Embryonic Morphogenetic Field Induces Phenotypic Reversion in Cancer Cells. Review Article

Abstract

Cancer cells introduced into developing embryos can be committed to a complete reversion of their malignant phenotype. It is unlikely that such effects could be ascribed to only few molecular components interacting according to a simple linear-dynamics model, and they claim against the somatic mutation theory of cancer. Some 50 years ago, Needham and Waddington speculated that cancer represents an escape from morphogenetic field like those which guide embryonic development. Indeed, disruption of the morphogenetic field of a tissue can promote the onset as well as the progression of cancer. On the other hand, placing tumor cells into a "normal" morphogenetic field - like that of an embryonic tissue - one can reverse malignant phenotype, "reprogramming" tumor into normal cells. According to the theoretical framework provided by the thermodynamics of dissipative systems, morphogenetic fields could be considered as distinct attractors, to which cell behaviors are converging. Cancer-attractors are likely positioned somewhat close to embryonic-attractors. Indeed, tumors share several morphological and ultra-structural features with embryonic cells. The recovering of an "embryonic-like" cell shape might enable the gene regulatory network to reactivate embryonic programs, and consequently to express antigenic and biochemical embryonic characters. This condition confers to cancer an unusual sensitivity to embryonic regulatory cues. Thus, it is not surprising that cancer cells exposed to specific embryonic morphogenetic fields undergoes significant modifications, eventually leading to a complete phenotypic reversion.

Cancer as a disorder of patterning information: computational and biophysical perspectives on the cancer problem

“…This requires long-range coordination among cells, and significant amounts of signaling that enables sensing of local and long-rage states, whether this takes place through a series of neighbor interactions or via a long-range signaling modality. It is easy to see that cells that cannot perceive the morphogenetic field of organizing cues [18,[68][69][70], or that end up in locales with a local lowpoint in the morphogenetic field, would be unable to coordinate with others and revert to single-cell behavior. In such a case, cells would proliferate, consume resources, migrate, and evolve, without regard for the whole of the organism, as observed in cancer.…”

“…Highly-regenerative organisms are resistant to carcinogenesis and indeed activating regenerative response (figure 1(D)) can normalize existing tumors [147][148][149][150][152][153][154][155][156], although this does not always occur [157]. The inverse relationship between regeneration and cancer susceptibility [72,158] is more compatible with the importance of morphogenetic field guidance than with cancer risk associated with the presence of highly-active, undifferentiated cells [68]. Mammalian liver regeneration can overcome cancer-early nodules initiated by carcinogens are remodeled to normal-appearing liver [159,160], hepatocarcinoma cells can be normalized by injection into wild-type liver [161,162], and over 95% of nascent tumor sites remodel into normal tissue by the highly-regenerative liver [163][164][165].…”

Chromatin remodeling system, cancer stem-like attractors, and cellular reprogramming

“…This direct conversion from germ cells into individual terminally differentiated neuron types demonstrates that the chromatin factor LIN-53 provides a barrier for cellular reprogramming. In dissipative systems far from the equilibrium, even weak forces might break symmetry in stable systems, leading to bifurcation and hysteresis [9,12]. Tiny perturbations do not always remain tiny [37].…”

“…2 (also see supplementary materials), the non-attractor status or the height of the ''mountain'' possibly provides a driving force for embryonic/stem/progenitor cell proliferation. This ''potential energy'' (i.e., an inverse of probability) in a realistic molecular items [12] could be the trend linking inherited genomic program, environmental stresses, the availability of nutrients, and the storage of ATPs for chromatin remodeling. The chemical gradient and/or the quantity of gene products could be the direct ''driver'' factor.…”

“…Nevertheless, cancer attractors have not yet answered why the stable gene expression profiles of cancer attractors often encode an immature or embryonic program, and the molecular term for such attractors is lacking, and it remains undetermined what its evolution is, why normal somatic cells can be entrapped in and how it couples with cell division [11,12]. The strategy of cancer prevention and targeting derived from cancer attractors theory remains rather hypothetical and elusive until incorporating the versatile chromatin remodeling systems.…”