Houston Methodist researchers review the similarities and contrasts of amphibian regeneration and mammalian cancer from an evolutionary biology perspective

There seems to be rudimentary regenerative potential in adult mammals in endogenous stem cells, which are not sufficient to regenerate a functional organ. However, in mammalian embryos, there is a process similar to organ formation in amphibians. Like amphibians, mammalian embryos hold an enormous number of undifferentiated cells that have the potential to have a proper position identity during tissue morphogenesis. These processes are consistent with the behavior of undifferentiated cell clusters in amphibians – the mammalian embryonic environment supports normal tissue development and it possibly has evolved to preclude or minimize malignant transformation. The question remains: What drives the outcome of embryogenesis, tumorigenesis and regeneration in mammals? What must happen to develop or restore tissue, or disrupt it? Neoplastic transformation in adults is often associated with chronic inflammation. Relatedly, inflammation in tumors is not a self-limiting, continuous activation of wound-healing. This inflammation causes scar tissue, which some investigators believe is the cause of anatomical polarity in tissues undergoing regeneration and is potentially the root of tumorigenesis at the site of an injury. Another possibility is the accumulation of senescent cells, which are a source of pro-inflammatory factors and represent the senescence-associated secretory phenotype (SASP). SASPs are rich with cytokines and chemokines that can induce a wound-healing response. The disappearance of senescent cells has been identified in the immune cells that surround them, which happens in salamanders during regeneration and in mammalian embryos during morphogenesis. These cells are putative macrophages, which can clear dysfunctional foreign cells. Macrophages also play a role in constructive and detrimental biological processes. They may hide cues behind the uncontrolled tumorigenic conditions seen in adult mammals. Current tissue engineering recruits and localizes macrophages at implant sites to restore tissue function while avoiding scar formation. Researchers believe anti-inflammatory macrophages are responsible for activating the biological process associated with extracellular matrix (ECM) formation, collagen fibril reorganization, angiogenesis and tissue morphogenesis, which lead to the complete integration of the scaffold within the tissue. Embryonic macrophages in mammals during early stages of development also can repair skin wounds or cardiac muscle after ischemic injury in a scarless manner. However, macrophage-depleted neonatal mice are unable to complete these repairs. Researchers performed a modeling exercise to demonstrate the effect of immune mechanisms in controlling tumor initiation and growth in embryonic stem cells versus embryonic fibroblasts. Based on an extensive literature review, they found the spontaneous mutation frequency in mouse embryonic stem cells is about two orders of magnitude smaller than in differentiated cells such as mouse embryonic fibroblasts. A cellular automaton is an agent-based model that works on a 2D rectangular lattice composed of square elements (side length 20 µm), representing individual cells that evolve through a set of possible states in discrete time steps based on a set of rules. The cells undergo division to form daughter cells and based on a probability of mutation can acquire mutations or repair them along the way. Over 384 days, from inception to growth up to one year after birth, simulation results demonstrated that despite a much faster proliferation rate, embryonic stem cells and embryonic fibroblasts gather no mutations until gestation and subsequently start to accumulate mutations only after birth. This observation contrasts with cancer cells in adults by at least three to four orders of magnitude. In this simplified modeling approach, the authors did not correlate cellular mutation load with malignant transformation, but it could still be inferred that the embryonic microenvironment elicits a protective effect capable of maintaining genomic stability and functionality to minimize the risk of malignant transformations. Based on the model, the authors conclude that during morphogenesis, the correct patterning for tissue growth is ensured by the precise recapitulation of specific developmental steps along with the immature status of the immune system and the interplay with neighboring cells. A comparison of the immunological relationship between embryo and tumor with that between embryo and the initial cluster of undifferentiated cells at the regeneration site in regenerating amphibians raises apparent paradoxes. If the investigation of these open questions can be formalized into an experimental hypothesis-generating model, researchers may be able to identify mechanisms that are capable of inducing tissue development in contrast to supporting tumor progression. Such an approach, based on comparative evolutionary biology, could yield effective regenerative medicine-based strategies to prevent and fight human cancer.