Nikolaos A. Chatzizacharias

Focal adhesion kinase: a promising target for anticancer therapy

Focal adhesion kinase (FAK) is a protein tyrosine kinase acting as an early modulator of the integrin signalling cascade, thus regulating various basic cellular functions. In transformed cells, upregulation of FAK protein expression and uncontroled signalling were held responsible for the promotion of malignant phenotypic characteristics, as well as resistance to chemotherapy and radiotherapy. Direct FAK targeting resulted in the inhibition of the malignant phenotype of cancer cells, whereas increased apoptotic rates of cancer cells, either used alone or in combination with conventional chemotherapeutic agents, radiotherapy or hormonal therapy. Furthermore, drugs used in cancer chemotherapy, besides their basic mode of action, were also shown to act through altering FAK signalling. Finally, positive results were noted by the transfection of cancer cells with fak mutants or genes that suppress FAK expression or activity, such as phosphatase and tensin homolog deleted on chromosome Ten (PTEN), ribonucleotide reductase M1 polypeptide (RRM1) and melanoma differentiation-associated gene-7 (mda-7). The purpose of this article is a comprehensive review of the existing data on the possible use of FAK targeting in anticancer therapy.

Disruption of FAK signaling: A side mechanism in cytotoxicity

Focal adhesion kinase (FAK) is a non-receptor protein tyrosine kinase (PTK) which acts as an early modulator in the integrin signaling cascade. FAK phosphorylation and its consequent activation regulate several basic biological cellular functions. On the contrary, dysregulation of FAK signaling is implicated in the malignant transformation of cells, as well as in nonmalignant pathological conditions. With respect to cytotoxicity, accumulating data indicate that FAK participates in the mechanism of action of the known cytotoxic reactive oxygen species (ROS). Additionally, evidence was presented that different cytotoxic substances, such as arsenic (As), lead (Pb), acrylamide, methylisothiazolinone (MIT), dichlorovinylcysteine (DCVC) and halothane, acted, at least in part, by downregulating FAK tyrosine phosphorylation, while the bacterial toxins Pasteurella multocida toxin and Escherichia coli cytotoxic necrotizing factor, have been shown to exert cytotoxic effects by inducing FAK tyrosine phosphorylation. The observation that upregulation as well as downregulation of FAK activity both result in cytotoxic effects seems contradictory. Even though a common mode of action, with respect to the dysregulation of FAK signaling, for these cytotoxic substances has not yet been discovered, a cumulative approach could be established by focusing on FAK activation and signaling cascade. According to these data, interfering with FAK signaling might be of a potential use in blocking these cytotoxic effects. Further studies are needed on the possible implication of FAK in substance-induced cytotoxicity, as well as the possibility that such effects might be hindered or even blocked by restoring FAK signaling.

Evaluation of the clinical significance of focal adhesion kinase and SRC expression in human pancreatic ductal adenocarcinoma.

Objectives: Focal adhesion kinase (FAK) and Src, 2 protein tyrosine kinases, have been suggested to regulate several fundamental cellular activities that promote the malignant phenotype in various human tumors, including pancreatic adenocarcinoma. Even though research has already turned in laboratory investigations and clinical trials on the possible use of agents blocking the 2 enzymes in cancer management, the data on the clinical significance of FAK and Src in pancreatic adenocarcinoma are still scarce. Methods: The FAK and Src protein expression was assessed immunohistochemically in tumor specimens of 65 patients with pancreatic ductal adenocarcinoma and was statistically analyzed in relation to various clinicopathological characteristics, tumor proliferative capacity, and patients survival. Results: The FAK expression correlated significantly with the T stage of the tumor (P = 0.037), whereas FAK staining intensity with patients age (P = 0.030), tumors histopathological grade of differentiation (P = 0.041), and M stage (P = 0.029). The Src expression correlated significantly with the stage of the tumor (P = 0.013) and patients survival (log-rank test, P = 0.027), being also identified as an independent prognostic factor in multivariate analysis (P = 0.047). Furthermore, trends that did not reach statistical significance were noted between FAK and Src expression and staining intensity and several clinicopathological parameters. Conclusions: The FAK and Src immunohistochemical expression was associated with certain clinicopathological parameters that are crucial for the patients management.Abbreviations: AJCC - American Joint Committee on Cancer, FAs - focal adhesions, FAK - focal adhesion kinase, PBS - phosphate buffered saline, PTKs - protein tyrosine kinases, TNM - tumor, node, metastasis

Expression and Clinical Significance of FAK and Src Proteins in Human Endometrial Adenocarcinoma

Focal Adhesion Kinase (FAK) is a protein tyrosine kinase, localised in the focal adhesions, which, upon activation interacts with Src, another tyrosine kinase, regulating several cellular signalling pathways. Both enzymes have been implicated in malignant transformation and disease progression. The aim of the present study was to evaluate the clinical significance of FAK and Src expression in cases of endometrial adenocarcinoma. The total (t) and the activated, phosphorylated (p) forms of FAK and Src proteins were assessed immunohistochemically in tumour specimens obtained from 43 endometrial adenocarcinoma patients and were statistically analyzed in relation to various clinicopathological parameters and tumour proliferative capacity, reflected by Ki-67 labelling index. t-FAK positivity was significantly correlated with FIGO disease stage (pu2009=u20090.031), and t-FAK overexpression with patients’ age (pu2009=u20090.015). No statistically significant correlation was identified between t-FAK staining intensity, t-Src positivity, overexpression or staining intensity and any of the clinicopathological parameters tested. No significant correlation was found between neither the positivity nor the intensity of staining of either p-FAk or p-Src with any of the parameters under study. Nonetheless, important, but non-significant, trends were identified between t-FAK staining intensity, t-Src positivity and overexpression and patients’ survival (log rank, pu2009=u20090.122, pu2009=u20090.090 and pu2009=u20090.057 respectively). Similarly, p-FAK and p-Src staining characteristics seemed to correlate, even though non-significantly, with patients’ survival (log rank, pu2009=u20090.051 and pu2009=u20090.070 for p-FAK and p-Src expression, respectively; log rank, pu2009=u20090.134 and pu2009=u20090.110 for p-FAK and p-Src staining intensity, respectively). These results support an important potential role of FAK-Src signalling in endometrial malignant disease progress and render further research in this field a necessity.

The role of ephrins' receptors and ephrins' ligands in normal placental development and disease

Introduction: Ephrin (Eph) receptors and their membrane-anchored ligands, the ephrins, participate in a wide spectrum of pathophysiological processes, regulating cellular adhesion, migration or chemo-repulsion and tissue/cell boundary formation. Recent evidence has further extended the role of Eph receptors and their ligands as critical regulators of vascular remodelling during embryogenesis. The role of Ephs/ephrins signalling in the angiogenic development of murine placentas and in the invasion of the maternal tissues and the development of the placental vasculature in humans has currently attracted considerable interest. Areas covered: A literature review summarising the most recent data in terms of the role of Ephs/ephrins in normal placental development and disease, highlighting on their expression status in the different cellular populations of the placental vascularity. Expert opinion: Despite the fact that the role of Eph/ephrins signalling in normal placental development is still unclear, some studies tried to investigate their potential implication in placental pathologies, such as preeclampsia and placenta accreta. Even though no evidence for their direct implication occurred, their role is an interesting field for future research.