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I have recently theorized that several similarities exist between the tumor process and embryo development. Starting from an initial cancer stem cell (CSC 0 ), similar to an embryonic stem cell (ESC), after implantation in a niche, primary self-renewing CSCs (CSC 1 s) would arise, which then generate secondary proliferating CSCs (CSC 2 s). From these epithelial CSCs, tertiary mesenchymal CSCs (CSC 3 s) would arise, which, under favorable stereotrophic conditions, by asymmetric proliferation, would generate cancer progenitor cells (CPCs) and then cancer differentiated cells (CDCs), thus giving a defined cell heterogeneity and hierarchy. CSC 1 s–CSC 2 s–CSC 3 s–CPCs–CDCs would constitute a defined “tumor growth module,” able to generate new tumor modules, forming a spherical avascular mass, similar to a tumor sphere. Further growth  in situ  of this initial tumor would require implantation in the host and vascularization through the overexpression of some aspecific checkpoint molecules, such as CD44, ID, LIF, HSP70, and HLA-G. To expand and spread in the host tissues, this vascularized tumor would then carry on a real growth strategy based on other specific checkpoint factors, such as those contained in the extracellular vesicles (EVs), namely, microRNAs, messenger RNAs, long non-coding RNAs, and integrins. These EV components would be crucial in tumor progression because they can mediate intercellular communications in the surrounding microenvironment and systemically, dictating to recipient cells a new tumor-enslaved phenotype, thus determining pre-metastatic conditions. Moreover, by their induction properties, the EV contents could also frustrate in time the effects of cytolytic tumor therapies, where EVs released by killed CSCs might enter other cancer and non-cancer cells, thus giving chemoresistance, non-CSC/CSC transition (recurrence), and metastasis. Thus, antitumor cytotoxic treatments, “shielded” from the EV-specific checkpoints by suitable adjuvant agents, simultaneously targeting the aforesaid aspecific checkpoints should be necessary for dismantling the hierarchic tumor structure, avoiding recurrence and preventing metastasis.

frontiers in cell and developmental biology

Specific and Aspecific Molecular Checkpoints as Potential Targets for Dismantling Tumor Hierarchy and Preventing Relapse and Metastasis Through Shielded Cytolytic Treatments