The issues with tissues: the wide range of cell fate separation enables the evolution of multicellularity and cancer

Abstract

Our understanding of the rises of animal and cancer multicellularity face the same conceptual hurdles: what makes the clade originate and what makes it diversify. Between the events of origination and diversification lies complex tissue organization that gave rise to novel functionality for organisms and, unfortunately, for malignant transformation in cells. Tissue specialization with distinctly separated cell fates allowed novel functionality at organism level, such as for vertebrate animals, but also involved trade-offs at the cellular level that are potentially disruptive. These trade-offs are under-appreciated and here we discuss how the wide separation of cell phenotypes may contribute to cancer evolution by (a) how factors can reverse differentiated cells into a window of phenotypic plasticity, (b) the reversal to phenotypic plasticity coupled with asexual reproduction occurs in a way that the host cannot adapt, and (c) the power of the transformation factor correlates to the power needed to reverse tissue specialization. The role of reversed cell fate separation for cancer evolution is strengthened by how some tissues and organisms maintain high cell proliferation and plasticity without developing tumours at a corresponding rate. This demonstrates a potential proliferation paradox that requires further explanation. These insights from the cancer field, which observes tissue evolution in real time and closer than any other field, allow inferences to be made on evolutionary events in animal history. If a sweet spot of phenotypic and reproductive versatility is key to transformation, factors stimulating cell fate separation may have promoted also animal diversification on Earth.

Cancer recurrence and lethality are enabled by enhanced survival and reversible cell cycle arrest of polyaneuploid cells

“…Metastatic cancer is ultimately resistant to virtually all systemic therapies and continues to kill more than 10 million people per year around the world ( 40 – 42 ). This suggests a common mechanism for cancer resistance that evolves convergently in 10 million people each year, regardless of the driver mutation or the tissue of origin ( 42 , 43 ). Resistance to therapeutic interventions has classically been attributed to genetic tumor cell heterogeneity: Among the billions of cancer cells in a tumor, mutations lead to at least one cancer cell becoming resistant to a particular therapy ( 44 – 65 ).…”

Mutation or not, what directly establishes a neoplastic state, namely cellular immortality and autonomy, still remains unknown and should be prioritized in our research

“…Pertinent to progression, tumor-related genes can be dichotomized into 1) mutators that are defined herein as the genes or genomic structures whose epigenetic or genetic alterations can cause or accelerate alterations at others and 2) non-mutators whose epigenetic or genetic alterations do not cause alterations at others (Table 2). While the "evolvability" theory of Pienta et al suggests the involvement of the ability of evolution in tumorigenesis [141,684], our "mutator" concept, which may entail any genomic level(s) illustrated in Figure 1 and not just canonically defined genes, emphasizes the ability of evolution in tumor progression to more-heinous states. With this dichotomy, neoplasms can be reclassified at the genomic level: Benign neoplasms are those bearing epigenetic or genetic anomalies at non-mutators and thus do not accumulate genetic abnormalities, whereas malignant neoplasms are those bearing epigenetic or genetic alteration(s) at the mutators and thus easily have accrued alterations (Table 3 and Fig.…”

“…In turn, fewer discourses have been focused on the immediate tumor-causing factors, i.e., those molecular or cellular alterations that directly establish cellular immortality and autonomy. The "immortality and autonomy" definition of neoplasia connotes that a neoplasm resembles a new or quasi-new unicellular organism [700] and thus should have some mutations, because a new organism should have something new in the genome [141]. Therefore, wrangling over "whether epigenetic abnormality alone can establish cellular immortality and autonomy, namely establishing a neoplastic state", is actually a debate on whether "difference(s) only at the epigenetic level are sufficient to define a new organism", making this issue a general question of taxonomy.…”

“…Of course, there are pediatric cancers, which are likely initiated during the embryonic stage [138,139] and occur via different mechanisms from those for the sporadic cancers in adults [140]. A related perplexity is called "the proliferation paradox" [141]: Some cell types that have the fastest turnover in the human body have the lowest cancer incidences [141], epitomized by the epithelial cancers in the hair follicles and the small intestine. Epithelial cells of the hair follicles grow so fast that men need to cut their hair once a month, but these cells rarely develop to cancer [142,143].…”

Modeling cancer’s ecological and evolutionary dynamics

“…In recent years, however, there has been a growing appreciation among both theorists and empiricists for cancer as an ecological and evolutionary process [ 35 , 58 , 100 ]. This view has led to a better understanding of the initiation and spread of cancer [ 2 , 12 , 45 , 95 ], innovations in evolutionarily informed therapies [ 19 , 20 , 47 , 105 ], and a reframing of the way we think about cancer [ 5 , 17 , 51 , 76 , 83 , 91 ]. In this paper, we introduce an evolutionary game theoretic (EGT) approach called G functions that allow us to mathematically formalize notions of ecology and evolution in cancer.…”