Epithelial–mesenchymal transition (EMT) is defined as a cellular process during which epithelial cells acquire mesenchymal phenotypes and behavior following the downregulation of epithelial features. EMT and its reversed process, the mesenchymal-epithelial transition (MET), and the special form of EMT, the endothelial-mesenchymal transition (EndMT), have been considered as mainstream concepts and general rules driving developmental and pathological processes, particularly cancer. However, discrepancies and disputes over EMT and EMT research have also grown over time. EMT is defined as transition between two cellular states, but it is unanimously agreed by EMT researchers that (1) neither the epithelial and mesenchymal states nor their regulatory networks have been clearly defined, (2) no EMT markers or factors can represent universally epithelial and mesenchymal states, and thus (3) EMT cannot be assessed on the basis of one or a few EMT markers. In contrast to definition and proposed roles of EMT, loss of epithelial feature does not cause mesenchymal phenotype, and EMT does not contribute to embryonic mesenchyme and neural crest formation, the key developmental events from which the EMT concept was derived. EMT and MET, represented by change in cell shapes or adhesiveness, or symbolized by EMT factors, are biased interpretation of the overall change in cellular property and regulatory networks during development and cancer progression. Moreover, EMT and MET are consequences rather than driving factors of developmental and pathological processes. The true meaning of EMT in some developmental and pathological processes, such as fibrosis, needs re-evaluation. EMT is believed to endow malignant features, such as migration, stemness, etc., to cancer cells. However, the core property of cancer (tumorigenic) cells is neural stemness, and the core EMT factors are components of the regulatory networks of neural stemness. Thus, EMT in cancer progression is misattribution of the roles of neural stemness to the unknown mesenchymal state. Similarly, neural crest EMT is misattribution of intrinsic property of neural crest cells to the unknown mesenchymal state. Lack of basic rationale in EMT and related concepts urges re-evaluation of their significance as general rules for understanding developmental and pathological processes, and re-evaluation of their significance in scientific research.

Epithelial–mesenchymal transition (EMT) is defined as a cellular process during which epithelial cells acquire mesenchymal phenotypes and behavior following the downregulation of epithelial features. EMT and its reversed process, the mesenchymal-epithelial transition (MET), and the special form of EMT, the endothelial-mesenchymal transition (EndMT), have been considered as mainstream concepts and general rules driving developmental and pathological processes, particularly cancer. However, discrepancies and disputes over EMT and EMT research have also grown over time. EMT is defined as transition between two cellular states, but it is unanimously agreed by EMT researchers that (1) neither the epithelial and mesenchymal states nor their regulatory networks have been clearly defined, (2) no EMT markers or factors can represent universally epithelial and mesenchymal states, and thus (3) EMT cannot be assessed on the basis of one or a few EMT markers. In contrast to definition and proposed roles of EMT, loss of epithelial feature does not cause mesenchymal phenotype, and EMT does not contribute to embryonic mesenchyme and neural crest formation, the key developmental events from which the EMT concept was derived. EMT and MET, represented by change in cell shapes or adhesiveness, or symbolized by EMT factors, are biased interpretation of the overall change in cellular property and regulatory networks during development and cancer progression. Moreover, EMT and MET are consequences rather than driving factors of developmental and pathological processes. The true meaning of EMT in some developmental and pathological processes, such as fibrosis, needs re-evaluation. EMT is believed to endow malignant features, such as migration, stemness, etc., to cancer cells. However, the core property of cancer (tumorigenic) cells is neural stemness, and the core EMT factors are components of the regulatory networks of neural stemness. Thus, EMT in cancer progression is misattribution of the roles of neural stemness to the unknown mesenchymal state. Similarly, neural crest EMT is misattribution of intrinsic property of neural crest cells to the unknown mesenchymal state. Lack of basic rationale in EMT and related concepts urges re-evaluation of their significance as general rules for understanding developmental and pathological processes, and re-evaluation of their significance in scientific research.

Epithelial-mesenchymal transition (EMT) is a conserved multi-step cellular program that plays an essential role across a range of biological processes. This review covers the roles and states of EMT i...

Cancer is a systemic disease with multilayered complexity. Some theories/hypotheses have been proposed to explain cancer. They are successful in explaining certain aspects of cancer, but meet serious challenges in other aspects. Inappropriate understanding of cancer cell and cancer also hinders the development of more effective strategies of cancer therapy. My previous studies demonstrated that the core property of cancer (tumorigenic) cells is neural stemness. The finding led to the subsequent discovery about the central role of neural stemness during tumorigenesis and a novel paradigm that can hopefully explain systemic complexity of cancer as a whole. In the review, I summarize the evidence from evolutionary, developmental biology and cancer biology research supporting that neural stemness, referring to the collective property of embryonic neural/neural stem cells, represents the general stemness, the cellular property that determines both pluripotency and tumorigenicity. I make detailed discussion about the key role of neural stemness in understanding the core property and phenotypic traits of cancer cell and in understanding cancer complexity. These pieces of evidence and discussion reveal that cancer is the manifestation of the power of general rules dictating both embryogenesis and tumorigenesis. Briefly, acquiring neural stemness in ectodermal cells during embryogenesis, i.e., neural induction, leads to body axis formation, and ectopic neural induction causes a conjoined twin in an embryo; whereas acquirement of neural stemness in cells of a postnatal animal/human results in a degenerated conjoined twin-like structure, i.e., a tumor. Due to the causal role of neural stemness in tumorigenesis, novel strategies of cancer therapy can be developed by targeting neural stemness using the principle of pluripotent cell differentiation. In addition, some essential issues worth considering in cancer research are also discussed.

Cancer is a systemic disease with multilayered complexity. Some theories/hypotheses have been proposed to explain cancer. They are successful in explaining certain aspects of cancer, but meet serious challenges in other aspects. Inappropriate understanding of cancer cell and cancer also hinders the development of more effective strategies of cancer therapy. My previous studies demonstrated that the core property of cancer (tumorigenic) cells is neural stemness. The finding led to the subsequent discovery about the central role of neural stemness during tumorigenesis and a novel paradigm that can hopefully explain systemic complexity of cancer as a whole. In the review, I summarize the evidence from evolutionary, developmental biology and cancer biology research supporting that neural stemness, referring to the collective property of embryonic neural/neural stem cells, represents the general stemness, the cellular property that determines both pluripotency and tumorigenicity. I make detailed discussion about the key role of neural stemness in understanding the core property and phenotypic traits of cancer cell and in understanding cancer complexity. These pieces of evidence and discussion reveal that cancer is the manifestation of the power of general rules dictating both embryogenesis and tumorigenesis. Briefly, acquiring neural stemness in ectodermal cells during embryogenesis, i.e., neural induction, leads to body axis formation, and ectopic neural induction causes a conjoined twin in an embryo; whereas acquirement of neural stemness in cells of a postnatal animal/human results in a degenerated conjoined twin-like structure, i.e., a tumor. Due to the causal role of neural stemness in tumorigenesis, novel strategies of cancer therapy can be developed by targeting neural stemness using the principle of pluripotent cell differentiation. In addition, some essential issues worth considering in cancer research are also discussed.