Some reports demonstrated that(1):reprogramming metastatic tumour cells with embryonic microenvironments. If genetic mutation is persistent ,How does this reversion (cancer to normal cell)happen?
1.Nature Reviews Cancer 7, 246-255
I am sorry to differ totally with my distinguished colegue's opinion. Cancer involves mutations, and as a matter of fact, mutations are basically the reason for cancer development. Oncogenic viruses act through changes in cell genome or by taking control of its protein synthesis machinery.
Regarding malignant cells being modified by the introduction of embrionyc genes, no doubt that those cells are modified by these embryonic genes, but this does not mean that those cells lose the pro-oncogenic mutations they have undergone. So that we should not consider them as normal cells.
Amended on 3 January 2017
I do not agree such an idea of mutation theory at all. This idea seems to be a representative "pathological science" as has already been suggested by Famous American Agnostic Dr. Irving Langmuir (please see file; Irving Langmuir). He has been the first Ph.D. to recognize that the quatitative determination method is essential to guide us to the truth of Nature.
Dr. Yutaka Aoyagi (School of Medicine, Niigata University, Chuoh-ku, Niigata-city, Niigata, Japan) has been the first to show that glycochains are changed in cancer by using quantitative HPLC-lectin-affinity method; i.e., in Aoyagi Y, Suzuki Y, Igarashi K, Yokota T, Mori S, Suda T, Naitoh A, Isemura M and Asakura H: Highly enhanced fucosylation of alpha-fetoprotein in patients with germ cell tumor. Cancer 72: 615-618, 1993 and in J Hepatol. 2000 Jun;32(6):946-54. Plasma fucosyltransferase activity in patients with hepatocellular carcinoma, with special reference to correlation with fucosylated species of alpha-fetoprotein. Mita Y, Aoyagi Y, Suda T, Asakura H..
Then, we have found that glycochain changes and Ki of cancer-biotinidase increases (please see file; Anticancer Res) in HCC by using quantitative HPLC-enzyme assay method. Glycochain changing induced by integrated phage (virus) has been long known in E. coli; i.e., phage conversion or lysogenic conversion in order to prevent other phages invade into the infected E. coli cell.
Cancers occur by invasion of microbes; i.e., co-invasion and co-integration of HIV-1 and HCV causes the hepatocellular carcinoma (HCC) (HBV is not linked to cancer; please see file; HepG2 fucoidan). It is found that both Gag-Pol polyprotein (HIV-1; with Reverse transcriptase (RT) and Integrase (IN)) and Genome polyprotein with Serine proteaseNS3 (HCV) expression is important (please see file; The Fascio Effect).
Therefore, induction of co-integrated two viral DNAs seems to be occurred by cancer-inducing excess excitements or excess stimuli such as mental and physical stresses, drugs, electromagnetic waves (visinity to the high-tension wire, radio wave, ultraviolet light, X-ray), reactive oygen species, asbestos, insomnia, excess of hormones, excess of nutrients, etc. (please see file; The Fascio effect). Thus, cancer may be occuring among the rich people. Then, the fucoidan (sulphated polyfucose) healed or prevented the hepatocellular carcinoma (HCC) in the DEN-treated WT SD-rat (please see file; Rat DEN Np-Fuco). Rat liver may have been spontaneously infected by retrovirus of AKT8 Murine leukemia virus (MLVAT) and co-integrated Murine hepatitis virus (MCoV; +ssRNA virus) with the helper virus of MLVAT, and I have done the stimulation by chemical carcinogen DEN (diethylnitrosamine), which is performed for 3 months plus 3 weeks for control rat. Sample rat (stimulation by DEN for 3 months) is fed Mozuku for 3 weeks (with DEN stimulation by abdominal injection). After one week of rest time (without no treatment; total eperimental time becomes 4 months), the livers of two groups have been compared (please see file; Rat DEN Np-Fuco). This discovery of healing or curing effect demonstrated by Japanese edible Mozuku (containing edible Fucoidan) within three weeks of therapy has most deeply impressed me throughout my biochemical research-life of c.a. 40 years, and I have surely shed happy tears to see this wonderful result.
