SPINK1: a new therapeutic target in cancer?

The serine protease inhibitor Kazal type 1 (SPINK1) was initially isolated from bovine pancreas by Kazal and colleagues. A similar protease inhibitor was later identified in human pancreatic juice and called “pancreatic secretory trypsin inhibitor.” By means of immunologic techniques, SPINK1 was later identified as a tumor-associated peptide and isolated from the urine of a patient with ovarian cancer. Hence, it was called “tumor-associated trypsin inhibitor” (TATI) (1 ). This name has been used in most studies of its use as a tumor marker [reviewed in (2 )]. TATI was shown to be a serum and urine marker for many types of cancer, but it was not found to be superior to earlier known markers that had been identified for diagnostic use. It was an independent prognostic marker for several types of cancer, however. Tumors producing SPINK1 have been shown to also produce trypsin, and because trypsin activates matrix metalloproteinases, which have been shown to mediate cancer invasion, an association between SPINK1 production and an adverse prognosis in cancer was ascribed to its coproduction with trypsin. SPINK1 was thought to have a role in cancer similar to the one it has in the pancreas, where it protects the pancreas by inhibiting prematurely activated trypsin (2 ). Mechanisms by which SPINK1 could exert alternative functions were suggested by its structural similarities with epidermal growth factor (EGF): a 50% sequence homology, a molecular size of approximately 6 kDa, and the presence of 3 intrachain disulfide bridges (2 ). This similarity with EGF prompted studies on the ability of SPINK1 to act as a growth factor. In 1985, SPINK1 was shown to bind to surface receptors and to stimulate DNA synthesis in fibroblasts, but EGF and several other growth factors did not compete with SPINK1 for binding. Results supporting the role of SPINK1 as a growth factor have been obtained in several recent studies. SPINK1 has been identified as a tumor-promoting factor in studies of altered gene expression in prostate and breast cancer and by proteomic analysis of the spent medium of colon cancer cell lines (3–5 ). SPINK1 has been shown to be the major proinvasive factor produced by colon cancer cells. The long-term prognostic value of SPINK1 has further been demonstrated by findings of its production in tissues in studies of archival samples of prostate, hepatocellular, colon, and breast cancers (2–5 ). The role of SPINK1 in tumor growth has also been confirmed experimentally in tissue culture studies and by studies of tumor xenografts in immune-deficient mice. Recombinant SPINK1 increases the invasion in collagen gel by several colon cancer cell lines, but a SPINK1 mutant, SPINK1 K18Y, which does not inhibit trypsin, has no effect on invasion. Furthermore, an antibody to SPINK1 inhibits the invasiveness of HT29 5M21 cells (4 ). In patients with colorectal cancer, high serum concentrations of SPINK1 have been shown to indicate an adverse prognosis (2 ). A recent study by Ateeq et al. has focused attention on the role of SPINK1 and, potentially, its use as a target in the treatment of prostate cancer (3 ). SPINK1 is known to be produced in the prostate and in prostate cancer, and its production increases with a higher tumor grade (2 ). Strongly increased SPINK1 production is found in about 10% of all prostate cancers, and this feature is associated with an adverse prognosis. In surgically resected patients, increased SPINK1 production is inversely related to E26 transformation–specific (ETS) rearrangements, but that is not the case in endocrine-treated patients (2 ). Ateeq et al. investigated the mechanisms by which SPINK1 is associated with an adverse prognosis in prostate cancer (3 ). They showed that SPINK1 induces an aggressive phenotype of the prostate cancer cell line 22RV1. Knock-down of SPINK1 production reduced these effects, whereas forced production increased cell proliferation and invasiveness. Administration of a monoclonal antibody to SPINK1 reduced cell proliferation and the invasion and growth of SPINK1-producing 22RV1 tumor xenografts in mice. This inhibitory effect was enhanced by coadministration of EGF receptor (EGFR) antibodies (3 ). SPINK1 has been shown to exert its effect by binding to EGFRs, but other mechanisms could also be in1 Department of Clinical Chemistry, Helsinki University and Helsinki University Central Hospital, Helsinki, Finland. * Address correspondence to the author at: Department of Clinical Chemistry, Helsinki University and Helsinki University Central Hospital, FIN-00014 Helsinki University, PB 63, Finland. Fax 358-9-5054653; e-mail ulf-hakan. [email protected]. Received August 16, 2011; accepted August 17, 2011. Previously published online at DOI: 10.1373/clinchem.2011.168476 2 Nonstandard abbreviations: SPINK1, serine protease inhibitor Kazal type 1; TATI, tumor-associated trypsin inhibitor; EGF, epidermal growth factor; ETS, E26 transformation–specific; EGFR, EGF receptor. Clinical Chemistry 57:11 1474–1475 (2011) Perspectives