Chromatin remodeling system, cancer stem-like attractors and
cellular reprogramming
Yue Zhang
Department of Radiation Oncology, Beth Israel Deaconess Medical Center, Harvard Medical
School, 99 Brookline Avenue, Boston, MA 02215, USA
Tel +1 617 667 0953
Fax +1 617 632-0275
Email yzhang1@bidmc.harvard.edu
Supplementary text.
Current cancer theories, multi-cellularity and cancer targeting
Current carcinogenesis theories
Currently there are a number of prevailing cancer initiation and progression theories [1], such
as:

the mutator phenotype theory[2],

the cancer stem cell hypothesis(see below),

the viral theory and quasi-species model for cancer[3],

genetic driver mutation for cancer[4],

the aberrant differentiation theory,

the “cancell” theory[5],

a multi-stage theory of somatic evolution and tumor progression[6],and

the tissue organization field theory[7].
Most of thse theories are useful in many instances, but ad hoc explanations are often required.
For example, clonal evolution has difficulty in reconciling the progression of metastasis in all
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carcinomas, while EMT struggles with the random nature of gene mutations. Such irreversible
mutations cannot explain why certain metastatic carcinomas can reform normal tissue
boundaries but with the tumor remaining dormant for years. Loeb (1991) [8] postulated the
existence of a so-called mutator phenotype and he further claimed that “cancer cells must
exhibit or have exhibited a mutator phenotype”. Others, however, have argued that selection
without an increased mutation rate is sufficient to explain tumorigenesis [9] and the mutations
seen in tumors, especially if the process of aging increases the selective conditions for clonal
expansion.
Another subject of much discussion is the origin of intratumor heterogeneity. The cancer stem
cell hypothesis suggests that a subset of self-renewal stem-like cells drive tumor initiation and
progression [10-12]. Their differentiation generates intratumor heterogeneity. In contrast, the
clonal evolution model maintains that a premalignant or malignant cell population accumulates
various hereditary changes over time and is hence subjected to Darwinian selection. Several
mutations in a single cell are required for cancer initiation [13], and further genetic and
epigenetic alterations will drive malignant cells to become aggressive, invasive and drugresistant, leading to heterogeneity [10]. The tumor cell plasticity model states that all or most
tumor cells have varying degrees of stem cell-like characteristics due to microenvironments
and/or cell intrinsic stochasticity [14-16], which could be responsible for intratumor
heterogeneity[16]. The inherently heterogeneous clonal populations of mammalian cells display
non-genetic variability resulting from gene expression noise and the gene networks of multiple
stable states. These stable, heritable variants within one cell type can respond differently to
environmental conditions and serve as a temporary substrate for natural selection in the
absence of mutations. However, the cancer attractor theory suggests that such non-genetic
variability can contribute to the somatic evolution of cancer cells (both Lamarckian and
Darwinian evolution) and tumor progression independently of genetic mutations [17].
The tissue organization field theory posits that tumors result from a flawed interaction among
cells and tissues, and that carcinogenesis is potentially reversible if cancer cells are exposed to
strong “normally oriented” morphogenetic fields. One new theoretical model united by nonequilibrium dynamics (attractors) and developmental biology (morphogenetic fields) can
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establish a meaningful theoretical framework that is able to give reliable explanatory insights
into the complex interactions taking place between cancer cells and embryonic cues.
Morphogen-induced network rewiring results in a shift of attractor boundaries, leading to a
displacement of the cell population toward a different attractor. This may explain how the same
signal can cause discretely disparate phenotype switches [18].
NuRD and its functionally related CRCs -orchestrated “archaic” cancer attractor and
the driving factor for “stemness” cell proliferation
Now this NuRD/CRCs -orchestrated “archaic” cancer attractor theory (see main text Figure 2)
provides molecular terms for this united theory. First, the metaphoric “walking” of cells along
the trajectories can be coupled with cell division, since the Mi-2/NuRD complexes couple with
cell division via an array of pathways [23, 25]. Considering the metaphorical “potential energy”
in Figure 2, the non-attractor status or the height of the “mountain” possibly provides a driving
force for embryonic/stem/progenitor cell proliferation. In C. elegans, although we could not
exactly define this “potential energy” (i.e, an inverse of probability) in a realistic molecular
items, we could speculate that this is the nature of one life form’s system, i.e. one open system
going toward the closed system and increasing its entropy to the end state[19]. This “potential
energy” should be the trend linking inherited genomic program, environmental stresses, the
availability of nutrients and the storage of ATPs, which Mi-2/NuRD complexes require for
chromatin remodeling. Such driving forces could originate from the evolution-driven primary
benefit of multi-cellularity, including:

the division of labor, or specialization provided by differentiated cells;

cooperation supported by the messaging, stigmergy and apoptosis[20];

