Critical Review Maspin and Tumor Metastasis Emily I. Chen and John R. III Yates Department of Cell Biology, The Scripps Research Institute, California, USA Summary For most cancer cell types, the acquisition of metastatic activity leads to clinically incurable disease. Improvements in surgery and radiotherapy, and the development of new chemotherapeutic agents or their use in new combinations, have, so far, only incrementally improved patient survival. Despite the obvious importance of metastasis, the process remains incompletely characterized at the molecular and biochemical levels. Tumor metastasis is a complex process and requires multiple cellular functions over time. From cellular invasion, extravasation from the primary tumor, intravasa- tion to the secondary organs, to successful colonization, tumor cells utilize many cellular or biochemical mechanisms to complete the metastatic spread. During the process of metastasis, there are consistent changes in gene expression. Studies of genes that are reduced or silenced have yielded surprising insights into in vivo mechanisms of regulating tumor metastasis. This review describes a tumor suppressor gene, Maspin, which is often silenced in cancer cells and exhibits suppressing activity against tumor growth and metastasis. Maspin has been shown to be involved in processes that are important to both tumor growth and metastasis such as cell invasion, angiogenesis, and more recently apoptosis. Hence, many efforts have been devoted to deciphering the molecular mechanism of maspin. While some insights have come from the protease inhibitory effect of maspin, more perceptive results on how maspin may function in suppressing tumor metastasis have come from studies of gene manipulation, protein interactions and global protein profiling. IUBMB Life, 58: 25 – 29, 2006 Keywords Tumor metastasis; tumor suppressor gene; maspin. INTRODUCTION Maspin was discovered as a human mammary tumor suppressor in 1994 (1) and has been shown to exert tumor suppressing activity against breast tumor growth and meta- stasis (2). Maspin is present at high concentration in normal mammary myoepithelial cells. However, its expression is shown down-regulated in primary breast cancer cell lines and lost in invasive mammary carcinoma (1, 3, 4). The anti- tumor effects of maspin are not limited to mammary carcinoma, as similar observations have been made in prostate carcinoma (5), and maspin also appears to inhibit angiogenesis (6). Although the structure of maspin is no mystery, the mechanism by which it elicits its anti-tumor and anti- metastatic effects remains unclear. Initially, the investigation of maspin’s function focused on structure, but not until recently have studies pointed to possible functions beyond the structural clues. In fact, multi-cellular expression of maspin already hints at its complex roles in nature. MASPIN STRUCTURE AND FUNCTION Maspin (SERPINB5) is a member of the serine protease inhibitor superfamily (7), like plasminogen activator inhibitors 1 and 2 (PAI-1 and PAI-2), and a1-antitrypsin (8). The structural homology of maspin to serpins led to the initial hypothesis that its tumor suppressor function might be attributed to its ability to inhibit proteolysis. This idea is supported by the fact that maspin was reported to inhibit the activity of tissue-type plasminogen activator (tPA) (9). Furthermore, it was shown that maspin can mediate the inhibition of urokinase-type plasminogen activator (uPA) on the surface of prostate carcinoma cells (10). Despite the reported activity as a serine protease inhibitor, other studies argue that the inhibitory activity of maspin is subject to debate. For example, maspin fails to undergo a ‘stressed to relaxed’ conformational transition that is char- acteristic of virtually all inhibitory serpins (11). In addition, contradictory studies have shown that maspin lacks the ability to inhibit either tPA or uPA, two of its presumed targets (12). Although, maspin may lack the ability to inhibit serine proteases, its biological function can be attributed to the reactive loop (RCL). Recent study shows that substitution of maspin’s RCL into ovalbumin enables inding to a cell surface receptor that promotes cell adhesion to type I collagen and fibronectin (13). Additional information of the RCL of maspin Received 29 November 2005; accepted 19 December 2005 Address correspondence to: Emily I. Chen, Department of Cell Biology, SR-11, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA92037, USA. Tel: þ1 858 784 8876. Fax: þ1 858 784 8883. E-mail: emilyc@scripps.edu IUBMB Life, 58(1): 25 – 29, January 2006 ISSN 1521-6543 print/ISSN 1521-6551 online Ó 2006 IUBMB DOI: 10.1080/15216540500531721