Cancer and Metastasis Reviews

Protein tyrosine phosphatase, PTPL1, (also known as PTPN13, FAP-1, PTP-BAS, PTP1E) is a non-receptor type PTP and, at 270 kDa, is the largest phosphatase within this group. In addition to the well-conserved PTP domain, PTPL1 contains at least 7 putative macromolecular interaction domains. This structural complexity indicates that PTPL1 may modulate diverse cellular functions, perhaps exerting both positive and negative effects. In accordance with this idea, while certain studies suggest that PTPL1 can act as a tumor-promoting gene other experimental studies have suggested that PTPL1 may function as a tumor suppressor. The role of PTPL1 in the cancer cell is therefore likely to be both complex and context dependent with possible roles including the modulation of growth, stress-response, and cytoskeletal remodeling pathways. Understanding the nature of molecular complexes containing PTPL1, its interaction partners, substrates, regulation and subcellular localization are key to unraveling the complex personality of this protein phosphatase.

In undertaking a quantitative estimation of carcinogenesis risk, it is essential to keep in mind that carcinogenesis is a multistage process, and that each stage can be affected by different classes of risk factors. Furthermore, different mechanisms are involved in the various stages of carcinogenesis. Thus, a dose-response analysis of one given factor cannot provide an accurate estimation of carcinogenic risk. Carcinogenic risk estimation is usually undertaken for a specific chemical or group of chemicals; however, the concept of multistage carcinogenesis is based on biological processes and not on the mechanisms of action of the agents involved. It is therefore important to consider three related, but different, factors involved in carcinogenesis: stage, agent, and activity of agent. This is especially important in developing a short-term test for stage-related risk factors, such as tumor-promoting agents. For this reason, carcinogens should not be classified according to only one chemical activity. This article briefly reviews the cellular and molecular mechanisms involved in multistage carcinogenesis, and discusses their implications for risk estimation. Special consideration is given to the effect of treatment frequency on the response of tumor-promoting agents, as seen in long-term tests in experimental animals. It is proposed that exposure frequency be taken into account together with exposure dose.

The mammalian cell cycle can be divided into four phases: G1 (gap phase 1), S (DNA synthesis), G2 (gap phase 2), and M (mitosis). Progression through each phase of the cell cycle is delicately controled by the activity of different cyclin-dependent kinases (CDKs) and their regulatory subunits known as cyclins. CDK2, CDK4, CDK6 and their associated cyclins control the G1 to S phase transition. The association of CDK4 or CDK6 with D-type cyclins is critical for G1 phase progression, whereas the CDK2-cyclin E complex is important for initiation of the S phase. Cancer can originate from dysregulation of these regulators. A variety of intrinsic and extrinsic signals were recently identified to regulate these G1 or G1/S CDKs and cyclins. Here we discuss the regulators of these protein kinases at different mechanistic level with a hope that these insights can be applied to develop therapeutic strategies for cancer treatment.

In prostate to bone metastases, the “vicious cycle” paradigm has been traditionally used to illustrate how metastases manipulate the bone forming osteoblasts and resorbing osteoclasts in order to yield factors that facilitate growth and establishment. However, recent advances have illustrated that the cycle is far more complex than this simple interpretation. In this review, we will discuss the role of exosomes and hematopoietic/mesenchymal stem/stromal cells (MSC) that facilitate the establishment and activation of prostate metastases and how cells including myeloid-derived suppressor cells, macrophages, T cells, and nerve cells contribute to the momentum of the vicious cycle. The increased complexity of the tumor–bone microenvironment requires a system level approach. The evolution of computational models to interrogate the tumor–bone microenvironment is also discussed, and the application of this integrated approach should allow for the development of effective therapies to treat and cure prostate to bone metastases.

