Ectokinases as novel cancer markers and drug targets in cancer therapy.
Bottom Line: While small-molecule kinase inhibitors became the most prominent anticancer drugs, novel combinatorial strategies need to be developed as the fight against cancer is not yet won.Our analysis of proteomic data reveals that fibronectin is heavily phosphorylated in cancer tissues particularly within its growth factor binding sites and on domains that regulate fibrillogenesis.We are thus making the case that cancer is not only a disease of cells but also of the ECM.
Affiliation: Harvard Medical School/Harvard School of Dental Medicine, Department of Developmental Biology, Harvard University, Boston, Massachusetts, 02115; Laboratory of Applied Mechanobiology, Department of Health Sciences and Technology, ETH Zurich, Switzerland.Show MeSH
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Mentions: Postulating that massive necrosis might temporarily upregulate ectokinase activity in extracellular space, we recently mined published proteomic data and found a significant upregulation of phosphorylated residues in tissue samples from cancer patients 30. This included the phosphorylation of ECM proteins, as well as of cell surface and extracellular domains of transmembrane proteins. Screening more than 60 different extracellular proteins revealed that nearly all can occur in phosphorylated states 30. Most compelling was the finding that the integrin subunits α4 and β1, two key players in cancer progression and signaling, were found in tissue samples to be phosphorylated in their extracellular domains 30,42–44. Since fibronectin 45–47 which is a key component of the ECM is known to be highly upregulated in cancer 48–53, we further analyzed published proteomic data and found that fibronectin is indeed heavily phosphorylated in clinical cancer tissue samples (Fig.2, Table2). Heavily phosphorylated regions in fibronectin include and are associated with growth factor binding sites (FnIII4, FnIII13-14) and with domains that regulate fibronectin fibrillogenesis. This is an important finding since growth factor signaling and ECM fibrillogenesis are essential regulators in cancer malignancy and progression 22. In addition to fibronectin, elevated levels of phosphorylated fibrinogen A are found in the plasma from patients with stage III or IV ovarian cancer compared to healthy controls 54.
Affiliation: Harvard Medical School/Harvard School of Dental Medicine, Department of Developmental Biology, Harvard University, Boston, Massachusetts, 02115; Laboratory of Applied Mechanobiology, Department of Health Sciences and Technology, ETH Zurich, Switzerland.