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.

HOXA10 induces BCL2 expression, inhibits apoptosis, and promotes cell proliferation in gastric cancer

“…Much scientific evidence indicated that the expression of genes responsible for normal embryo development was aberrant and contributed to carcinogenesis. [22][23][24] In the past years, HOX genes emerged as transcriptional regulators responsible for embryogenesis and were involved in the development of various cancers. 4 As an essential part of HOXA family genes, HOXA10 expression was crucial for ensuring normal development and differentiation of hematopoietic stem cells.…”

EMT Factors and Metabolic Pathways in Cancer

“…However, the same processes can be hijacked by tumor cells during cancer development (4). Indeed, several analogies have been drawn between organismal development and tumorigenesis (5).…”

Large intestine embryogenesis: Molecular pathways and related disorders (Review)

“…These results support the hypothesis of embryonic basis of cRc carcinogenesis, which is depended on colonic stem cells via transformation to a more juvenile proliferation state, turning them into cScs and finally leading to CRC. A very recent theoretical model tries to unify the cSc and embryonic hypothesis in the context of carcinogenesis based on the principles of gastrulation (343). According to this proposal, a normal adult differentiated cell can transform into a cSc, after undergoing deprogramming (dedifferentitation) and reprogramming in the lack of genomic stability.…”

“…In distant metastatic niches, cSc3s would be localized in a dormant state as an effect of hypoxia and EMT signaling. contrarily, when normoxia or MET signaling prevail in the metastatic niche, a cSc3/cSc1 reversion would then be induced, and the newly formed cSc1s, as tumor-initiating cells would reproduce the same cell hierarchy of the primary tumor as macro-metastases (343).…”