BBA - Reviews on Cancer (v.1756, #1)

The role of pH dynamics and the Na+/H+ antiporter in the etiopathogenesis and treatment of cancer. Two faces of the same coin—one single nature by Salvador Harguindey; Gorka Orive; José Luis Pedraz; Angelo Paradiso; Stephan J. Reshkin (1-24).
Looked at from the genetic point-of-view cancer represents a daunting and, frankly, confusing multiplicity of diseases (at least 100) that require an equally large variety of therapeutic strategies and substances designed to treat the particular tumor. However, when analyzed phenotypically cancer is a relatively uniform disease of very conserved ‘hallmark’ behaviors across the entire spectrum of tissue and genetic differences [D. Hanahan, R.A. Weinberg, Hallmarks of cancer, Cell 100 (2000) 57–70]. This suggests that cancers do, indeed, share common biochemical and physiological characteristics that are independent of the varied genetic backgrounds, and that there may be a common mechanism underlying both the neoplastic transformation/progression side and the antineoplastic/therapy side of oncology. The challenge of modern oncology is to integrate all the diverse experimental data to create a physiological/metabolic/energetic paradigm that can unite our thinking in order to understand how both neoplastic progression and therapies function. This reductionist view gives the hope that, as in chemistry and physics, it will possible to identify common underlying driving forces that define a tumor and will permit, for the first time, the actual calculated manipulation of their state. That is, a rational therapeutic design. In the present review, we present evidence, obtained from a great number of studies, for a fundamental, underlying mechanism involved in the initiation and evolution of the neoplastic process. There is an ever growing body of evidence that all the important neoplastic phenotypes are driven by an alkalization of the transformed cell, a process which seems specific for transformed cells since the same alkalinization has no effect in cells that have not been transformed. Seen in that light, different fields of cancer research, from etiopathogenesis, cancer cell metabolism and neovascularization, to multiple drug resistance (MDR), selective apoptosis, modern cancer chemotherapy and the spontaneous regression of cancer (SRC) all appear to have in common a pivotal characteristic, the aberrant regulation of hydrogen ion dynamics [S. Harguindey, J.L. Pedraz, R. García Cañero, J. Pérez de Diego, E.J. Cragoe Jr., Hydrogen ion-dependent oncogenesis and parallel new avenues to cancer prevention and treatment using a H+-mediated unifying approach: pH-related and pH-unrelated mechanisms, Crit. Rev. Oncog. 6 (1) (1995) 1–33]. Cancer cells have an acid–base disturbance that is completely different than observed in normal tissues and that increases in correspondence with increasing neoplastic state: an interstitial acid microenvironment linked to an intracellular alkalosis.
Keywords: Cancer etiopathogenesis and treatment; pH, Na+/H+ antiporter and cancer; Multiple drug resistance; Apoptosis; Neovascularization; Spontaneous regression of cancer;

Over 90% of all human neoplasia is derived from epithelia. Significant progress has been made in the identification of stem cells of many epithelia. In general, epithelial stem cells lack differentiation markers, have superior in vivo and in vitro proliferative potential, form clusters in association with a specialized mesenchymal environment (the ‘niche’), are located in well-protected and nourished sites, and are slow-cycling and thus can be experimentally identified as ‘label-retaining cells’. Stem cells may divide symmetrically giving rise to two identical stem cell progeny. Any stem cells in the niche, which defines the size of the stem cell pool, may be randomly expelled from the niche due to population pressure (the stochastic model). Alternatively, a stem cell may divide asymmetrically yielding one stem cell and one non-stem cell that is destined to exit from the stem cell niche (asymmetric division model). Stem cells separated from their niche lose their stemness, although such a loss may be reversible, becoming ‘transit-amplifying cells’ that are rapidly proliferating but have a more limited proliferative potential, and can give rise to terminally differentiated cells. The identification of the stem cell subpopulation in a normal epithelium leads to a better understanding of many previously enigmatic properties of an epithelium including the preferential sites of carcinoma formation, as exemplified by the almost exclusive association of corneal epithelial carcinoma with the limbus, the corneal epithelial stem cell zone. Being long-term residents in an epithelium, stem cells are uniquely susceptible to the accumulation of multiple, oncogenic changes giving rise to tumors. The application of the stem cell concept can explain many important carcinoma features including the clonal origin and heterogeneity of tumors, the occasional formation of tumors from the transit amplifying cells or progenitor cells, the formation of precancerous ‘patches’ and ‘fields’, the mesenchymal influence on carcinoma formation and behavior, and the plasticity of tumor cells. While the concept of cancer stem cells is extremely useful and it is generally assumed that such cells are derived from normal stem cells, more work is needed to identify and characterize epithelial cancer stem cells, to address their precise relationship with normal stem cells, to study their markers and their proliferative and differentiation properties and to design new therapies that can overcome their unusual resistance to chemotherapy and other conventional tumor modalities.
Keywords: Cancer stem cell; Clonality; Niche; Progression; Carcinogenesis; Therapy;

Haematogenous distant metastasis is the leading cause of cancer-related death in solid tumours. By applying sensitive immunocytochemical and molecular assays, disseminated tumour cells (DTC) in bone marrow (BM) can be detected in 20–40% of cancer patients without any clinical or even histopathological signs of metastasis, and the presence of these DTC at primary diagnosis predicts the subsequent occurrence of overt metastases in bone and other organs. The detection and characterisation of DTC in BM may lead to a better understanding of the biology initiating metastatic spread in cancer patients and will eventually contribute to the development of more effective strategies to eliminate DTC. In this review, we will therefore discuss the detection and characterisation of DTC in the light of new therapeutic strategies targeting tumour-associated molecules and signalling pathways.
Keywords: Tumour cell; Metastasis; Micrometastasis; Bone marrow; Cancer therapy;

A new frontier for molecular medicine: Noncoding RNAs by Maciej Szymanski; Miroslawa Z. Barciszewska; Volker A. Erdmann; Jan Barciszewski (65-75).
It is now becoming evident that the variety of noncoding RNA (ncRNA) molecules play important roles in many cellular processes and they are not just mere intermediates in transfer of genetic information from DNA to proteins. Recent data, from the analyses of transcriptional activity of human genome, suggest that it may contain roughly equal numbers of protein- and RNA-encoding transcription units. Many of the ncRNAs described in humans as well as in other mammals have been linked, through specific chromosomal localization or expression patterns, with certain diseases including complex congenital syndromes, neurobehavioral and developmental disorders and cancer. These findings clearly indicate that an expression of genes of which end-products are RNA molecules is crucial for development, differentiation and normal functioning of the cells. The ncRNAs expression patterns can therefore be used as molecular markers for specific diagnostic methods.
Keywords: Molecular medicine; RNA; DNA;

ASPP—Apoptotic specific regulator of p53 by Ze-Jun Liu; Xin Lu; Shan Zhong (77-80).
The p53 protein is one of the best-known tumor suppressors. The recently identified ASPP family (apoptosis-stimulating protein of p53) can interfere with the working of p53. Three members of ASPP family are proved to be apoptotic specific regulators of p53. The discovery of ASPP family may answer such questions as “how cells choose to die”. Understanding the ASPP status in human cancer will allow us to develop better strategies to treat cancer.
Keywords: Human cancer; ASPP; Tumor; p53; Apoptosis;