Then, human stomach cancer may be caused by RNA-phage of Helicobactor pylori together with retrovirus (HIV-1), and human cervical cancer (such as HeLa cell) may be caused by HHV-2 or RNA-phages of Chlamydophila felis and HIV-1 (HPV may not be linked to cancer; non-parametric statistics and quantitative HPLC method other than ELISA is necessary to be concluded; please see the article in Tiss.Cult.Res.Commun., 16, 181-187, 1997 (in Japanese). Can SV40 become a murderer in human cancer. Masayoshi Namba and Kazuo Fushimi (Graduate School of Medicine and Dentistry, Okayama University, 2-5-1 Shikada-cho, Okayama, Okayama 700-8558, Japan)). They says that "SV40 (Simian Virus 40) was discovered as a contaminant of poliovaccine propagated in rhesus monkey kidney cells and then was found to be highly oncogenic in hamsters when injected. At that time it was feared that the overall cancer incidence of humans who were vaccinated against polio could increase. However, the follow-up examination has not determined yet the significant increase of cancers. Since SV40 plays a critical role for immortalization of human cells, a relationship between SV40 and human carcinogenesis can not be denied. Recently SV40 genome has been detected in various human tumors. We review some reports on SV40 in human tumors."
I have once been selected as one of the reader's panel in scientific magazine "Nature", and I have repeatedly demanded that Nature magazine should appraise the research articles from the biochemists studying about glycoproteins and polysaccharides rather than DNA/RNA.
Furthermore, I must have to add about the genes. We must recognize that humans and Escherichia coli have not have all the genes of other creatures at all. Nitrogen molecules must be incorporated into the cells of nitrogen-fixing bacterium (nitrogen fixing genes), and resistance to mercuric ions is only performed by Pseudomonas bacterium, but not able to be performed by any species of Escherichia coli at all (please see file; Resistance to Hg). Therefore, the gene expression change and/or the reversion to normal human cell is not the truth in the cancer at all.
I am sorry to differ totally with my distinguished colegue's opinion. Cancer involves mutations, and as a matter of fact, mutations are basically the reason for cancer development. Oncogenic viruses act through changes in cell genome or by taking control of its protein synthesis machinery.
Regarding malignant cells being modified by the introduction of embrionyc genes, no doubt that those cells are modified by these embryonic genes, but this does not mean that those cells lose the pro-oncogenic mutations they have undergone. So that we should not consider them as normal cells.
There is no reversion of cancer cell to normal cell. What happens is that a cancer cell is modified by embryonic genes...but they still remain to be cancer cells.
The fact that they do not show proliferation, migration or invasion, does not mean that they are not cancer cells any more. Do they enter into dormancy? or senecense? This I cannot answer, but I think it may be a very interesting issue to investigate.
Contrary to established consensus, mutation of genes may be the consequence and not the cause of cancer. After all, how can carcinogenic chemical molecules only attack those genes (about 5% of the total) which are involved in cell division? As James Watson recently hinted, root cause of carcinogensis is likely to a biochemical pathway, rather than genetic mutations.
This is not a difficult question at least for simple point mutations. Many tumor cell lines have a mutator phenotype that increases rates of mutation many fold some by orders of magnitude But this is true of reversion (back) mutations also including those that restore a wildtype phenotype.One would expect then numerous patches of cells with normal histopathology throughout a growing tumor cell mass.
Mutation in cancer is required but not enough. So called -driver- mutations such as BRAF, EGFR is well defined in cancer. Besides mutations, epigenetic events and translational modification and microenvironment also important in carcinogenesis. So mutation is only one component in carcinogenesis, other mechanisms involved in carcinogenesis may be revert in embriyonel environment.
It looks like there is a bit of confusion in this field. Cancer is caused by accumulation of genetic mutations (single nucleotide, small indels, structural variants..) plus epigenetic modifications.
@Jay Kulsh: how can carcinogenic chemical molecules only attack those genes (about 5% of the total) which are involved in cell division?
They do not! carcinogenic compounds increase the rate of mutations and therefore lead to accumulation of mutations in the entire genome. The reason why we do see only mutations in that 5% of oncogenes/oncosuppressors is darwinian selection. Mutations hitting non-driver genes don't cause clonal expansion of the target cell (i.e. no cancer -> no 'positive' selection), therefore we do not detect them, unless we go single-cell.
