New molecular targets (ARF GTPases) can improve early diagnosis of prostate cancer and prediction of its progression

springplusProstate cancer (PCa) is the most common cancer in men (excluding non melanoma skin cancer) in the UK with over 40,000 cases diagnosed each year (CancerResearchUK [2015]). However, for some men with early stage PCa that is confined to the prostate the disease may never be life threatening and can follow and indolent course which does not require urgent or invasive treatment. Unfortunately prostate specific antigen levels (PSA), Gleason score and clinical and pathological grading used to diagnose and grade PCa lack the specificity or sensitivity to distinguish between patients with indolent PCa and those requiring radical treatment. Changes in PSA can precede clinical disease progression by months or years. Thus the question of when to start therapy in PCa patients can be problematic. This poses a significant problem for clinicians when deciding the best treatment for their patients. There is, therefore, the clear need for a better understanding of the mechanisms involved in the development, progression and metastasis of prostate cancer. Key molecular targets need to be identified that discriminate normal tissue from benign tumours and benign tumours from aggressive disease and which could also function as targets of inhibition for future cancer therapeutics.

Adenosine diphosphate-ribosylation factors (ARFs) are a family of Ras-related GTP binding proteins. (Li et al. [2009]). Out of the ARF GTPases, ARF 6 in particular, has received much attention; ARF6 functions are concerned with actin cytoskeletal remodelling, cell polarity and cell migration and thus may have an important role in driving carcinogenesis (Donaldson [2003]). Indeed, analysis of several breast cancer cell lines of differing metastatic capacity showed a direct correlation between ARF6 protein expression and their invasive potential (Hashimoto et al. [2004]). Elevated levels of activated ARF6 (ARF6-GTP) have been found to increase the invasive capacity of melanoma cells both in vitro (Tague et al. [2004]) and in vivo (Muralidharan-Chari et al. [2009]), while silencing ARF6 by small-interfering RNA inhibits the ability of breast cancer cells to invade through an artificial basement membrane, thereby providing evidence that ARF6 may be particularly important in driving tumour metastasis (Hashimoto et al. [2004]). ARF6, therefore, may be a potential cancer biomarker, however its role in prostate carcinogenesis has yet to be investigated.

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