Abstract
I have recently theorized that several similarities exist between the tumor process and embryo development. Starting from an initial cancer stem cell (CSC0), similar to an embryonic stem cell (ESC), after implantation in a niche, primary self-renewing CSCs (CSC1s) would arise, which then generate secondary proliferating CSCs (CSC2s). From these epithelial CSCs, tertiary mesenchymal CSCs (CSC3s) 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. CSC1s–CSC2s–CSC3s–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.
Highlights
I have recently theorized that several similarities exist between the tumor process and embryo development (Manzo, 2019)
Specific signals, similar to those occurring in the embryonic inductions, would induce an epithelial–mesenchymal transition (EMT)/mesenchymal–epithelial transition (MET) switch (Thiery et al, 2009; Liu et al, 2014), allowing the reversion of quiescent CSC3s into proliferating CSC1s
Factors able to induce ureteric bud (UB) cells are present in MM cell-conditioned media and include the glial cell line-derived neurotrophic factor (GDNF), hepatocyte growth factor (HGF), and extracellular matrix (ECM) proteins, which could be indicated as “mesenchymal inductors” (Balinsky, 1970; Ratajczak et al, 2006; Velagapudi et al, 2012), with HGF as both an epithelial and mesenchymal inductor
Summary
I have recently theorized that several similarities exist between the tumor process and embryo development (Manzo, 2019). A tumor growth module would generate new modules after about 10 division cycles, when the cell number would become presumably too large for survival under unfavorable stereotrophic conditions (Hamilton and Rath, 2019; Manzo, 2020) Such a modular growth process seems to occur when CSCs, cultured in vitro in the absence of implantation conditions, form solid, round cellular structures with a diameter of about 50–250 μm, named tumor spheres, displaying a modular growth behavior similar to that of avascular tumors in vivo (Johnson et al, 2013; Vinnitsky, 2014). I intend to point out and analyze crucial factors in the different phases of the cancer process for detecting potential checkpoints to be targeted in therapeutic treatments
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