Cancer Hypotheses
Cancer Hypotheses

Cancer Hypotheses considers publishable any paper that has new views on any aspect of cancer, preferably where there is some evidence that leads towards  a new concept.

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Dual origin of endemic Burkitt’s lymphoma

Cancer Hypotheses 2018 2, 1, 1-20

Received:   7 Nov 2017, Accepted: 20 Dec 2017, Published: 16 Jan 2017

Brandon P Reines

Adjunct Assistant Professor

Department of Biomedical Informatics

University of Pittsburgh School of Medicine

Pittsburgh, PA, USA

REINESB@pitt.edu

 

©  The Author 2018

Abstract

Endemic Burkitt’s lymphoma (eBL) is presumed to be caused by Epstein-Barr virus EBV) present in mother’s saliva and breast milk.  However, the anatomical topography and age incidence of eBL tumors is not easily explained by either saliva or milk transmission.  In particular, jaw tumors are maximal at 3 years, and abdomen-centered tumors at 14 years.  The anomalous cephalic tendency of early eBL is more simply explained by transplacental passage of EBV: most microbes passed to the fetus and spread via umbilical veins preferentially damage structures developing within the fetal head, because maternally-derived microbes are first deposited there in highest concentrations.  As fetal jaw marrow is where most early B cells are located in the fetal head, and EBV has tropism for B cells, it makes sense that the earliest tumors to develop occur mainly in jaws.  In contrast, eBL abdominal tumors which occur in later childhood are likely induced by swallowing infected saliva.  The fact that most cases of eBL without obvious jaw tumors nonetheless show damage to lamina dura underlying molars suggests that an osteolytic step may be rate limiting for clinical expression of tumor.  Hence, many children with eBL may have two slightly different EBV-driven pathogenetic processes co-occurring and possibly competing within individual bodies.  

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Dual origin of endemic Burkitt’s lymphoma
CH-Reines[2]-DWFV.pdf
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  • Prateek Sharma (Saturday, October 06 18 11:40 am BST)

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Stress-induced polyploidy shifts somatic cells towards a pro-tumourogenic unicellular gene transcription network 

Cancer Hypotheses 2018 1, 1, 1-20

Received:   5 Nov 2017, Accepted: 12 Jan  2017, Published: 17 Jan 2017

Jekaterina Erenpreisa1*, Alessandro Giuliani2, Alexander E Vinogradov3, Olga V Anatskaya3, Alejandro Vazquez-Martin4, Kristine Salmina1, Mark S Cragg5

1Latvian Biomedical Research and Study Centre, Ratsupites 1, Riga, LV1067, Latvia

2Istituto Superiore di Sanità, Rome, Italy

3Institute of Cytology, St Petersburg, Russian Federation

4AsturBiotech, Gijón, Principality of Asturias, Spain

5Southampton University School of Medicine, Southampton, UK

*corresponding author: katrina@biomed.lu.lv

* Corresponding author

©  The Authors 2018

Hypothesis: Polyploidy enables access to transcriptional networks of unicellular organisms, which in the absence of tumour suppressors provides immortality and resistance from treatment for cancer cells

Abstract: Theories of cancer are central to our understanding of biology and receive frequent refinement. Here, we propose a link between key aspects of the atavistic theory of cancer and the capacity of polyploidy to access transcriptional networks of unicellular organisms. Polyploid cells are known to display greater capacity for adaptation to environmental challenge than their diploid counterparts. Whole genome duplication (WGD) induced by environmental crisis is crucial for facilitating the genetic bias of speciation and for providing the long-term increase in genetic and biological complexity. Somatic tumour cells appear to reverse this process in response to stress. Our recent studies reveal that polyploidy is cooperatively linked by cellular stress to stemness, dedifferentiation and a shift towards the transcriptional networks typical of unicellular organisms.  We hypothesise that when cells undergo polyploidy they enter a transcriptional continuum enabling rapid epigenetic adaptation to environmental challenge followed by clonal selection of genetic differences. For tumour cells, in the absence of tumour suppressors this polyploidy-induced stemness state provides access to the transcriptional network of eukaryotic precursors, whose immortality and survival fitness are supported by their a-sexual ploidy life cycles. This process can be equated to a reversal along the phylogenetic tree of evolution providing the single-cell autonomy and immortality that are fundamental hallmarks of cancer. 

