BBA - Reviews on Cancer (v.1786, #2)

Transcriptional inhibitors, p53 and apoptosis by Andrei L. Gartel (83-86).
Transcriptional inhibitors (TI) repress global transcription and induce apoptosis. It has been suggested that induction of p53 is one of the hallmarks of global transcriptional repression. Two recent papers suggested that treatment of human cancer cells with TIs, leads to p53-dependent, transcription-independent or p53-dependent, transcription-dependent apoptosis. The latter mechanism is linked to the fact that TIs can be selective in their inhibitory effects thereby permitting transcription of some genes. However, the majority of other published data suggest that these drugs induce p53-independent apoptosis. In this article I discuss the mechanisms of TI-dependent cell death and the potential role of p53 in this process.
Keywords: Transcriptional inhibitors; p53; mdm2; Apoptosis; ARC; DRB;

Drug development against metastasis-related genes and their pathways: A rationale for cancer therapy by Megumi Iiizumi; Wen Liu; Sudha K. Pai; Eiji Furuta; Kounosuke Watabe (87-104).
It is well recognized that the majority of cancer related deaths is caused by metastatic diseases. Therefore, there is an urgent need for the development of therapeutic intervention specifically targeted to the metastatic process. In the last decade, significant progress has been made in this research field, and many new concepts have emerged that shed light on the molecular mechanism of metastasis cascade which is often portrayed as a succession of six distinct steps; localized invasion, intravasation, translocation, extravasation, micrometastasis and colonization. Successful metastasis is dependent on the balance and complex interplay of both the metastasis promoters and suppressors in each step. Therefore, the basic strategy of our interventions is aimed at either blocking the promoters or potentiating the suppressors in this disease process. Toward this goal, various kinds of antibodies and small molecules have been designed. These include agents that block the ligand-recepter interaction of metastasis promoters (HGF/c-Met), antagonize the metastasis-promoting enzymes (AMF, uPA and MMP) and inhibit the transcriptional activity of metastasis promoter (β-Catenin). On the other hand, the intriguing roles of metastasis suppressors and their signal pathways have been extensively studied and various attempts have been made to potentiate these factors. Small molecules have been developed to restore the expression or mimic the function of metastasis-suppressor genes such as NM23, E-cadherin, Kiss-1, MKK4 and NDRG1, and some of them are under clinical trials. This review summarizes our current understanding of the molecular pathway of tumor metastasis and discusses strategies and recent development of anti-metastatic drugs.
Keywords: Metastasis; Cancer therapy; Metastasis suppressor; Drug development; Anti-metastatic drug; Invasion; Motility; Signal pathway;

Predicting the efficacy of trastuzumab-based therapy in breast cancer: Current standards and future strategies by Christian F. Singer; Wolfgang J. Köstler; Gernot Hudelist (105-113).
Breast cancer is the most common female malignancy in many industrialized countries. Approximately one fourth of all women diagnosed with early breast cancer present with tumors that are characterized by erbB2 amplification. While the associated Her-2/neu receptor overexpression results in a high risk of relapse and poor prognosis, these tumors also represent a target for a selective monoclonal antibody therapy with trastuzumab (Herceptin®). The combination of trastuzumab with chemotherapy has led to a considerable reduction of recurrences and to a significant reduction in breast cancer mortality both in the adjuvant and metastatic setting. Unfortunately, despite Her-2/neu overexpression, not all patients equally benefit from trastuzumab treatment, and almost all women with metastatic breast cancer eventually progress during antibody therapy. Moreover, trastuzumab is burdened with cardiotoxicity, thus increasing the risk of symptomatic congestive heart failure. In addition, the marginal costs for a 1 year therapy of trastuzumab-based therapy, which is currently considered to be the most effective treatment regimen in the adjuvant setting, may amount for up to US$ 40.000. Testing for erbB2 oncogene amplification by fluorescence in situ hybridization (FISH) and chromogenic in situ hybridization (CISH), respectively, and staining for Her-2/neu receptor overexpression by immunohistochemistry (IHC) represent the current standard for determining patient eligibility for trastuzumab-based therapy. However, while the negative predictive value of these assays for predicting the absence of benefit from trastuzumab-based therapy is sufficiently high, their positive predictive value remains insufficient, i.e. only a proportion of patients selected by these tests substantially benefit from trastuzumab-containing regimen. Accordingly, over the last years a number of biomarkers have been evaluated in their potential to predict response to trastuzumab-based therapies. These include markers auf activation of Her-2/neu (e.g., tyrosine phosphorylated Her-2/neu in tissue and cleaved Her-2/neu extracellular domain in serum) and its dimerization partners (e.g., EGFR), respectively, but also components of Her-2/neu-induced downstream signaling pathways that are crucial for the growth inhibitory effects of trastuzumab (e.g., PTEN and PI3K). Other parameters, such as topoisomerase-II alpha and c-myc co-amplifications, have also been identified as potentially useful predictors of response to trastuzumab-based chemotherapy regimen. While the benefit of these predictive biomarkers in the metastatic setting is currently explored, their usefulness in the adjuvant setting is still largely unknown. It is, however, undisputable that, within the group of Her-2/neu overexpressing tumors, further response predictors are needed in order to minimize trastuzumab-associated side effects, and to reduce the considerable societal costs that are associated with trastuzumab-based treatment regimen.
Keywords: Her-2; Response prediction; Herceptin; ECD; Phospho Her-2;