As opposite, driver mutations (i.e. mutations occurring in critical oncogenes/oncosuppressors) cause oncogenic transformation and clonal expansion of the target cell. Sequencing analysis of such a clonal population reveals the presence of somatic, oncogenic variants (plus passenger, plus subclonal variants but this is another story..).
Back to the original question: cancer occurs because mutations cause oncogenic signalling. If external factors such as small molecule inhibitors, antibodies, reprogramming, siRNA and so on disrupt this signalling this may lead to 'suppression' of the cancer phenotype. However, unless the cancer cell is killed, the genome of that cell will still contain the oncogenic variants.
@Dr Bozdogan I agree completely. As we approach 2017 there are a number of theories of carcinogenesis that have solid empirical support from decades of studies in both the laboratory and in the clinic: somatic mutation, epigenetic, tissue field organization, metabolic/bioenergetic and aneuploidy, In my view none explains the data well by itself but neither are these theories mutually exclusive. To my mind they all have merit but are part of a larger whole that we just do not understand at present. What is needed is a simplifying and unifying hypothesis of carcinogenesis that accommodates at least the essential elements of each and much more cooperation and collaboration in our research efforts worldwide.
I think it is possible that a dominant mutation driving a tumor, could be epigeneticaly silenced by a embryonic microenvironment since tumours have a tendency to turn back to time concerning differentiation stages
If we see cells as single life units then environmental changes awaken evolution at the cellular level, I believe that the first cell is the most dynamic of all and maybe the reason for loss of differentiation by cancerous cells, the cells effort to adopt to a hostile environment
Dear Piazza
If it is simple as you stated why we can't cure the cancer?
Dear Barclay
It wii be an unified theory of cancer? as you know "theory of everything" is dream of physicts for several years.
Lastly Do we need a theory to cure cancer? experiments may be useful , For example embrriyonic environment may be used for cancer therapy
Dear Tez, Yes as the sub mentioned study showed atypical lymphocytes in a case Primary Cutaneous Follicular Lymphoma with an antigen of H. pylori detected at cell membrane and cytoplasm ( immunohistochemistry) and its disappearance after eradication with triple therapy where lymphocytes return normal to typical cells.
A. H. Bashir (Adil HH Bashir)1,6,*, S M Yousif2, Lamyaa A M EL Hassan3, W M Elamin4, Ameera Adam5, M. E. Ibrahim5, K. O. Alfarouk5,6, A. K. Muddathir7, A M EL Hassan5. Primary Cutaneous Follicular Lymphoma Associated with Helicobacter pylori Infection A. American Journal of Dermatology and Venereology 2013, 2(3): 27-30.
@Mesut Tez "If it is simple as you stated why we can't cure the cancer?"
Because unfortunately knowing the list of driver somatic mutation(s) present in a cancer doesn't automatically lead to a cure. Even if we know that in a neoplasm P53 is knocked-out, selectively restoring its expression in ALL cancer cells is far beyond our current technologies.
Generally speaking, at present we are much more efficient in blocking the activity of constitutively active oncogenes, especially kinases (see Imatinb to inhibit BCR/ABL1 fusion protein in chronic myeloid leukemia as a perfect example of this approach), than in restoring loss of function events (loss of oncosuppressors).
dear rocco
far beyond our current technologies?
How far is it to replace nucleotide gene parts with crispr technology?
As for darwinian selection and cancer;
the lack of cancerous events regarding the small intestine bothers my statistics
as well as the accumulation part when it comes to tissues of high proliferation rate
Actually Mesut you are right we don't need a unifying theory before we make tremendous advances in treatment because there may be no such thing. I think it likely that there are many ways to begin a tumor and many chaotic paths in disease progression. What I mean by a unifying and simplyfying model is that we need to understand tumor biology much better before we can hope to make important advances in treatment. On the other hand many new treatments these days are technology driven and reveal important insights into the malignant process in the absence of any model.
@Evripidis Diamantopoulos: "dear rocco: far beyond our current technologies? How far is it to replace nucleotide gene parts with crispr technology?"