the advantages of scale, circuit control and management provided specifically by the
elements, such as promoters, enhancers and ncRNAs, allowing the organism to have a
range of competitive strategies available for foraging, hunting and defense.
But the chemical gradient could be the direct “driver” factor. In general, the multi-potency of
organisms is lost during development. In molecular terms, chemical diversity decreases along
with a decrease in the number of activated genes. Stem cells with multi-potency, such as ES
cells and HSCs have been proposed to have a variety of weakly activated genes, but a
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terminally differentiated cell has a smaller number of strongly activated genes. In addition, the
temporal variation in intra-cellular dynamics is larger for the stem cell, e.g. the dependence of
Ca oscillation on the cell type is variable. The complexity in dynamics changes with the loss of
multi-potency, beginning with the ES cell. It remains unclear about the relationship between the
growth of multi-cellular organisms and some characteristics of intra-cellular chemical dynamics,
although the cause and effect of chemical reactions on evolution of multi-cellularity dynamics
are robust [21-22].
Evolution and mult-cellularity
Furthermore, attractor theory could also help us to better understand the evolution of the rules
and the mechanisms when multi-cellular organisms emerged in the world. Defective Mi-2/NuRD
complexes have been linked directly to oncogenesis [23] and have potential as therapeutic
targets for cancer treatment. In the quasi-species cancer model, several features are clearly
shared by both RNA viruses and unstable tumors, such as high levels of heterogeneity, both at
the genotype and phenotype level, and different replication and infection mechanisms in RNA
viruses that can be matched to the wide levels of variability in cancer cells, affecting cell
communication, growth and apoptosis. Accordingly, a means of eluding the immune system
(and other selection barriers) operates in both systems [24]. Indeed, the virus-like cancerous
cells also hijack the host tissue and seem to behave like a virus [25-26].It could be asked if it is
possible that the cells, tissues or organisms with defective Mi-2/NuRD complexes (losing their
control of the Mi-2/NuRD complex “core”) are somehow similar to GASP in bacteria and ADDD in
yeasts [27]. Speculatively, cancer cells could somehow need reverse/retrograde evolution. If
this is the case, lethal mutagenesis might be meaningful to cancer prevention and therapy; we
could thus profit and even further expand the therapy cocktail for cancer patients, similar to the
highly active antiretroviral treatment [28] cocktail used for HIV patients.
The Mi-2/NURD is versatile and, presumably, the organisms with defective Mi-2/NuRD
complexes could somehow be characterized by “promiscuous” chromosome and nuclear
organization of an evolutionally sub-optimized/retrograde “intermediate” between
archaebacteria, bacteria and eukaryotes. As mentioned earlier, the zygote stage for germline
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cell somehow mimics the unicellular life form or prokaryotic cell. Starting from the single-cell
stage, some organisms with defective Mi-2/NuRD complexes could experience a re-evolution at
this point or at different multi-cellular stages [29]. Similar to this, cancer “organisms” can be
regarded as a novel uni-/bi-cellular tumor initiation cells and later a multi-cellular organism that
tries to evolve independently during the lifetime of their host [21]. Cancer tumors as Metazoa
1.0 hypothesizes that “cancer is an atavistic condition that occurs when genetic or epigenetic
malfunction unlocks an ancient ‘toolkit’ of pre-existing adaptations, re-establishing the
dominance of an earlier layer of genes that controlled loose-knit colonies of only partially
differentiated cells, similar to tumors. The existence of such a toolkit implies that the progress
of the neoplasm in the host organism differs distinctively from normal Darwinian evolution. The
cancer attractors theory without CRCs could conclude that cancer might be indeed an
inevitable process ( Dr. Sui Huang comments, personal communication). Although in-detail
investigations need, our NuRD/ CRCs -linked cancer archaic attractors theory get cancer
prevention and therapy optimism among oncologists in that necessity of understanding of cancer
as atavism is limited (even its evolution during the past ) and further studies of cell- tissue- stage-or
organisms of NuRD/ CRCs are not infinite.
Novel strategy of cancer targeting
Since the Mi-2/NuRD and its functionally related CRCs–orchestrated “archaic” cancer attractor
theory could unify multi-cellularity, it would imply reorientation of current treatment principles
from cellular destruction therapies to cellular retraining or cyto-education [31]. To resolve these
complex questions, a strategy from “simple” to “simpler” (i.e. to resolve a simple question first
so as to reduce the complexity) could be a sensible direction for research. Because the context
is critical, systematic multi-cellular in vivo drug screening for co-clinical trials could be
accelerated by using the model organisms such as mouse, zebrafish (Danio rerio) and C.
elegans. Moreover, the side-effects of drugs on humans sometimes take years or decades to
show up; a whole animal systematic in vivo drug screening trial with short-lived model
organisms such as C. elegans is advantageous since it could provide invaluable information
about the potential long-term and/or dormant side-effects on potential aging-related diseases,
such as cancer and neurodegenerative diseases.
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Obviously, this novel theory integrates well with differentiation theory, i.e. a block of normal
differentiation and abnormal reversal of differentiation (i.e. de-differentiation) being the
hallmarks of cancer. However, “chemotherapeutic intervention in advanced cancer alone has
been an exercise in futility.” [32] One could somehow combine chemotherapeutic intervention
targeting this Mi-2/NuRD complex with the differentiation therapy designed to facilitate cancer
cells re-entering the differentiation program. Its success depends on appropriate molecular
“lever points”, the perturbations of which place the bio-molecular system into states that are
poised to differentiate. Indeed, a therapeutic agent or embryonic extracts could allow the
system to naturally flow toward an attractor that corresponds to the desired cellular endpoint.
Some intriguing preliminary results have been obtained from both in vivo and in vitro studies
with proteins extracted from frog (Xenopus I) or zebrafish (Danio rerio) at different embryonic
stages. Clinical trials performed using zebrafish embryo extracts administered to advanced
cancer patients who no longer respond to conventional treatment had marked beneficial effects
[33].
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