Understanding cancer as a systemic disease through comprehension of neural stemness as the core property of cancer cell and the basic rules it dictates.

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 complexity 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 paradigm that can hopefully explain systemic complexity of cancer as a whole. In the review, I summarize the evidence from research of evolutionary, developmental and cancer biology supporting that neural stemness, representing the general stemness predestined by its evolutionary advantage, determines both pluripotency and tumorigenicity, the key cellular properties underlying developmental and cancer biology, respectively. I made detailed discussions about the central role of neural stemness in understanding the core property and phenotypic traits of cancer cell and in understanding phenotypic heterogeneity in cancer. These pieces of evidence and discussions reveal that cancer is the manifestation of the power of basic rules dictating both embryogenesis and tumorigenesis. Briefly, acquiring neural stemness, hence a pluripotent state in ectodermal cells during embryogenesis, leads to neural development and body axis formation, i.e., embryonic neural induction, and ectopic neural induction causes a conjoined twin (secondary body axis); whereas acquirement of neural stemness, hence a pluripotent state in cells of a postnatal animal/human, results in a degenerated conjoined twin-like structure, i.e., a tumor. Tumors as conjoined twin-like structures formed in postnatal animals/humans helps understand the complex crosstalks within tumors and crosstalks between tumors and hosts. Moreover, neural stemness being the core property of cancer cell should account for the inverse correlation between cancer and neurodegeneration, and the neurodegeneration effect in patients after cancer therapies. Due to the central role of neural stemness in contributing to 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.