Dysfunctional, Tissue-Resident, Very Small Embryonic-Like Stem Cells (VSELs) Initiate Cancer and Result in its Progression and Metastasis, Independent of Epithelial-Mesenchymal Transition.

It is widely believed that epithelial cells in solid tissues undergo epithelial-mesenchymal transition (EMT) during carcinogenesis. EMT transforms polar and adherent epithelial cells in solid tumors into mesenchymal cells that get mobilized as circulating tumor cells (CTCs) and trigger metastasis. Isolating normal and neoplastic epithelial stem cells and their characterization remains challenging and vague even today. Most deaths in cancer patients are due to metastasis and hence a huge interest exists in understanding and developing tools to prevent and overcome metastasis. EMT during cancer remains clouded by controversies and questions persist as to its precise role. Besides a lack of histological evidence, lineage tracing studies have also failed to provide definitive proof supporting role of EMT in metastasis. Pluripotent, very small embryonic-like stem cells (VSELs) express sex hormone receptors and exist in a quiescent state in all tissues. They are responsible for regular turnover of epithelial cells, maintain lifelong homeostasis and their dysfunctions result in various pathologies including cancer. Developmental exposure to endocrine disrupting chemicals directly impacts VSELs, results in epigenetic changes that transform VSELs into cancer stem cells (CSCs). CSCs enter cell cycle, undergo excessive self-renewal and initiate cancer. CSCs (epigenetically altered and dysfunctional VSELs) are mobilized into circulation and are studied by our group for early prediction of cancer unlike CTCs, in a liquid biopsy, that fail to detect cancer in early stages. In this article, we discuss that besides initiation, CSCs also play a key role in cancer spread. Open questions surrounding EMT are reviewed and discussed in the context of VSELs biology. Existing hallmarks of metastasis-initiating cells produced by EMT are critically examined considering CSCs with a crucial role in cancer initiation, progression, metastasis and recurrence, challenging the existing focus on EMT and CTCs.