BBA - Reviews on Cancer (v.1704, #2)

RANKL/RANK/OPG: new therapeutic targets in bone tumours and associated osteolysis by Y. Wittrant; S. Théoleyre; C. Chipoy; M. Padrines; F. Blanchard; D. Heymann; F. Rédini (49-57).
The emergence of the molecular triad osteoprotegerin (OPG)/Receptor Activator of NF-kB (RANK)/RANK Ligand (RANKL) has helped elucidate a key signalling pathway between stromal cells and osteoclasts. The interaction between RANK and RANKL plays a critical role in promoting osteoclast differentiation and activation leading to bone resorption. OPG is a soluble decoy receptor for RANKL that blocks osteoclast formation by inhibiting RANKL binding to RANK. The OPG/RANK/RANKL system has been shown to be abnormally regulated in several malignant osteolytic pathologies such as multiple myeloma [MM, where enhanced RANKL expression (directly by tumour cells or indirectly by stromal bone cells or T-lymphocytes)] plays an important role in associated bone destruction. By contrast, production of its endogenous counteracting decoy receptor OPG is either inhibited or too low to compensate for the increase in RANKL production. Therefore, targeting the OPG/RANK/RANKL axis may offer a novel therapeutic approach to malignant osteolytic pathologies. In animal models, OPG or soluble RANK was shown both to control hypercalcaemia of malignancy and the establishment and progression of osteolytic metastases caused by various malignant tumours. To this day, only one phase I study has been performed using a recombinant OPG construct that suppressed bone resorption in patients with multiple myeloma or breast carcinoma with radiologically confirmed bone lesions. RANK-Fc also exhibits promising therapeutic effects, as revealed in animal models of prostate cancer and multiple myeloma. If the animal results translate to similar clinical benefits in humans, using RANK-Fc or OPG may yield novel and potent strategies for treating patients with established or imminent malignant bone diseases and where standard therapeutic regimens have failed.
Keywords: RANK; OPG; Tumour;

Intracellular signaling mechanisms in photodynamic therapy by Ramiro D. Almeida; Bruno J. Manadas; Arsélio P. Carvalho; Carlos B. Duarte (59-86).
In photodynamic therapy (PDT) a sensitizer, light and oxygen are used to induce death of tumor cells and in the treatment of certain noncancerous conditions. Cell death in PDT may occur by apoptosis or by necrosis, depending on the sensitizer, on the PDT dose and on the cell genotype. Some sensitizers that have been used in PDT are accumulated in the mitochondria, and this may explain their efficiency in inducing apoptotic cell death, both in vitro and in vivo. In this review we will focus on the events that characterize apoptotic death in PDT and on the intracellular signaling events that are set in motion in photosensitized cells. Activation of phospholipases, changes in ceramide metabolism, a rise in the cytosolic free Ca2+ concentration, stimulation of nitric oxide synthase (NOS), changes in protein phosphorylation and alterations in the activity of transcription factors and on gene expression have all been observed in PDT-treated cells. Although many of these metabolic reactions contribute to the demise process, some of them may antagonize cell death. Understanding the signaling mechanisms in PDT may provide means to modulate the PDT effects at the molecular level and potentiate its antitumor effectiveness.
Keywords: Photodynamic therapy; Apoptosis; Necrosis; Calcium; Phosphorylation;

DNA methylation in prostate cancer by Long-Cheng Li; Steven T. Okino; Rajvir Dahiya (87-102).
Prostate cancer is the most common malignancy and the second leading cause of cancer death among men in the United States. There are three well-established risk factors for prostate cancer: age, race and family history. The molecular bases for these risk factors are unclear; however, they may be influenced by epigenetic events. Epigenetic events covalently modify chromatin and alter gene expression. Methylation of cytosine residues within CpG islands on gene promoters is a primary epigenetic event that acts to suppress gene expression. In tumorigenesis, the normal functioning of the epigenetic-regulatory system is disrupted leading to inappropriate CpG island hypermethylation and aberrant expression of a battery of genes involved in critical cellular processes. Cancer-dependent epigenetic regulation of genes involved in DNA damage repair, hormone response, cell cycle control and tumor-cell adhesion/metastasis can contribute significantly to tumor initiation, progression and metastasis and, thereby, increase prostate cancer susceptibility and risk. In this review, we will discuss current research on genes that are hypermethylated in human prostate cancer. We will also discuss the potential involvement of DNA methylation in age-related, race-related and hereditary prostate cancer, and the potential use of hypermethylated genes as biomarkers to detect prostate cancer and assess its risk.
Keywords: Methylation; Prostate cancer; Biomarker; Diagnosis;

Author Index (103).