DECIPHERING THE ROLE OF ADAMTS5 IN ANGIOGENESIS AND CANCER

Abstract

ADAMTS5 is a member of A Disintegrin-like and Metalloproteinase with ThromboSpondin Motifs (ADAMTS) family of secreted metalloproteinases with multiple proteoglycan substrates. Although ADAMTS5 is well characterized as the major aggrecanase, how it influences angiogenesis and cancer remains unclear. Our lab has previously shown that the first thrombospondin type 1 repeat (TSR1, the central TSR) but not TSR2 (the C-terminal TSR) of ADAMTS5 is anti-angiogenic in vitro. Coupled with prior reports that ADAMTS5 expression is altered in several human cancers, we hypothesized that this proteoglycanase may play an important role in angiogenesis and cancer. ADAMTS5 and its autocatalytic N-terminal fragment inhibit angiogenesis in vitro. Stable overexpression of ADAMTS5 suppressed subcutaneous mouse melanoma and human lung adenocarcinoma growth in mice. The reduced tumor growth is primarily a result of diminished tumor angiogenesis, decreased tumor cell proliferation and increased tumor cell apoptosis. Domain mapping and mechanistic studies revealed that the anti-tumorigenic function of ADAMTS5 is independent of its catalytic activity and is mediated through its TSR1 domain by suppressing tumor angiogenesis likely by down-regulating pro-angiogenic factors in the tumor milieu. In addition, overexpression of ADAMTS5 or its catalytically inactive mutant also suppressed mouse melanoma metastasis to lung. In summary, this work identified a previously un-realized function of ADAMTS5 as an anti-angiogenic, anti-tumorigenic and anti-metastatic protein independent of its proteoglycanase function.