BBA - Reviews on Cancer (v.1776, #1)

Erythropoietin (EPO) has been used clinically both as an erythropoietic stimulating agent in the treatment of anemia and as a tissue-protective agent in diverse clinical settings including stroke, multiple sclerosis, acute myocardial infarction and others. However, use of EPO or EPO-analogues leads to simultaneous targeting of both the erythropoietic and tissue-protective properties of EPO, and this strategy has been associated with several problems. Specifically, the benefit of correction of cancer-related anemia can be offset by the tissue-protective effects of EPO, which may lead to stimulation of cancer cell proliferation. Conversely, the benefit of tissue-protection in patients with stroke or myocardial infarction can be offset by adverse effects associated with the erythropoietic effects of EPO such as elevation of red blood cell mass, hypertension and prothrombotic phenomena. The finding that the erythropoietic and tissue-protective properties of EPO are conferred via two distinct receptor systems raises the interesting possibility of discovering novel drugs that selectively stimulate either the erythropoietic or the tissue-protective activities of EPO. This article reviews the current status of the clinical use of EPO and EPO-analogues in the treatment of cancer-related anemia and for tissue protection, outlines the distinct molecular biology of the tissue-protective and erythropoietic effects of EPO and discusses strategies of selective targeting of these activities with the goal of exploiting the full therapeutic potential of EPO.
Keywords: Erythropoietin; Cancer-related anemia; Tissue protection; Erythropoietic effect; Selective targeting;

Epithelial metaplasia and the development of cancer by Jonathan M. Quinlan; Benjamin J. Colleypriest; Mark Farrant; David Tosh (10-21).
Metaplasia means the conversion, in postnatal life, of one cell type to another. Understanding the steps leading to metaplasia is important for two reasons. Firstly, it tells us something about the normal developmental biology of the tissues that interconvert. Secondly, metaplasia predisposes to certain forms of neoplasia. So understanding the molecular and cellular mechanisms underlying metaplasia will provide insights into clinical diagnosis and potential therapies. One of the best-described examples of metaplasia is Barrett's metaplasia or the appearance of intestinal-like columnar tissue in the oesophagus. Barrett's metaplasia develops as a result of gastro–oesophageal reflux and is considered the precursor lesion for oesophageal adenocarcinoma. While we know quite a bit about the molecular events associated with the development of oesophageal adenocarcinoma, our understanding of the initial events leading to Barrett's metaplasia is lacking. In the present review we will focus on examples of metaplasia that lead to neoplasia and discuss some of the underlying molecular and cellular mechanisms.
Keywords: Metaplasia; Barrett's oesophagus;

Tissue kallikrein proteolytic cascade pathways in normal physiology and cancer by Georgios Pampalakis; Georgia Sotiropoulou (22-31).
Human tissue kallikreins (KLKs or kallikrein-related peptidases) are a subgroup of extracellular serine proteases that act on a wide variety of physiological substrates, while they display aberrant expression patterns in certain types of cancer. Differential expression patterns lead to the exploitation of these proteins as new cancer biomarkers for hormone-dependent malignancies, in particular. The prostate-specific antigen or kallikrein-related peptidase 3 (PSA/KLK3) is an established tumor marker for the diagnosis and monitoring of prostate cancer. It is well documented that specific KLK genes are co-expressed in tissues and in various pathologies suggesting their participation in complex proteolytic cascades. Here, we review the currently established knowledge on the involvement of KLK proteolytic cascades in the regulation of physiological and pathological processes in prostate tissue and in skin. It is well established that the activity of KLKs is often regulated by auto-activation and subsequent autolytic internal cleavage leading to enzymatic inactivation, as well as by inhibitory serpins or by allosteric inhibition by zinc ions. Redistribution of zinc ions and alterations in their concentration due to physiological or pathological reasons activates specific KLKs initiating the kallikrein cascade(s). Recent studies on kallikrein substrate specificity allowed for the construction of a kallikrein interaction network involved in semen liquefaction and prostate cancer, as well as in skin pathologies, such as skin desquamation, psoriasis and cancer. Furthermore, we discuss the crosstalks between known proteolytic pathways and the kallikrein cascades, with emphasis on the activation of plasmin and its implications in prostate cancer. These findings may have clinical implications for the underlying molecular mechanism and management of cancer and other disorders in which KLK activity is elevated.
Keywords: Human tissue kallikreins; Proteolytic cascades; Prostate cancer; Semen liquefaction; Skin desquamation; Skin cancer;