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Stress-induced polyploidy shifts somatic cells towards a pro-tumourogenic unicellular gene transcription network
CH-ErenpreisaFinal2-DWFE.pdf
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  • Vladimir Niculescu (Tuesday, April 10 18 01:16 pm BST)

    The present work is of particular interest and value. The authors belong to the group of cancer cell biologists focusing attention on the atavistic elements in cancer development. In the last years, the authors have worked extensively on the post-genotoxic repair and transdifferentiation of somatic cancer cells to reproductive neotic CSCs capable of CSC-EMT conversion. They underline the pivotal role of tetraploidy, polyploidy and WGD in the process of post-genotoxical CSC formation. As a cell biologist with interest to protists and cancer cell development, I am particularly delighted.
    Genotoxically stressed p53 cancer cells arrest to beginning of the genotoxic crisis in a tetraploid G1 state (that follows mitotic blockage in G2) forming several cell fractions: Some of the damaged cells (MC fraction) repair partially the DSB strand breaks. As a result they enter mitosis with damaged DNA and die by mitotic catastrophe (MC); Most of the genotoxically damaged cells remain in the state of mitotic blockage (premature senescense) and die by premature apoptosis (Apoptotic cell fraction); Finally a minor cell fraction escapes apoptotic death by conversion into the reproductive/neotic pathway (Mitosis bypassing fraction). The reasons of this differentiation are unknown. The asynchronous progression of the culture at the time of irradiation may be a possible factor.
    The amitotic tetraploid G1 cell state decides if somatic damaged cells may switch into the alternative neotic pathway forming atavistic PGCCs and micro-CSCs (PGCC's progeny) or not. Cells switching to the neotic cell state express the atavistic differentiation potential, hidden in the somatic cancer cell genome. The decision to enter the polyploidisation-depolyploidisation pathway bypassing mitosis is taken in the tetraploid G1 state. It is the same decision taken by the cell of origin (cancer initiating cell) that activates the atavistic cancer genes (UGs) (Doi: 10.15406/mojtr.2018.01.00004)

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Hypothesis of the Basic Biological Sense of Cancer Revisited - A Putative Explanation of Peto’s Paradox

Cancer Hypotheses 2017 4, 9, 1-16

Received:  2017, Accepted: 26 December  2017, Published: 28 December  2017

Oscar D Bustuoabad and Raúl A Ruggiero*

Laboratory of Experimental Oncology, IMEX-Conicet, Academia Nacional de Medicina de Buenos Aires, Pacheco de Melo 3081, 1425 Buenos Aires, Argentina

* Corresponding author

©  The Authors 2017

Abstract

The conventional interpretation of cancer, summarized in the unified genetic theory of carcinogenesis, assumes that the malignant cell is the anatomical and physiological unit of cancer. This assumption means that any evolutionary increase in the number of cells (and thus body size) should lead to a higher tumor incidence since the population at risk is higher. However, the available data fail to support this prediction: most animals, in particular most mammals, exhibiting wide differences in body size and lifespan, from the mouse to the blue whale, display a roughly similar tumor incidence.  This unexpected lack of correlation between body size, lifespan and cancer is usually called Peto’s paradox and it has intrigued theoretical oncologists for decades.

In this essay, we attempt to offer a putative explanation of this paradox based on the notion that the unit at risk of carcinogenesis is actually the tissue or organ rather than the individual cell. In turn, this notion is based on a different interpretation of neoplastic diseases that we proposed some years ago and that has been called the hypothesis of the biological sense of cancer.

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Hypothesis of the Basic Biologic Sense of Cancer Revisited
Bustuoabad and Ruggiero
CH-Raul-Peto.pdf
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Table 1
Table 1
Table 1.pdf
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Hypothesis and theoretical model of the role of therapy-mediated cell loss in promoting recurrences in glioblastomas

Cancer Hypotheses 2017 3, 8, 1-15

Received:  2017, Accepted: 23 May  2017, Published: 15 June 2017

Mrinmay Kumar Mallik

©  The Author 2017

 

Abstract

A hypothesis and theoretical model incorporating the role of dynamically distinct cell compartments in governing growth and relapses in glioblastoma was published in 2010. Subsequent reports have given a further insight into some of the mechanisms that might influence the functional properties of the model and its implication on the functional biology and therapeutic implications for this tumor, which usually has a dismal prognosis. This updated essay is an attempt to document some of the relevant developments in this regard. It also proposes an extension of the model by contemplating on the existence of an exploitable weakness or "Achilles Heel" in these tumors. Although the model has been developed with respect to glioblastomas, conceptually it might well be applicable to other tumors. READ MORE:

