Trends in Molecular Medicine
ReviewPEDF: a potential molecular therapeutic target with multiple anti-cancer activities
Section snippets
PEDF – a pluripotent molecule with therapeutic potential
Substantial progress has been made over the past few decades in understanding the various mechanisms that are involved in tumorigenesis and metastasis [1]. With this ever-growing knowledge comes the prospect of numerous novel strategies to counteract the development and progression of cancer. However, the so-called ‘magic bullet’ still eludes researchers, as it is becoming more apparent that a multidimensional approach to targeted anti-cancer therapy is required 2, 3. Of the various factors
Anti-cancer therapy – the need for a more-targeted approach
It is undeniable that considerable strides have been made in improving the overall long-term survival of patients suffering from cancer. This can be attributed to substantial advances in cancer detection, imaging and surgical resection, more-precise radiotherapy and effective neo/adjuvant chemotherapy. However, despite these improvements, for many malignancies there are still many patients that, even after aggressive conventional treatment, present with a poor long-term prognosis. Such is the
PEDF – more than meets the eye
PEDF is a 50-kDa secreted glycoprotein that is a non-inhibitory member of the serpin (serine protease inhibitor) superfamily of proteins, and its gene (SERPINF1) is located on chromosome 17p13 19, 20. The role of PEDF in the human body is still unclear and, in some cases, controversial. PEDF seems to be widely expressed throughout foetal and adult tissues, including the adult brain [21] and spinal cord [22], eye [6], liver [23], plasma [24], bone [25], heart and lung [26]. However, it is
PEDF – a potent inhibitor of tumour angiogenesis
The role of angiogenesis in tumour development, growth and metastasis has been the focus of extensive research over the past three decades [35]. Angiogenesis, the process by which new blood vessels develop from pre-existing ones, is an essential step that enables tumours to gain their own sustainable blood supply, therefore supporting further growth and metastatic potential. Hence, the prospect of inhibiting neovascular formation, by either causing EC death or targeting pro-angiogenic signals,
Anti-proliferative effects of PEDF
In addition to its potent anti-angiogenic activity, PEDF also has the ability to induce tumour-cell apoptosis directly. This activity is likely to be due to a distinct functional epitope on the PEDF protein, which was discovered by Filleur et al. [13], who showed reduced prostate-tumour proliferation in vitro with the 34-mer peptide sequence, but not with the 44-mer. Further studies in human melanoma cells (G361 [48]) and human osteosarcoma cells (MG63 [46]) demonstrated significant reduction
Therapeutic strategies and delivery
The interest in the field of protein- and peptide-based therapeutics has been renewed with the advent of proteomics. Hand in hand with genomics, proteomics has fuelled a renewed desire amongst researchers and, importantly, by big pharmaceuticals for research and development of peptidic drug candidates. Proteins and peptides are increasingly being recognized as worthwhile leads for the development of new therapeutics for a broad spectrum of diseases. Their usually specific mode of action
Summary and future directions
PEDF is a unique endogenously produced multifunctional protein that can target tumours through various destructive pathways, resulting in anti-proliferation, anti-angiogenesis and pro-differentiation. However, further research is required to elucidate the various mechanisms and interactions through which PEDF exerts such different biological responses (Box 1). Because PEDF is a molecule that is widely expressed in the body, it seems unlikely that its therapeutic administration elicits major
Acknowledgements
The authors acknowledge the generous support of the Australian Orthopaedic Association, the Victorian Orthopaedic Research Trust Grant and the Cancer Council of Victoria. Eugene T.H. Ek is supported by scholarships awarded by the University of Melbourne, the Royal Australasian College of Surgeons, and the National Health and Medical Research Council of Australia (NH and MRC).
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2016, Journal of Inorganic BiochemistryCitation Excerpt :These results are consistent with previous studies, which showed that phosphaplatins induced downregulation of VEGFR-2 and its ligands (VEGF-A, VEGF-C) in A2780 ovarian cancer cells [50]. A decrease in Akt-1 has been shown to interfere with the transmission of growth-promoting signals [51,52] and an increase in PEDF has been strongly implicated in anti-angiogenesis [53–55]. For comparison, PCR analysis of the cisplatin-treated cells showed only upregulation of VEGF-A (+ 1.3 ×) and downregulation of Akt-1 (− 2.4 ×) but statistical insignificant differences in VEGF-C, VEGFR-2, and PEDF levels.
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