Breast cancer is a major cause of morbidity and mortality in women in many parts of the world. Breast carcinomas are heterogenous in their biological and clinical behaviour and a greater understanding of how they develop and progress could lead to more directed forms of screening and therapy. It is important to determine the molecular mechanisms underlying the natural history of breast cancer. Developments in the techniques for molecular analysis have meant that they can now be applied to a large range of clinical material such as cytological preparations and fixed, embedded material, so increasing the potential for relating any molecular alterations to clinical behaviour and response to therapy. In this review we consider recent developments in three areas of importance to breast cancer; genetic analysis — oncogenes, tumour suppressor genes, loss of heterozygosity, microsatellite instability, familial breast cancer; steroid receptors, oestrogen regulated proteins, epidermal growth factor receptor, growth factors particularly transforming growth factor beta; and cell adhesion, invasion and metastasis — E-cadherin, integrins, proteases. These are discussed in relation to potential for screening, prognosis and treatment.

In this short essay, we have taken the opportunity to review briefly the history of anticancer drug screening, consider the changes that have been made throughout that history, and reflect on the suitability of current screening practices and the models employed. A major change in emphasis in drug discovery has influenced the development and selection of new model tumor systems as well as screening practices. This new direction, a search for drugs that are selective for particular tumor histotypes, especially solid tumors, was stimulated by the paucity of drugs that have clinical solid tumor activity. The new approach to drug discovery and screening is in itself an experiment. Only time will tell if this approach is successful.

Polyunsaturated fatty acids (PUFA) play important roles in the normal physiology and in pathological states including inflammation and cancer. While much is known about the biosynthesis and biological activities of eicosanoids derived from ω6 PUFA, our understanding of the corresponding ω3 series lipid mediators is still rudimentary. The purpose of this review is not to offer a comprehensive summary of the literature on fatty acids in prostate cancer but rather to highlight some of the areas where key questions remain to be addressed. These include substrate preference and polymorphic variants of enzymes involved in the metabolism of PUFA, the relationship between de novo lipid synthesis and dietary lipid metabolism pathways, the contribution of cyclooxygenases and lipoxygenases as well as terminal synthases and prostanoid receptors in prostate cancer, and the potential role of PUFA in angiogenesis and cell surface receptor signaling.

Multi-specific drug-transport mechanisms are intricately involved in mediating a pleiotropic drug-resistance in cancer cells by mediating drug-accumulation defects in cells in which they are over-expressed. The existence and over-expression in drug-resistant neoplasms of transporter proteins belonging to ATP-binding cassette (ABC) family indicate that these myriad transporters contribute to the multidrug-resistance phenomena by removing or sequestering of toxins and metabolites. Another prominent mechanism of multispecific drug-resistance involves glutathione and glutathione linked enzymes, particularly those of the mercapturic acid pathway, which are involved in metabolism and excretion of both endogenous and exogenous electrophilic toxins. A key step in the mercapturic acid pathway, efflux of the glutathione-electrophile conjugate has recently been shown to be catalyzed largely by the stress-responsive protein RLIP76, a splice variant peptide endowed by the human gene RALBP1. The known involvement of RLIP76 in membrane signaling pathways and endocytosis has resulted in a new paradigm for transport and metabolism related drug-resistance in which RLIP76 plays a central role. Our recent studies demonstrating a key anti-apoptotic and stress-responsive role of RLIP76, and the demonstration of dramatic response in malignancies to RLIP76 depletion indicate that targeting this mercapturic acid pathway transporter may be a highly effective and multifaceted antineoplastic strategy.

Management of patients diagnosed with localized prostate cancer is complicated by the diverse natural history of the disease and variable response to treatment. Prognostic criteria currently in use cannot fully predict tumor behavior and thus limit the ability to recommend treatment regimens with the assurance that they are the best course of action for each individual patient. The search for better prognostic markers is now focussed on the molecular mechanisms which underlay tumor behavior, such as altered cell cycle progression, apoptosis, neuroendocrine differentiation, and angiogenesis. As the number of potential molecular markers increases, it is becoming evident that no single marker will provide the prognostic information necessary to make a significant improvement in patient care. In addition, it seems likely that traditional methods of assessing the prognostic value of this multitude of new markers will prove inadequate. In this review, we briefly examine the current state of prognostication in localized prostate cancer and some of the promising new molecular markers. Next, we examine how new technologies may allow the multiplex analysis of vast numbers of markers and how computational methods such as artificial neural networks will provide meaningful interpretation of the data. In the near future, such an integrated approach may provide a comprehensive prognostic tool for localized prostate cancer.