Dear Evripidis, please consider that:
1) In order to cure a cancer we need to EFFICIENTLY repair oncogenic mutations, where efficiently means in virtually ALL the cancer cells. Even an efficiency of 99%, which is much much much more than standard cas9 efficiency wouldn't be enough to cure a clonal disease (the remaining 1% would keep growing). That's why cas9 has been proposed (with several caveat) to treat genetic disorders and most notably genetic disorders characterized by loss of function of an enzyme. In these cases even an efficiency below 5% is enough to at least activate a bit of enzymatic activity.
2) When we deal with genome-modifying strategies such as cas9 we must be very careful, because these techniques may also target off-target loci leading to unpredictable effects to the patients (and potentially also to progeny).
3) How would you repair large TP53 deletions with cas9 ?
I think that "Integration" is key to fully understand cancer or any other genetic disease. The same driver mutation will not cause oncogenesis in different cells. Several other factors are needed: the cell environment, house keeping gene expression, localisation and co-expression of co-factors,....At experimental level, systematic interrogation tools will help to design a sort of network of events needed for a given mutation to drive oncogenesis. There are several important initiatives out there that are going to help to better understand diseases such as interactome mapping, the human cell atlas, RNA-seq for the ~ 300 cells that compose the human body, etc. Gene reparation will also help if the cellular context is verified.
Happy new year of science discovery!
Dear piazza
Tallens, znfs, crispr-cas, show ways not far beyond our technologies
since attachment of 20 or so nucleotide sequences to nucleotide
excission -repair proteins is naturally occuring then engineering of them for attacment of custom made sequences for a100% specifity- sensitivity
(R-D)NP complex is near, meganucleases maybe, as for deletions if we locate the presence of a sequence then in a way we highlight the coordinates that lack this sequence
I do agree with Dr Tomas Koltai opinion as we should not consider them as normal cells as these cell were under what may consider side influencers (induced embryonic genes) part from their genetic control machinery
I think that scientific research is much like putting together a jigsaw puzzle in the dark. After much hard work and inspiration from others one gets to shine a light on a portion of the puzzle. In the case of cancer we have the somatic mutation, epigenetic, aneuploidy, metabolic bioenergetic and tissue field organizational theories all of which have considerable empirical support so to my mind they cannot be rejected out of hand and replaced with new paradigm. We need a light that shines on the whole puzzle that shows the big picture. For a problem as big as cancer this will require much more international cooperation and collaboration.
Reprogramming Malignant Cancer Cells toward a Benign Phenotype following Exposure to Human Embryonic Stem Cell Microenvironment.
Zhou S1,2, Abdouh M1, Arena V3, Arena M4, Arena GO1,5.
Author information
PLoS One. 2017 Jan 9;12(1):e0169899. doi: 10.1371/journal.pone.0169899. eCollection 2017.
Abstract
The embryonic microenvironment is well known to be non-permissive for tumor development because early developmental signals naturally suppress the expression of proto-oncogenes. In an analogous manner, mimicking an early embryonic environment during embryonic stem cell culture has been shown to suppress oncogenic phenotypes of cancer cells. Exosomes derived from human embryonic stem cells harbor substances that mirror the content of the cells of origin and have been reported to reprogram hematopoietic stem/progenitor cells via horizontal transfer of mRNA and proteins. However, the possibility that these embryonic stem cells-derived exosomes might be the main effectors of the anti-tumor effect mediated by the embryonic stem cells has not been explored yet. The present study aims to investigate whether exosomes derived from human embryonic stem cells can reprogram malignant cancer cells to a benign stage and reduce their tumorigenicity. We show that the embryonic stem cell-conditioned medium contains factors that inhibit cancer cell growth and tumorigenicity in vitro and in vivo. Moreover, we demonstrate that exosomes derived from human embryonic stem cells display anti-proliferation and pro-apoptotic effects, and decrease tumor size in a xenograft model. These exosomes are also able to transfer their cargo into target cancer cells, inducing a dose-dependent increase in SOX2, OCT4 and Nanog proteins, leading to a dose-dependent decrease of cancer cell growth and tumorigenicity. This study shows for the first time that human embryonic stem cell-derived exosomes play an important role in the tumor suppressive activity displayed by human embryonic stem cells.
...The embryonic microenvironment is well known to be non-permissive for tumor development...
...SOX2, OCT4 and Nanog are potent oncosuppressors...
...world is changing...