All along the watchtower: Is the cilium a tumor suppressor organelle? by Dorus A. Mans; Emile E. Voest; Rachel H. Giles (114-125).
Cilia or flagella have been around since almost the beginning of life, and have now developed specialized cell-type specific functions from locomotion to acting as environmental sensors participating in cell signalling. Genetic defects affecting cilia result in a myriad of pathological instances, including infertility, obesity, blindness, deafness, skeletal malformations, and lung problems. However, the consistency in which the common kidney cyst is coupled with cilia dysfunction has raised interest in the possibility that ciliary dysfunction might contribute to other neoplasms as well. A suite of recent papers convincingly linking cilia to hedgehog signalling, platelet-derived growth factor signalling, Wnt signalling and the von Hippel–Lindau tumor suppressor protein has rapidly expanded the knowledge base connecting cilia to cancer. We propose that these data support the notion of the cilium as a cellular Watchtower, whose absence can be an initiating event in neoplastic growth. Furthermore, we predict that we are just now seeing the tip of the iceberg, and that the list of cancers associated with altered ciliary signalling will grow exponentially in the next few years.
Keywords: Cilia; Wnt; Hedgehog; von Hippel–Lindau; Polycystic kidney disease; Renal cell carcinoma;

Cell-penetrating and cell-targeting peptides in drug delivery by Eric Vivès; Julien Schmidt; André Pèlegrin (126-138).
During the last decade, the potential of peptides for drug delivery into cells has been highlighted by the discovery of several cell-penetrating peptides (CPPs). CPPs are very efficient in delivering various molecules into cells. However, except in some specific cases, their lack of cell specificity remains the major drawback for their clinical development. At the same time, various peptides with specific binding activity for a given cell line (cell-targeting peptides) have also been reported in the literature. One of the goals of the next years will be to optimize the tissue and cell delivery of therapeutic molecules by means of peptides which combine both targeting and internalization advantages. In this review, we describe the main strategies that are currently in use or likely to be employed in the near future to associate both targeting and delivery properties.
Keywords: Cancer; Cell-penetrating peptide; Cell-targeting peptide; Cell delivery; Drug;

Chromosomal translocations in cancer by Mridula Nambiar; Vijayalakshmi Kari; Sathees C. Raghavan (139-152).
Genetic alterations in DNA can lead to cancer when it is present in proto-oncogenes, tumor suppressor genes, DNA repair genes etc. Examples of such alterations include deletions, inversions and chromosomal translocations. Among these rearrangements chromosomal translocations are considered as the primary cause for many cancers including lymphoma, leukemia and some solid tumors. Chromosomal translocations in certain cases can result either in the fusion of genes or in bringing genes close to enhancer or promoter elements, hence leading to their altered expression. Moreover, chromosomal translocations are used as diagnostic markers for cancer and its therapeutics. In the first part of this review, we summarize the well-studied chromosomal translocations in cancer. Although the mechanism of formation of most of these translocations is still unclear, in the second part we discuss the recent advances in this area of research.
Keywords: Leukemia; Lymphoma; Neoplasia; DNA repair; Double-strand break; Carcinoma; Sarcoma; Genomic instability; V(D)J recombination;

Ubiquitin-independent degradation of proteins by the proteasome by Isabelle Jariel-Encontre; Guillaume Bossis; Marc Piechaczyk (153-177).
The proteasome is the main proteolytic machinery of the cell and constitutes a recognized drugable target, in particular for treating cancer. It is involved in the elimination of misfolded, altered or aged proteins as well as in the generation of antigenic peptides presented by MHC class I molecules. It is also responsible for the proteolytic maturation of diverse polypeptide precursors and for the spatial and temporal regulation of the degradation of many key cell regulators whose destruction is necessary for progression through essential processes, such as cell division, differentiation and, more generally, adaptation to environmental signals. It is generally believed that proteins must undergo prior modification by polyubiquitin chains to be addressed to, and recognized by, the proteasome. In reality, however, there is accumulating evidence that ubiquitin-independent proteasomal degradation may have been largely underestimated. In particular, a number of proto-oncoproteins and oncosuppressive proteins are privileged ubiquitin-independent proteasomal substrates, the altered degradation of which may have tumorigenic consequences. The identification of ubiquitin-independent mechanisms for proteasomal degradation also poses the paramount question of the multiplicity of catabolic pathways targeting each protein substrate. As this may help design novel therapeutic strategies, the underlying mechanisms are critically reviewed here.
Keywords: Proteasome; Ubiquitin; Oncogene; Tumor suppressor;

Many faces of Ras activation by László Buday; Julian Downward (178-187).
Ras proteins were originally identified as the products of oncogenes capable of inducing cell transformation. Over the last twenty-five years they have been studied in great detail because mutant Ras proteins are associated with many types of human cancer. Wild type Ras proteins play a central role in the regulation of proliferation and differentiation of various cell types. They alternate between an active GTP-bound state and an inactive GDP-bound state. Their activation is catalysed by a specialized group of enzymes known as guanine nucleotide exchange factors (GEFs). To date, four subfamilies of GEF molecules have been identified. Although all of them are able to activate Ras, their structure, tissue expression and regulation are significantly diverse. In this review we will summarize the various mechanisms by which these exchange factors activate Ras.
Keywords: Ras; Sos; RasGRF; RasGRP; CNrasGEF;