The emerging roles of human tissue kallikreins in cancer

Top Cited Papers
Publisher Website
Google Scholar
Abstract
Human tissue kallikreins (hKs) comprise a subgroup of 15 homologous secreted trypsin or chymotrypsin-like serine proteases, encoded by a tightly clustered multigene family on chromosome 19q13.4. KLK transcription is modulated by an assortment of stimulatory and inhibitory factors, among which steroid hormones are the best characterized. The proteolytic activity of hKs is regulated in several ways, including zymogen activation; complex formation with endogenous plasma and/or tissue inhibitors, such as α2-macroglobulin and serpins; inhibition by inorganic ions; and inactivation through internal (auto)fragmentation. hKs are primarily expressed within the glandular epithelia of many organs and implicated in a range of normal physiological functions. New proteomic technologies could facilitate the identification of putative in vivo substrates and/or the substrate specificity for many of the newer, relatively uncharacterized hKs. Kallikrein genes/proteins are aberrantly expressed in many cancer types and their expression is often associated with patient prognosis. So far, experimental evidence indicates that hKs might promote or inhibit cancer-cell growth, angiogenesis, invasion and metastasis by proteolytic processing of growth-factor-binding proteins, activation of growth factors and other proteases, release of angiogenic or anti-angiogenic factors, and degradation of extracellular-matrix components. hKs are also implicated in the development of osteoblastic bone metastasis in prostate cancer. The initial claim to fame of hKs is mainly attributed to the clinical impact of prostate-specific antigen as a biomarker for screening, diagnosis, staging and monitoring of prostate cancer. Recent reports indicate that many other kallikrein genes/proteins might prove to be promising tissue and/or serological cancer markers. Exploitation and modulation of hK protease activity are attractive therapeutic approaches. hKs have been used in the activation of prodrugs and in the development of cancer vaccines, whereas hK promoters have been used for the specific delivery of toxic genes to tumour cells. Highly specific inhibitors of hK activity have also been developed and might represent promising agents for cancer treatment.