...and I'm getting old... :)
Epigenetic modifications are usually understimated. In colon cáncer is fully demonstrated, just to say an example and it is the case with the embryonic niche.
It is known that replication of DNA is completely accurate, but when mutations happened errors will be copied at subsequent replications, alters the amino-acid sequence and hence the structure and function of the protein product, so if the cause of that error removed whatever it was for example bacterial (H.pylori) then replication of DNA will be completely accurate i.e mutation theory is correct, and cancer cell revert to normal cell.
American Journal of Dermatology and Venereology 2013, 2(3): 27-30
DOI: 10.5923/j.ajdv.20130203.03
Primary Cutaneous Follicular Lymphoma Associated with Helicobacter pylori Infection A. H. Bashir1,6,*, S M Yousif2, Lamyaa A M EL Hassan3, W M Elamin4, Ameera Adam5, M. E. Ibrahim5, K. O. Alfarouk5,6, A. K. Muddathir7, A M EL Hassan5
Evolutionary biology teaches us that there two fundamental mechanisms that drive genetic change. Mutagenesis and recombinagenesis. Genetic continuity requires that these two processes be maintained within tolerable limits by DNA replication (once and only once per cell division) and DNA repair both as a proofreading function of mismatch errors made during S phase and as a correction mechanism of environmental insults. Mutations that survive are fixed in the genome and become the genetic novelty upon which selection forces act in the case of cancer in the local microenvironment. Recombination events on the other hand generate new gene combination and connections and have a profound effect on gene expression epigenetic effects bioenergetics and metabolism. In the case of cancer it is my view that all of these processes come into play.
Yes I agree but the phenotype must be heritable in some fashion or it is lost in a single generation. Does not have to be genetic. Could also be epigenetic or adaptive but still must be passed on from generation to generation.
Amended on 13 July 2018
I have newly found that the morphology in humans is also ruled by virus at about half a year ago.
Since virus rules gene expression (due thanks to Dr. Joel Subach, Rutgers, The State University of New Jersey, New Brunswick, NJ, USA), I have further studied about the abnormal expression of Mucin, which is usually expressed in the Epithelial cells. Mucin genes in cultured liver cells seem to be up-regulated by HHV (except HHV-5 and HHV-6) and down-regulated by HIV and HCV.
Further, I have considered about the grief Down syndrome. It seems to be mainly due to infection by Human adenovirus (HAdV). Only three specimens have the Down syndrome cell adhesion molecule (membrane glycoprotein; Hydrophobicity is 0.510, similar to the hydrophobicity to another representative membrane glycoprotein of Growth hormone receptor of 0.499).
Then, another Morphological Disease of Harelip or Cleft lip may be occurred similar mechanism to Alopecia. As has also been recently reported in this ResearchGate that Transcription factors of Homeobox proteins have been up-regulated by some inducing virus (HAV, VSIV, LIV, hPIV-5, MuV), and repressed by Flu virus.
Harelip-linked Homeobox protein MSX-1/Hox-7 seems to be up-regulated by Hepatitis A virus (HAV). HAV infection to pregnant mother may be occurred by biotin deficient state, which induces lowered innate immunity. HAV seems to infect preferably to female, and Flu seems to virulently infect to male (harelip seems to be higher in male persons; my unpublished observation). As shown in Alopecia case, Morphological change is also co-induced by biotin deficiency, which leads to instable membrane structures.
Since fucoidan (sulphated poly-L-fucose) can reduce virus and bacteria without any side effect (very safe even to pregnant womem), taking edible fucoidan or edible brown algae (except inedible fucoidan from Ireland) may rescue the miserable morphological changes in the birth of humans.
Adequate Nutrition (biotin (vitamin H) and lipoic acid (thioctic acid))is also an important issue in morphogenesis and growth (please see file; Feed by Measure).
Furthermore, I have recently found about the causes of cancer.
(1) human hepatocellular carcinoma (HCC) is caused by HCV and HIV-1. HBV seems not related to cancer at all.
(2) human stomach cancer may be caused by RNA-phage of Helicobactor pylori together with retrovirus (HIV-1),
(3) human cervical cancer (such as HeLa cell) may be caused by HHV-2 or RNA-phages of Chlamydophila felis and HIV-1.
