Similarities Between Embryo Development and Cancer Process Suggest New Strategies for Research and Therapy of Tumors: A New Point of View

Abstract

Here, I propose that cancer stem cells (CSCs) would be equivalent to para-embryonic stem cells (p-ESCs), derived from adult cells de-re-programmed to a ground state. p-ESCs would differ from ESCs by the absence of genomic homeostasis. A p-ESC would constitute the cancer cell of origin (i-CSC or CSC0), capable of generating an initial tumor, corresponding to a pre-implantation blastocyst. In a niche with proper signals, it would engraft as a primary tumor, corresponding to a post-implantation blastocyst. i-CSC progeny would form primary pluripotent and slow self-renewing CSCs (CSC1s), blocked in an undifferentiated state, corresponding to epiblast cells; CSC1s would be tumor-initiating cells (TICs). CSC1s would generate secondary CSCs (CSC2s), corresponding to hypoblast cells; CSC2s would be tumor growth cells (TGCs). CSC1s/CSC2s would generate tertiary CSCs (CSC3s), with a mesenchymal phenotype; CSC3s would be tumor migrating cells (TMCs), corresponding to mesodermal precursors at primitive streak. CSC3s with more favorable conditions (normoxia), by asymmetrical division, would differentiate into cancer progenitor cells (CPCs), and these into cancer differentiated cells (CDCs), thus generating a defined cell hierarchy and tumor progression, mimicking somito-histo-organogenesis. CSC3s with less favorable conditions (hypoxia) would delaminate and migrate as quiescent circulating micro-metastases, mimicking mesenchymal cells in gastrula morphogenetic movements. In metastatic niches, these CSC3s would install and remain dormant in the presence of epithelial/mesenchymal transition (EMT) signals and hypoxia. But, in the presence of mesenchymal/epithelial transition (MET) signals and normoxia, they would revert to self-renewing CSC1s, reproducing the same cell hierarchy of the primary tumor as macro-metastases. Further similarities between ontogenesis and oncogenesis involving crucial factors, such as ID, HSP70, HLA-G, CD44, LIF, and STAT3, are strongly evident at molecular, physiological and immunological levels. Much experimental data about these factors led to considering the cancer process as ectopic rudimentary ontogenesis, where CSCs have privileged immunological conditions. These would consent to CSC development in an adverse environment, just like an embryo, which is tolerated, accepted and favored by the maternal organism in spite of its paternal semi-allogeneicity. From all these considerations, novel research directions, potential innovative tumor therapy and prophylaxis strategies might, theoretically, result.

Keywords: CSCs; ESCs; HLA-G; HSP70; MSCs; tumor hierarchy/immunoevasion/therapy/prophylaxis.

FIGURE 1

Human Embryo development. Main phases and structures of the embryogenesis process. (A) Zygote to morula transition; (B) pre-implantation blastocyst; (C) implanted blastocyst; (D) early gastrula; (E) late gastrula; (F) somito-histo-organogenesis; (G) fetal growth-differentiation.

FIGURE 2

Theoretical similarities between cancer process and ontogenetic development. Correspondence of steps and structures between the cancer process and embryo development.

FIGURE 3

Theoretical cancer process. A normal differentiated cell (NDC), in the absence of genomic homeostasis, would be de-programmed and re-programmed to a para-ESC (p-ESC), constituting the initial cancer stem cell (i-CSC or CSC0). (1) An i-CSC, by anchorage-independent proliferation, would generate p-ESC progeny, forming an initial tumor in vivo (1-red) (or a tumorsphere in vitro), corresponding to a pre-implantation blastocyst (TE/ICM). (2) The initial tumor would install in a niche with proper factors and develop a primary tumor, mimicking an implanted blastocyst in the endometrium. (3) By PGRN activity, primary undifferentiated, pluripotent, slow self-renewing CSCs (CSC1s/TICs) would arise. CSC1s, epigenetically blocked in a ground/primed state, corresponding to the epiblast state, would form a “tumor germinal center,” continuously feeding the tumor. (4) Through autocrine/paracrine growth, from CSC1s, committed non-self-renewing secondary CSCs (CSC2s) would arise. CSC1s and CSC2s, together, would form a “tumor growth nucleus” corresponding to the epiblast/hypoblast state. (5) From CSC1s/CSC2s, tertiary CSCs (CSC3s), with a mesenchymal phenotype (EMT), would be generated. CSC3s would be able to migrate and invade adjoining sites, mimicking delamination of mesodermal precursors at the primitive streak. CSC1s, CSC2s, and CSC3s, together, would form a “tumor expansion module”. In the growing primary tumor, favorable conditions (normoxia) would induce CSC3s to proliferate asymmetrically and generate CPCs and, then, CDCs. This would determine a CSC1-CSC2-CSC3-CPC-CDC cell hierarchy and tumor progression, thus mimicking a partial, rudimentary somito-histo-organogenesis process. (6) In parallel, unfavorable conditions (hypoxia) would induce CSC3s to migrate as circulating micro-metastases, mimicking the gastrula morphogenetic movements. (7) In distant niches with proper EMT signals, CSC3s in the niche would locate as quiescent micro-metastases, mimicking embryonic locations of mesodermal cells at somitogenesis sites. (8) Micro-environmental proper MET signals, would induce mesenchymal CSC3 to revert, into epithelial self-renewing CSC1s mimicking gastrular induction (TICs). Self-renewing CSC1s, as TICs, would form a new tumor germinal center and re-initiate the tumor process in metastatic sites, repeating the same steps and reproducing the same cell types and hierarchy of the primary tumor. Tumorsphere figure was adapted from Bond et al. (2013).