The Systemic–Evolutionary Theory of the Origin of Cancer (SETOC): A New Interpretative Model of Cancer as a Complex Biological System

Mazzocca, Antonio

doi:10.3390/ijms20194885

Cited by 27 publications

(26 citation statements)

References 20 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The complex life cycle experienced by PGCCs that can result in the emergence of therapy resistant progeny is consistent with the atavistic model of cancer [60][61][62][63][64][65][66][67][68][69]. In this model, "cancer is interpreted as a reversion to phylogenetically prior capabilities, namely the release of a highly conserved survival program encrypted in every eukaryotic cell, and hence in every multicellular animal.…”

Section: Multinucleated/polyploid Cancer Cellssupporting

confidence: 68%

“…Thus, as cancer is an extremely complex disease, its prevention has proven to be equally complex, extending far beyond modulating the DNA damage response and/or cell death pathways. It is becoming increasingly evident that, to realize the monumental goal of combating cancer, one must take into account not only the mutational basis of intrinsic/acquired therapy resistance of cancer cells, but also non-mutational events such as cancer cell dormancy, horizontal (cell-to-cell) transfer of genetic material containing cancer stem cell markers [53], an atavistic process whereby cancer cells re-express ancestral traits that includes severe stress resistance [60][61][62][63][64][65][66][67][68][69], and cancer cell fusion (e.g., cancer cell-leukocyte [28,144]) which facilitates cancer cell circulation and metastasis. Irrespective of this complexity, one must hope that a better understanding of the multifactorial nature of cancer cell resistance to therapeutic agents will finally lead to novel strategies to prevent, or at least significantly suppress, cancer recurrence.…”

Section: Can Cancer Recurrence Be Prevented?mentioning

confidence: 99%

See 1 more Smart Citation

Intratumor Heterogeneity and Therapy Resistance: Contributions of Dormancy, Apoptosis Reversal (Anastasis) and Cell Fusion to Disease Recurrence

Mirzayans

Murray

2020

IJMS

View full text Add to dashboard Cite

A major challenge in treating cancer is posed by intratumor heterogeneity, with different sub-populations of cancer cells within the same tumor exhibiting therapy resistance through different biological processes. These include therapy-induced dormancy (durable proliferation arrest through, e.g., polyploidy, multinucleation, or senescence), apoptosis reversal (anastasis), and cell fusion. Unfortunately, such responses are often overlooked or misinterpreted as “death” in commonly used preclinical assays, including the in vitro colony-forming assay and multiwell plate “viability” or “cytotoxicity” assays. Although these assays predominantly determine the ability of a test agent to convert dangerous (proliferating) cancer cells to potentially even more dangerous (dormant) cancer cells, the results are often assumed to reflect loss of cancer cell viability (death). In this article we briefly discuss the dark sides of dormancy, apoptosis, and cell fusion in cancer therapy, and underscore the danger of relying on short-term preclinical assays that generate population-based data averaged over a large number of cells. Unveiling the molecular events that underlie intratumor heterogeneity together with more appropriate experimental design and data interpretation will hopefully lead to clinically relevant strategies for treating recurrent/metastatic disease, which remains a major global health issue despite extensive research over the past half century.

show abstract

Section: Multinucleated/polyploid Cancer Cellssupporting

confidence: 68%

Section: Can Cancer Recurrence Be Prevented?mentioning

confidence: 99%

Intratumor Heterogeneity and Therapy Resistance: Contributions of Dormancy, Apoptosis Reversal (Anastasis) and Cell Fusion to Disease Recurrence

Mirzayans

Murray

2020

IJMS

View full text Add to dashboard Cite

show abstract

“…In general, our results address the conceptualization of diseases as complex systems, like in the case of cancer 64,65 . In fact, the multiple interactions between virus RNA and host cells operate as a dynamic system, capable to overcome the action of external driving forces.…”