(4) human pancreatic cancer seems to be caused by coinfection of HIV-1 and HCoV.
(5) human breast cancer (HBC) may be caused by co-infection of HIV-1 and some +ssRNA virus such as Sindbis virus (SINV) or Dengue virus (DENV).
(6) human bile-duct cancer or Cholangiocarcinoma may be caused by co-infection of HIV-1 and Liouping ill virus (LIV), Mosquit cell fusing agent (CFA flavivirus), HCV. Interestingly, Japanese encephalitis virus (JEV) and Hog cholera virus (Classical swine fever virus, CSFV) seem to suppress the bile-duct cancer, which seems to these virus can battle to get the hegemony against the inducing virus.
These findings are harmony with the previous findings about serum. "Determination of human serum biotinidase activity with biotinyl-6-aminoquinoline as substrate: Application to the serum of cholangiopancreatic diseases. Kou Hayakawa, et al. (1998) Vitamin (Kyoto), 72, 172-172."
Serum biotinidase activity (V) decreases in HCC and Cholangiocarcinoma, however it increases in the Pancreatic cancer.
This result suggest that different virus changes differently onto the glycochain structure of serum biotinidase.
Therefore, if cancer cell is returned to normal cell, it is because the other virus (non-cancer inducing virus) have the hegemony or have driven away the cacer-inducing virus (such as HIV-1, HCV and/or HCoV). But, fucoidan is best to drive away the cancer-inducing virus.
Thus, notorious Mutation theory or hypothesis is not true at all.
Dear Barry
How can we explain result of Anglesio 's study?
"We found that lesions in deep infiltrating endometriosis, which are associated with virtually no risk of malignant transformation, harbor somatic cancer driver mutations. Ten of 39 deep infiltrating lesions (26%) carried driver mutations; all the tested somatic mutations appeared to be confined to the epithelial compartment of endometriotic lesions. "
Anglesio, M.S., et al., Cancer-Associated Mutations in Endometriosis without Cancer. New England Journal of Medicine, 2017. 376(19): p. 1835-1848.
Nice question –it also highlight the current entrenched view that cancer is a ‘disease of the genome’. Here is my take on this plasticity:
Firstly, cancer status is not a Boolean state - cancer is a phenotype that exist on a spectrum, i.e. there are different degrees of ‘cancerness’. Secondly, biological systems are information rich, and the instructions for cell behavior/phenotype is not only embedded in the genome, but is also inscribed in tissue architecture and of course, the paracrine signalling context. So any given cell phenotype is not only an intrinsic property of the cells, but also of its microenvironment (ecological terms: Phenotype = genotype + environment + interaction between environment and genome). (Thus, though cancer may be a ‘disease of the genome’, when we try and treat cancer, we are not targeting a genome, but a phenotype!)
In highly advanced cancer cells will be less able to revert to a ‘normal’ state. But in the early phases, the ‘cancer phenotype’ only becomes apparent under ideal conditions (such as tissue disruption of tissue architecture and inflammation). An ecological analogy is the phenomenon of phenotypic plasticity –the ability of one genome to give rise to different phenotypes. An example, is aphids usually they don’t have wings.
Similar, the pre-neoplastic lesions may result in a ‘normal cells’ that becomes cancerous if other inhibitory signals becomes removed. Cancer arising from these cells can revert back to a normal phenotype is the appropriate signalling context is re-established (i.e. if external pro-proliferation signals are removed, or is the oncostatic signals are imposed).
So WHY cancer cells revert back do is because they have no say in this (they lack agency- they cannot strategise proactively, but only respond in a short sighted manner). They simply respond to the blind forces of natural selection and the dry, stale mechanics of biology: if the situation allow them to become cancerous, they become cancerous. As cancer cells acquire change mutations, they may end up more and more independent- those subclones with a better ability to persist and multiply persist and multiply –and acquire even more mutations in the process. ‘Rinse and repeat’: you end up with a de-differentiated cell that proliferate independent of any signalling information. But in the early phases, cancer cells remaind 'shackled' by environmental cues. Remove the cues, and you have cancer: reinstall them, and the cells are forced to revert back to a 'normal' state.
because "synchronization" of all existing mutations is important to initiate and then drive cancer
The environmental context differs from organ to organ tissue to tissue and from individual to individual requiring new high tech tools of precision medicine including AI.
