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.