Section: Discussionmentioning

confidence: 95%

Energy dynamics for systemic configurations of virus-host co-evolution

Romano

Casazza

Gonella

2020

Preprint

View full text Add to dashboard Cite

ArticlePositive single-stranded RNA ((+)ssRNA) viruses, including picornaviruses, flaviviruses, togaviridae and human coronaviruses (h-CoVs) 1-4 cause multiple outbreaks, for which tailored antiviral strategies are still missing [5][6][7] . (+)ssRNA viruses package their genomes as messenger sense, single stranded RNA and replicate those genomes solely through RNA intermediates in the cytosol of the host cells 8 . RNA-dependent RNA polymerases lack co-and post-replicative fidelity-enhancing pathways, and final RNA genome copies incorporate mutations at a much higher rate than that observed for DNA genomes 9,10 providing the viral quasispecies a higher probability to evolve and adapt to new environments and challenges during infection 11,12 . The diversity is essential for both viral fitness and pathogenesis, due to the complex relationship between virus replication, host cells and immune system, since almost +RNA viruses can delay antiviral innate immune response 13 in multiple ways [14][15][16][17][18][19][20] . Host immunogenetic factors can be sensitive to a variation in the viral load, conveying to a defective response of the innate immunity that could explain the variable clinical course of infection 20,21 . Among (+)ssRNA viruses, h-CoVs have unusually large genomes (∼30 kb) associated with low mutation rates 20,22 . Three novel h-CoVs are etiological agents of serious viral interstitial pneumonia 23 . They include the severe acute respiratory syndrome, first described in Guandong province in China in 2002 24 , the Middle East respiratory syndrome (caused by MERS-CoV), emerged in June 2012 in Saudi Arabia and Qatar 25 , and the SARS-CoV-2, emerged in China in January 2020, cause of the largest outbreak in the modern history 23 .Recent studies confirmed the complexity of viral dynamics, whose fitness is improved by the complex interactions with the host proteins 26,27 as previously described in modelling the virus-host interactions at sub-cell and cell levels 6,28-31 . However, models that address a specific aspect of the virus-host interaction do not capture the wide range of intertwined spatial and temporal (hours to days) dynamic scales 32 , that are related to the interaction of different concurrent hierarchical levels.All these factors address the need for a description able to connect all the levels at which the infection proceeds within a single cell, from the recruitment of RNA-synthesis factory to the final host cell damage. Several drugs, such as chloroquine 33,34 , hydroxychloroquine, ribavirin, lopinavir-ritonavir 35 , were used in patients with SARS [33][34][35] or MERS 7 and are currently under investigation, alone or in combination, to control the COVID-19 infection [36][37][38][39][40][41][42][43][44][45][46][47] . However, there is an urgent need of a new class of compounds, other than nucleotides mimetics, due their low-fidelity viral RNA polymerase 48 to combine with host factor targeting agents, recently identified to lead to a therapeutic regimen to treat COVID-19 6 .We show that, b...

show abstract

“…Interestingly, this finding brings us back to the world of prokaryotes that provide specific functions while being intracellular residents, as a possible case of what could be called "oncologic symbiosis". Furthermore, the intracellular location of the tumor microbiota connects it to some of the most recent theories on the origin of tumors [195,196]. One of these notions sees the roots of cancer etiology as grounded in the two transitions (from prokaryotic to eukaryotic, and from unicellular to multicellular beings) that ultimately lead to the establishment of higher organisms [195].…”

Section: Conclusion and New Perspectivesmentioning

confidence: 99%

“…One of these notions sees the roots of cancer etiology as grounded in the two transitions (from prokaryotic to eukaryotic, and from unicellular to multicellular beings) that ultimately lead to the establishment of higher organisms [195]. The other, the so-called "Systemic-Evolutionary Theory of Cancer (SETOC)", proposes that, as a consequence of long-term injuries caused by cancer-promoting factors, cancer results from a process of regression of the eukaryotic cells towards a situation in which its prokaryotic component assumes uncoordinated behaviors, which ultimately break the integration of the components of the endosymbiotic cellular system [196]. It will be extremely interesting to see whether the newly identified intracellular prokaryotic cells of the tumor microbiota play any role in these proposed regressive processes.…”

Section: Conclusion and New Perspectivesmentioning

confidence: 99%

A Significant Question in Cancer Risk and Therapy: Are Antibiotics Positive or Negative Effectors? Current Answers and Possible Alternatives

Amadei

Notario

2020

Antibiotics

View full text Add to dashboard Cite

Cancer is predominantly considered as an environmental disease caused by genetic or epigenetic alterations induced by exposure to extrinsic (e.g., carcinogens, pollutants, radiation) or intrinsic (e.g., metabolic, immune or genetic deficiencies). Over-exposure to antibiotics, which is favored by unregulated access as well as inappropriate prescriptions by physicians, is known to have led to serious health problems such as the rise of antibiotic resistance, in particular in poorly developed countries. In this review, the attention is focused on evaluating the effects of antibiotic exposure on cancer risk and on the outcome of cancer therapeutic protocols, either directly acting as extrinsic promoters, or indirectly, through interactions with the human gut microbiota. The preponderant evidence derived from information reported over the last 10 years confirms that antibiotic exposure tends to increase cancer risk and, unfortunately, that it reduces the efficacy of various forms of cancer therapy (e.g., chemo-, radio-, and immunotherapy alone or in combination). Alternatives to the current patterns of antibiotic use, such as introducing new antibiotics, bacteriophages or enzybiotics, and implementing dysbiosis-reducing microbiota modulatory strategies in oncology, are discussed. The information is in the end considered from the perspective of the most recent findings on the tumor-specific and intracellular location of the tumor microbiota, and of the most recent theories proposed to explain cancer etiology on the notion of regression of the eukaryotic cells and systems to stages characterized for a lack of coordination among their components of prokaryotic origin, which is promoted by injuries caused by environmental insults.

show abstract

The Systemic–Evolutionary Theory of the Origin of Cancer (SETOC): A New Interpretative Model of Cancer as a Complex Biological System

Cited by 27 publications

References 20 publications

Intratumor Heterogeneity and Therapy Resistance: Contributions of Dormancy, Apoptosis Reversal (Anastasis) and Cell Fusion to Disease Recurrence

Intratumor Heterogeneity and Therapy Resistance: Contributions of Dormancy, Apoptosis Reversal (Anastasis) and Cell Fusion to Disease Recurrence

Energy dynamics for systemic configurations of virus-host co-evolution

A Significant Question in Cancer Risk and Therapy: Are Antibiotics Positive or Negative Effectors? Current Answers and Possible Alternatives

Contact Info

Product

Resources

About