Cardiotonic steroids on the road to anti-cancer therapy by Tatjana Mijatovic; Eric Van Quaquebeke; Bruno Delest; Olivier Debeir; Francis Darro; Robert Kiss (32-57).
The sodium pump, Na+/K+-ATPase, could be an important target for the development of anti-cancer drugs as it serves as a versatile signal transducer, it is a key player in cell adhesion and its aberrant expression and activity are implicated in the development and progression of different cancers. Cardiotonic steroids, known ligands of the sodium pump have been widely used for the treatment of heart failure. However, early epidemiological evaluations and subsequent demonstration of anti-cancer activity in vitro and in vivo have indicated the possibility of developing this class of compound as chemotherapeutic agents in oncology. Their development to date as anti-cancer agents has however been impaired by a narrow therapeutic margin resulting from their potential to induce cardiovascular side-effects. The review will thus discuss (i) sodium pump structure, function, expression in diverse cancers and its chemical targeting and that of its sub-units, (ii) reported in vitro and in vivo anti-cancer activity of cardiotonic steroids, (iii) managing the toxicity of these compounds and the limitations of existing preclinical models to adequately predict the cardiotoxic potential of new molecules in man and (iv) the potential of chemical modification to reduce the cardiovascular side-effects and improve the anti-cancer activity of new molecules.
Keywords: Cardiotonic steroid; Na+/K+-ATPase; New anti-cancer drug; Sodium pump targeting;

Ras proteins play a direct causal role in human cancer with activating mutations in Ras occurring in ∼ 30% of tumours. Ras effectors also contribute to cancer, as mutations occur in Ras effectors, notably B-Raf and PI3-K, and drugs blocking elements of these pathways are in clinical development. In 2000, a new Ras effector was identified, RAS-association domain family 1 (RASSF1), and expression of the RASSF1A isoform of this gene is silenced in tumours by methylation of its promoter. Since methylation is reversible and demethylating agents are currently being used in clinical trials, detection of RASSF1A silencing by promoter hypermethylation has potential clinical uses in cancer diagnosis, prognosis and treatment. RASSF1A belongs to a new family of RAS effectors, of which there are currently 8 members (RASSF1–8). RASSF1–6 each contain a variable N-terminal segment followed by a Ras-association (RA) domain of the Ral-GDS/AF6 type, and a specialised coiled-coil structure known as a SARAH domain extending to the C-terminus. RASSF7–8 contain an N-terminal RA domain and a variable C-terminus. Members of the RASSF family are thought to function as tumour suppressors by regulating the cell cycle and apoptosis. This review will summarise our current knowledge of each member of the RASSF family and in particular what role they play in tumourigenesis, with a special focus on RASSF1A, whose promoter methylation is one of the most frequent alterations found in human tumours.
Keywords: RASSF; Tumour suppressor; Methylation; Cell cycle; Apoptosis; Microtubule;

Molecular effectors of multiple cell death pathways initiated by photodynamic therapy by Esther Buytaert; Michael Dewaele; Patrizia Agostinis (86-107).
Photodynamic therapy (PDT) is a recently developed anticancer modality utilizing the generation of singlet oxygen and other reactive oxygen species, through visible light irradiation of a photosensitive dye accumulated in the cancerous tissue. Multiple signaling cascades are concomitantly activated in cancer cells exposed to the photodynamic stress and depending on the subcellular localization of the damaging ROS, these signals are transduced into adaptive or cell death responses. Recent evidence indicates that PDT can kill cancer cells directly by the efficient induction of apoptotic as well as non-apoptotic cell death pathways. The identification of the molecular effectors regulating the cross-talk between apoptosis and other major cell death subroutines (e.g. necrosis, autophagic cell death) is an area of intense research in cancer therapy. Signaling molecules modulating the induction of different cell death pathways can become useful targets to induce or increase photokilling in cancer cells harboring defects in apoptotic pathways, which is a crucial step in carcinogenesis and therapy resistance. This review highlights recent developments aimed at deciphering the molecular interplay between cell death pathways as well as their possible therapeutic exploitation in photosensitized cells.

Challenges and prospects of immunotherapy as cancer treatment by Maria Rescigno; Francesca Avogadri; Giuseppe Curigliano (108-123).
The concept of cancer immunotherapy stems from the proposed function of the immune system, called immunosurveillance, to protect against growing tumors. Due to genetic aberrations, tumor cells display an altered repertoire of MHC-associated peptides that can lead to the activation of immune cells able to eliminate the transformed cells. In some instances, under the pressure of the immune system, both the tumor and its microenvironment are shaped and immune-resistant tumor variants are selected initiating the process of cancer immunoediting. This can impair not only host-generated immunosurveillance, but also attempts to harness the immune response for therapeutic purposes, namely immunotherapy. Rather than being an exhaustive review of the different approaches of cancer immunotherapy, the focus of this review is to provide the reader with future challenges of the field by proposing ‘second generation’ immunotherapy approaches that take into account immunosubversive mechanisms adopted by tumor cells. After an introduction on the process of immunosurveillance and immunoescape we will analyze why current immunotherapy approaches have not fulfilled their promise and will finish by summarizing what are the challenges for future approaches.
Keywords: Immunotherapy; Immunoevasion; Cancer immunoediting; Clinical trial; Monoclonal antibodies; Dendritic cell;