Mrinmay Kumar Mallik
Hypothesis and theoretical model of the role of therapy-mediated cell loss in promoting recurrences in glioblastomas
Mallik.pdf
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Chronic inflammation leads to adapted immune cells forming local and distant tumors at sites of inflammation

Cancer Hypotheses 2017 2, 7, 1-12

Received:  2017, Accepted: 23 March  2017, Published: 23 March 2017

Leili Shahriyari

Mathematical Biosciences Institute, Ohio State University, Columbus, Ohio OH 43210, USA

©  The Author 2017

Hypothesis

It is hypothesized that chronic inflammation leads to a deficient immune system that forms tumors not only at the primary site of chronic inflammation, but in other inflammatory sites.

Abstract

The main drivers of some tumors are defective immune cells, not epithelial cells. In particular, epithelial cells are just the victims; mutations occur in epithelial cells due to high levels of inflammatory signals secreted from defective immune cells. Therefore, I hypothesize that some metastases are the result of inflammatory processes by defective immune cells at sites of inflammation rather than migration of tumor cells from one site to another site. Consequently, common cancer treatments such as chemotherapy are not effective for some tumors, because theses treatments cause inflammation in tumor and other organs. Furthermore, since chemotherapy increases the chance of inflammation in some organs such as lung and liver, it facilitates metastases to these organs. READ MORE:

Leili Shahriyari
Chronic inflammation leads to adapted immune cells forming local and distant tumors at sites of inflammation
CH-1008-Lieli.pdf
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Microsatellite instability as a driving force for cancer progression

Cancer Hypotheses 2017 1, 6, 1-16

Received: 7 February 2017, Accepted: 7 March  2017, Published: 7 March 2017

 

*Nives Pećina-Šlaus 1, 2 , Anja Bukovac 1,2  Iva Salamon3, Anja Kafka 1,2

1    Laboratory of Neuro-oncology, Croatian Institute for Brain Research, School of Medicine University of Zagreb, Salata 12, Zagreb, Croatia

2    Department of Biology, School of Medicine, University of Zagreb, Salata 3, Zagreb, Croatia

3 University of Zagreb School of Medicine, Croatian Institute for Brain Research, Laboratory    for Stem Cells, Šalata 12, HR-10000 Zagreb, Croatia

*- Corresponding author

©  The Authors 2017

Abstract

Impaired cellular DNA repair mechanisms are greatly involved in cancer initiation and progression. In the present paper we would like to draw attention to microsatellite instability (MSI) - a part of genomic instability that characterizes cancer cell and to propose its role in cancer initiation and the promotion of cancer progression. We believe that malfunctioning of mismatch DNA repair (MMR) plays an important role in cancer, sometimes as the main driving force and sometimes as an influential bystander. Appearance of MSI as a consequence of MMR deficiency has many potential clinical implications. It can be used for assessment of cancer risk, precision grading, and prognosis as well as for the explanation why some cancers become resistant to chemotherapy.. READ MORE:

Cancer Hypotheses 2017 1,6,1-16
Pecina-Slaus et al
CH-NivesMicrosatellite.pdf
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Is spontaneous regression of cancer due to immunity or failed healing? A view from the “danger model” of immunity

Cancer Hypotheses 2016 1, 5, 1-13

Received: 1 November 2016, Accepted: 10 December 2016, Published: 13 December 2016

Brandon P. Reines

Adjunct Assistant professor, Department of Biomedical Informatics, University of Pittsburgh Medical School, 5607 Baum Blvd. Rm. 521, Pittsburgh , and 1270 Route 30, North Huntington, PA, USA

©  The Author 2016

Abstract

The view of tumours as inflamed wounds that will not heal conflicts with the notion that they are parasite-like growths controlled by the immune system. The need to resolve this central paradox of onco-immunology is cast in stark relief by our limited understanding of human cases of spontaneous regression of metastatic cancer.  It is argued that most regressions are not due to anti-tumour immunity per se, but to ultimate failure of an inflammatory healing process due to loss of support from monocyte-derived cells (MDCs).  This may occur because tumours and/or inflamed tissues out-compete one another for MDCs, leading to failed healing and cataclysmic regression of all deposits. Alternatively, remote inflammation may out-compete myeloid-derived suppressor cells thought to block T cell mediated attack on tumours. READ MORE:

Cancer Hypotheses 2016 1,5,1-13
Reines
CH-ReinesRegression-DWFV-[3].pdf
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On forces involved in cancer cell migration and invasion; a hypothesis

