Ectokinases as novel cancer markers and drug targets in cancer therapy

Abstract

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. We review emerging literature showing that the release of several ectokinases is significantly upregulated in body fluids from cancer patients and that they leave behind their unique signatures on extracellular matrix (ECM) proteins. 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. Targeting extracellular kinases or the extracellular signatures they leave behind might thus create novel opportunities in cancer diagnosis as well as new avenues to interfere with cancer progression and malignancy.

Keywords: Cancer marker; drug design; ectokinases; exokinases; extracellular matrix; extracellular phosphorylation; extracellular protein kinase; personalized medicine.

Figure 1

Extracellular enzymes in cancer. (A) To alter the extracellular matrix (ECM) biology of cancer, matrix metalloproteinases (MMPs) served as first extracellular drug targets. The hypothesis was that matrix metalloproteinases (MMP) inhibition can prevent the local degradation of ECM and thus the escape of metastatic stroma cells. (B) Vesicle secretion and cell necrosis transiently releases intracellular content high in kinases and ATP into the surrounding tissue as indicated by the graded plume. For a short time period, the ATP levels are sufficiently high for the kinases to be active in extracellular space leaving behind phosphorylated ECM. Ectokinases and phosphatases thus provide unique opportunities as novel extracellular drug targets.

Figure 2

Experimentally verified phosphorylation sites on fibronectin. Schematic representation of plasma fibronectin with modules type I (gray), type II (turquoise), and type III (orange). (A) Locations of various bacterial and cell binding sites on the fibronectin monomer. (B) Experimentally identified phosphorylation sites by mass spectrometry techniques as retrieved from protein data banks Phosida, PhosphoSitePlus, PhosphoNet, HPRD, dbPTM, and UniProt for human Fn (P02751). (C) Locations of protein binding sites on the fibronectin monomer with a special focus on matrix metalloproteinases (MMPs).

Figure 3

From tumor sites to the blood stream: ectokinases and phosphatases as cancer markers. Enhanced ectokinase and ectophosphatase secretion is seen in intact tumor cells as well as from dying necrotic cells. Blood samples from cancer patients have significantly enhanced ectokinase and ectophosphatase concentrations and activities and might thus serve as novel biomarkers. Several studies report higher selectivity and specificity of markers for early stage cancer detection.