FIGURE 2 | Putative roles of human tissue kallikreins in tumour development.

a | Human tissue kallikrein 1 (hK1), hK2 and hK3 might stimulate the growth and survival of tumour cells by degrading insulin-like growth factor binding proteins (IGFBP2, 3, 4 and 5), thereby liberating the mitogenic growth factor insulin-like growth factor 1 (IGF1), which binds to its cell-surface receptor (IGF1R) and induces cell proliferation and prevents apoptosis. hK2 and hK4 also activate the urokinase plasminogen activator–urokinase plasminogen activator receptor (uPA–uPAR) system, leading to release and/or activation of latent growth factors from the extracellular matrix (ECM). hKs could directly stimulate tumour-cell growth through protease-activated receptors (PARs). Conversely, hK3 could also suppress tumour growth by releasing transforming growth factor- (TGF) from its latent complex, allowing it to bind to its receptor (TGFR). b | hKs might promote angiogenesis by independently cleaving structural components of the subendothelial basement membrane (BM) and ECM. hKs also participate in a pericellular proteolytic cascade in which they activate the uPA–uPAR system (leading to plasmin activation) and matrix metalloproteinases (MMPs) to further promote ECM degradation, facilitating endothelial invasion and migration. hK3 activates latent TGF and hK1 releases bradykinin from kininogen, stimulating the angiogenic response through the bradykinin receptor. hKs might be implicated in PAR signalling that induces endothelial-cell proliferation. Conversely, hK3, hK6 and hK13 might also inhibit angiogenesis by generating angiostatin-like fragments from plasminogen. c | hK3 could indirectly promote epithelial-to-mesenchymal transition (EMT) by liberating TGF from its latent complex. Other hKs might directly and indirectly regulate invasion by dissolution of ECM barriers. hKs could activate PAR signalling, which can have a stimulatory or inhibitory effect on tumour-cell invasion. d | hKs could promote the formation of osteoblastic bone metastases in prostate cancer. hK3 might be involved in the preferential adherence of prostate cancer cells to the bone-marrow endothelium. Prostate tumours produce hKs, TGF and IGF1, which directly stimulate osteoblastic activity and subsequent bone formation. hK3 activates latent TGF and releases IGFs from IGFBPs. hK3 also inactivates parathyroid-hormone-related protein (PTHrP), an osteoclastic stimulator. sc-uPA, single-chain uPA

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