Cancer Hypotheses 2016 1, 4, 1-7

Received: 1 November 2016, Accepted: 3 December 2016, Published: 5 December 2016

Wolfgang H Goldmann

Department of Physics, Biophysics Group, Friedrich-Alexander-University Erlangen-Nuremburg, D-91052 Erlangen Germany

©  The Author 2016

Abstract

The development of new methods to measure tractions of single cells during migration in connective tissue and test whether cancer cell invasion is correlated with higher force generation are of prime interest. Therefore a better understanding of the role of forces may therefore help to explain tumor-specific differences of invasiveness, tissue preferences and metastasis formation. The question whether forces generated by tumor cells are influenced by stiffness of the stroma surrounding it, adhesive ligands, mesh size and other factors in the surrounding environment. READ MORE:

Cancer Hypotheses 2016 1,4,1-7
Goldmann
CH-Goldman25-11-16-DWFV[2].pdf
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The cell ancestral line - personalizing the sub-telomere profile through generations as a translatable cancer hypothesis

Cancer Hypotheses 2016 1, 3, 1-7

Received: 1 September 2016, Accepted: 25 September 2016, Published: 28 September 2016

Parvin Mehdipour

Affiliated with:Department of Medical Genetics, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran

©  The Author 2016

Abstract

Cellular diversity and heterogeneity are the highlights of evolution through pedigrees, and bridging insight could translate these definitions to the applicable elements. Amongst these, subtelomeres, as the gift provided by nature; they are the sensitive and reliable destination for “personalizing” (customizing) parts of the genomic make-up. The personalized subtelomeric profile may be considered as a translatable cancer hypothesis. READ MORE:

Cancer Hypotheses 2016 1, 3, 1-6
Mehdipour
Mehdipour.pdf
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Chicken and egg: a cause-effect relationship between viral infections and cancers?

Cancer Hypotheses 2016  1, 2, 1-15

Received: 24 June 2016; Accepted: 20 July 2016, Published: 21 August 2016

Mark Henderson 

Former editor: Theoretical Biology and Medical Modelling (BMC) c/o BioMedES UK      ©  The Author 2016

Abstract

It is now well established that the multistep cellular transformation process involved in many types of cancer are is initiated by viruses. Interestingly, there are anecdotal reports that cancers originating from non-viral causes (chemical, radiation, etc.) contain intracellular viruses. These viruses could have entered the transformed cells as secondary infections, but in this essay an alternative explanation is suggested: they are products of the cellular transformation process that generated the cancer.

There are two main models of viral origin: prebiotic ancestry, and “gene escape” from prokaryotic or eukaryotic cells. The former model has lately gained support. This is a developing field; the virosphere remains poorly characterized and many aspects of viral evolution remain obscure. Nevertheless, it is clear that at least some viruses are of recent origin, and in so far as the “gene escape” model is tenable, the conjecture that cancers act as wellsprings of viruses should merit consideration. If valid, it could imply that as the human population ages and the per capita incidence of cancer concomitantly rises, increasingly more novel and potentially carcinogenic viruses will emerge.  READ MORE:

 

Cancer Hypotheses 2016 1, 2, 1-5
Henderson
Henderson.pdf
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Cancer-Mutational Resurrection of Prokaryote Endofossils

Cancer Hypotheses 2016  1, 1, 1-15

Received: 24 June 2016; Accepted: 20 July 2016, Published: 21 August 2016

Wolfgang Sterrer

Bermuda Natural History Museum, Flatts, Bermuda       ©  The Author 2016

Abstract

I argue that cancer shares its roots with incipient eukaryogenesis. The eukaryote genome most likely originated within Archaea as a multiple of prokaryote genomes, acquired by massive horizontal gene transfer. Transferred genomes, many of them parasites, were attenuated by having their cell cycle ‘drivers’ cleaved and disassembled, then recombined into a new three-dimensional genome architecture and function, serving the emerging host as immune protection, and as the source (‘toolkit’) of most genetic innovation in eukaryote evolution.

 

Carcinogenesis in turn is initiated when, from among the many somatic mutations that accumulate with mitoses and cell line age, a first mutation restores the ‘driver’ of a constituent prokaryote endosymbiont. Cancer henceforth progresses akin to asexual evolution, generating more mutations, including additional drivers, accelerating cell proliferation and decay, and eventually overwhelming its host as a chaotically driven endoparasite.  READ MORE:

 

Cancer Hypotheses 2016 1, 1, 1-15
Sterrer
SterrerFV.pdf
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