Defined Mathematical Relationships Among Cancer Cells Suggest Modular Growth in Tumor Progression and Highlight Developmental Features Consistent With a Para-Embryonic Nature of Cancer

Manzo, G.

doi:10.3389/fcell.2020.00804

Cited by 1 publication

(4 citation statements)

References 43 publications

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“…The tumor bulk hierarchic structure, for which I suggested a modular organization of different cancer cell populations ( Figures 1 , 3 ) ( Manzo, 2020 ), also might be a crucial problem to be considered in cytotoxic therapeutic strategies.…”

Section: Discussion and Proposals: “Tumor Checkpoint Profiles” For “Shielded” Cancer Treatmentsmentioning

confidence: 99%

“…Here, 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 CSC 3 s into proliferating CSC 1 s. These cells would be able to generate macro-metastases with the same cell hierarchy as their primary tumors ( Marjanovic et al, 2013 ). Within this proliferation model, CSC 1 s–CSC 2 s–CSC 3 s–CPCs–CDCs would constitute a defined “tumor growth module” with a cord-finger structure ( Manzo, 2019 , 2020 ; Figure 1 ), where it is possible to find well-defined mathematical relationships between CSCs (CSC 1 s, CSC 2 s, and CSC 3 s) and non-CSCs (CPCs and CDCs) at each ( n ) cell division ( Manzo, 2020 ). 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 ).…”

Section: Introductionmentioning

confidence: 99%

“…Within this proliferation model, CSC 1 s–CSC 2 s–CSC 3 s–CPCs–CDCs would constitute a defined “tumor growth module” with a cord-finger structure ( Manzo, 2019 , 2020 ; Figure 1 ), where it is possible to find well-defined mathematical relationships between CSCs (CSC 1 s, CSC 2 s, and CSC 3 s) and non-CSCs (CPCs and CDCs) at each ( n ) cell division ( Manzo, 2020 ). 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 also 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 ).…”

Section: Introductionmentioning

confidence: 99%

“…Beyond this limit, avascular tumor growth could occur only with a simultaneous death of the core cells ( Hamilton and Rath, 2019 ). Up to this point, the tumor process would be similar and equivalent to that of a preimplantation blastocyst ( Manzo, 2020 ). Now, further tumor growth would require implantation and vascularization for the oxygen and nutrient supply by the host microenvironment, like in embryo development.…”

Section: Introductionmentioning

confidence: 99%

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

Manzo¹

2021

Front. Cell Dev. Biol.

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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 (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.

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Section: Discussion and Proposals: “Tumor Checkpoint Profiles” For “Shielded” Cancer Treatmentsmentioning

confidence: 99%