The Epithelial-Myeloid-Transition (EMyeT) of cancer cells as a wrongly perceived primary inflammatory process eventually progressing to a bone remodeling malignancy: the alternative pathway for Epithelial- Mesenchymal-Transition hypothesis (EMT)?

Cancer cells express multiple markers expressed by mesenchymal as well as myeloid cells in common and in addition specific markers of the myeloid lineages, especially those of dendritic cells, macrophages and preosteoclasts. It has also been possible to identify monocyte-macrophage gene clusters in cancer cell specimens as well as in cancer cell lines. Accordingly, like myeloid cells cancer cells often express pro-inflammatory cytokines, and consequently the carcinoma may be perceived by the organism as a primary inflammatory process comparable to the immune inflammatory reactions in the eye or in the case of arthritis. This would explain why a carcinoma may induce a certain alarm state in the organism by increasing a fatal sympathetic tone in the patient, supplying the carcinomas with nutrients at the cost of other requirements, inducing tolerance against the cancer cells mistaken as myeloid cells, provoking fibrosis and neoangiogenesis, and increasing inflammatory cells at the carcinoma site. This seemingly inflammatory process of Epithelial-Myeloid-Transition (EMyeT) is superimposed by the progression of part of the myeloid cancer cells to stages comparable to preosteoclasts and osteoclasts, and their development to metastasizing carcinomas often at the site of bone. This concept of carcinogenesis and malignant progression described here challenges the widely accepted EMT-hypotheses and could deliver the rationale for the various peculiar aspects of cancer and the variety of therapeutic antitumoral measures.

Should EMT of Cancer Cells Be Understood as Epithelial-Myeloid Transition?

Cancer cells express epithelial markers, and when progressing in malignancy they may express markers of the mesenchymal cell type. Therefore an epithelial-mesenchymal transition of the cancer cells is assumed. However the mesenchymal markers can equally well be interpreted as myeloid markers since they are common in both types of cell lineages. Moreover, cancer cells express multiple specific markers of the myeloid lineages thus giving rise to the hypothesis that the transition of cancer cells may be from epithelial to myeloid cells and not to mesenchymal cells. This interpretation would better explain why cancer cells, often already in their primary cancer site, frequently show properties common to those of macrophages, platelets and pre-/osteoclasts.

The role of the osteoimmune axis in the inflammation of the inner auditory ear and with regard to the putative anticarcinogenetic principle: part 2.

Having defined a putative anticarcinogenic principle under physiological conditions of the auditory inner ear in the previous part of this study, part 2 is the continuation to evaluate this hypothesis under pathological conditions, i.e. with regard to the inflamed auditory inner ear. Inflammation of the auditory inner ear shows three characteristic phases. It starts with an acute phase, progresses to a fibrotic one and ends with ossification as the last phase. At the end of the fibrotic phase the inflammatory cells disappear, probably due to apoptosis, the ganglion neurons die and the fibrous matrix ossifies. No proliferating cells can be found in this area any more. Thus this kind of inflammation does not result in a restoration of the former state, but always in the destruction of the hearing organ and corresponding neurons. The osteoimmune axis is involved in this characteristic type of inflammation. Important factors hereby are M-CSF, RANKL/RANK and osteoprotegerin. In the inner auditory ear they inhibit the resorption of the fibrotic matrix, induce apoptosis of inflammatory cells and calcification. This inflammatory osteoimmune axis plays an important role at the cancer site as well. The relation of each factor to the other ones is however fundamentally different from that in the inner ear. Consequently inflammatory processes induced by a tumour foster its progression and may induce bone metastasis. Instead of a dominating and enclosing osteoblastic activity like in the inner ear, matrix resolving and often osteoclastic properties are developed allowing the spread of cancer cells. These processes allows us to set out the anticarcinogenic hypothesis more precisely and define its putative mechanistic rationale for the inflamed auditory inner ear.

