatic endothelial cells. In contrast to this, we observed that high sHA concentrations inhibit lymphangiogenesis. This anti-proliferative effect is mediated by TGF‑β, an inhibitor of lymphangiogenesis. Together, these results show that sHA regulated lymphangiogenesis is highly concentration dependent. In order to determine the pathophysiological sHA concentrations in the context of tumors we established a novel method that allows analysis of sHA levels in interstitial fluid derived from tumor samples. In tumor interstitial fluid from syngeneic rodent tumors and human colorectal tumors, most of the HA content is HMW HA. However, interstitial fluid from some tumors also contains sHA concentrations in the pro-lymphangiogenic range. These results suggest that tumor-produced sHA may contribute to lymphangiogenesis and metastasis. To provide functional data to support this conclusion, we have begun to investigate the role of hyaluronidases in sHA production in tumors and their significance for metastasis. Among different expressed hyaluronidases, Hyal1 is the prime suspect for being responsible for sHA production, but functional evidence for a role in metastasis is lacking. We found that manipulation of the expression of Hyal1 is not sufficient to influence sHA levels in tumor interstitial fluid but nevertheless promoted metastasis formation. These results allow novel conclusions concerning the function of Hyal1 in the context of tumors to be made.