Mammalian cells, including
cancer cells, are covered by a surface layer containing cell bound
proteoglycans,
glycoproteins, associated
glycosaminoglycans and bound
proteins that is commonly referred to as the glycocalyx. Solid
tumors also have a dynamic fluid microenvironment with elevated interstitial flow. In the present work we further investigate the hypothesis that interstitial flow is sensed by the
tumor glycocalyx leading to activation of cell motility and
metastasis. Using a highly metastatic
renal carcinoma cell line (SN12L1) and its low metastatic counterpart (SN12C) we demonstrate in vitro that the small molecule
Suberoylanilide Hydroxamic Acid (SAHA) inhibits the
heparan sulfate synthesis
enzyme N-deacetylase-N-sulfotransferase-1, reduces
heparan sulfate in the glycocalyx and suppresses SN12L1 motility in response to interstitial flow. SN12L1 cells implanted in the kidney
capsule of SCID mice formed large primary
tumors and metastasized to distant organs, but when treated with SAHA
metastases were not detected. In another set of experiments, the role of
hyaluronic acid was investigated.
Hyaluronan synthase 1, a critical
enzyme in the synthetic pathway for
hyaluronic acid, was knocked down in SN12L1 cells and in vitro experiments revealed inhibition of interstitial flow induced migration. Subsequently these cells were implanted in mouse kidneys and no distant
metastases were detected. These findings suggest new therapeutic approaches to the treatment of kidney
carcinoma metastasis.