A unique intracellular, extracellular and transmembrane circulation of potassium ions in the auditory inner ear as an anticarcinogenic principle? Part 1.

A total of 4668 patients from four university hospitals, all representing cases with inner ear tumours or other inner ear disorders were evaluated. No primary cancer or melanoma could be detected. These results are in compliance with publications of other institutions discussing their own results in detecting inner ear pathologies. This finding is unusual and leads to the assumption that the epithelial cells of the auditory inner ear may be protected from malignant transformations. The aim of this study is to investigate the reasons for this supposed anticarcinogenic privilege of the auditory inner ear. The auditory inner ear has some unique features in the organism by reversing the relationship between intra- and extracellular ion concentrations of potassium and sodium in the endolymph. Furthermore it has a physiologically extremely high membrane potential and an unusual transmembrane and extracellular circulation of potassium ions. How these aspects contrast with the corresponding features at the carcinoma site, will be investigated. This comparison will be further deepened by reviewing the published actions of antitumoral substances in connection with these issues. On the basis of this comparative study one might speculate that the auditory inner ear is privileged by an anticarcinogenic principle and that the specific features of membrane potential, certain potassium channels and the unique transmembrane as well as extracellular potassium movements may play a decisive role in it.

Comparison of the impact of pro- and antiinflammatory immune processes at the two immune-deviated sites, eye and solid tumor and possible consequences for the antitumoral therapy with fever inducers.

Findings from various epidemiological studies suggest that acute inflammation and fever may decrease the risk of developing certain types of cancer. In an established tumor situation acute inflammation and fever resulted in tumor regression in some cases, however, treatment was sometimes ineffective or even deleterious. It has been suggested that chronic inflammation contributes to carcinogenesis and in an established tumor situation to malignancy. In order to better understand the role of acute inflammation and fever in the treatment of cancer, we compare some of the current knowledge about the effects of pro- and antiinflammatory immunological processes in the two immune-deviated sites, eye and cancer. Striking similarities between these two sites have been demonstrated. The knowledge gained in experimental studies abrogating immune privilege in the eye could provide insights into the inconsistent results of proinflammatory cancer therapy. The eye could be used as a model to develop hypotheses on how to abolish the immunological tolerance state of a solid tumor and make it susceptible to immunological destruction. The immune privilege of the eye is abrogated, at least transiently, in the initial stages of tissue- or organ-specific cellular autoimmune responses and this effect is possibly supported by complement- fixing/proinflammatory antibodies. An overview of possible consequences for the tumor therapy especially in connection with inflammation and fever inducers such as bacterial vaccines or mistletoe preparations, which are therapeutically used to interfere with the privileged immune state of the tumor, is given.

Optimal operation of simulated moving bed chromatographic processes by means of simple feedback control.

In this contribution, simple methods are presented for controlling a simulated moving bed (SMB) chromatographic process with standard PI (proportional integral) controllers. The first method represents a simple and model-free inferential control scheme which was motivated from common distillation column control. The SMB unit is equipped with UV detectors. The UV signals in the four separation zones of the unit are fixed by four corresponding PI controllers calculating the ratio of liquid and solid flow in the respective separation zone. In order to be able to adjust the product purity a second, model-based control scheme is proposed. It makes use of the nonlinear wave propagation phenomena in the apparatus. The controlled chromatographic unit is automatically working with minimum solvent consumption and maximum feed throughput--without any numerical optimization calculations. This control algorithm can therefore also be applied for fast optimization of SMB processes.

Simulated moving bed process with cyclic modulation of the feed concentration.

The improvement of the simulated moving bed (SMB) process based on the introduction of a cyclic modulation of the feed concentration is described. It is demonstrated that such a feed concentration gradient during the shifting cycle can improve the performance significantly. The productivity and the product concentrations can be increased while simultaneously the solvent consumption can be decreased compared to the conventional SMB process with constant feed parameters.