... Take the blood,
for example: 1% of all newborn babies have cells with an
acute lymphoblastic leukaemia-associated mutation and
histopathologically identifiable precursor lesions that are
present at ~100 times the corresponding rates of clinical
cancers...
from: An evolutionary perspective on field
cancerization
Kit Curtius, Nicholas A. Wright and Trevor A. Graham
But why does it have to be either or? Although ultimately it is a genetic disease, it is regulated by so many other factors that there is no absolute which is why cancer is so difficult to treat.
Reversion to a phenotypically "normal" status does not mean it is normal. There are so many layers in order to fully revert them back to normal, we are talking about signalling, the microenvironment, cell-to-cell interactions, epigenetics and etc. Analogous to that, if the problem lies in the government, fixing a problem at a departmental level is not going to solve the root cause.
Some cancer cells are known to be heavily dependent on their microenvironment. For instance, CLL cells, if you take them out of the microenvironment, they do not survive for long.
Therefore one of the prospective methods to eradicate CLL would logically be to alter the microenvironment. The question is how much modification can you have before the normal cells start to die? Will that modification alter the response in normal cells? Will that cause them to start to change and mutate as well? Is it well-tolerated by the body? Can it actually be a treatment for patients?
Realistically, as of now, there are/will be no "cures". If you can provide palliative care that is sufficient to ensure patients can have a fulfilling life (long enough to the end of their term, maybe 70-80 years old), does it really matter if it is a "cure"? Also, as the saying goes, prevention is better than cure so perhaps an area to stress on is preventive care.
Cancer Cells rarely revert to normal genotype or phenotype, however, this happens with retinoids in some leukemias, also it can be the mechanism behind Arsenium trioxide anti-leukemia action, coming from Traditional Chinese Medicine, some neural crest tumors revert to a normal phenotype under metabolic products. Beta-blockers, used for face Angiomas, revert some Angiosarcomas, the field is just opening
Cancer to my mind is the evolution of an emerging pathogen starting with a tumorigenic stem cell. Evolutionary biology teaches us that at a mechanistic level there are two genomic processes that would give rise to the genetic novelty upon which selection forces might act in the local tumor microenvironment to give rise to the heterogeneity seen in many tumors ( including clonal populations of normal cells). Firstly, mutations in both nDNA and mtDNA are a primary mechanism and such tumor cells would have 2n diploidy for the most part and have formed the basis of the somatic mutation theory for many years but to my mind represent only part of the story. Just as important (and responsible for tumor cell lineages with loss of heterozygosity, gross chromosomal rearrangements and aneuploidy not 2n lineages) are recombination events between homologous chromosomes or more importantly between non-homologues that gives rise to new combinations of hundreds of genes simultaneously and alterations in their expression levels creation of new genes by fusion events and dearchiving of genes silenced since embryogenesis and organ formation (dedifferentiation). So my comment speaks to the mechanistic and kinetic nature of the heterogeneity that gives rise to normal cells in some tumorsl. To my mind such heterogeneity does not only arise with very early events but is ongoing ie with each turn of the cell cycle with the generation of new mutation and recombination events. Such genomic instability in both the nucleus and mitochondrion giving rise to chaotic gene expression patterns (not stochastic) and resultant heterogeneous tumor cell populations over time and favoring those that have adapted to survival in a hostile human host environment as a developing pathogenic entity.
Hi Mesut Both. Pre-exising cells favorable to tumor growth and development are selected for by selection forces in the local microenvironment. Others by extrachromosmoal elements (circles hairpin palindromes chromothripisis events) are adapative and Lamarckian. They are also important adaptive elements in acquired resistance to chemotherapeutic drugs like MTX and 5-FU.
it is tricky because cancer development will never lead to a multicellular organism. For this reason, this type of development does not look like evolution, but as a permanent transformation of unicellular beings.
Someone clearly wants to show us something, i.e. what is the result of unprogrammed evolution...
That's a very interesting point of view Adnzej. I didn't mean to suggest that tumour development as an evolutionary process generated a functional multicellular organism. What I mean,t was that to my mind, cancer is a pathological state that has the ability to access the developmental program of a species that has evolved over millions of years, but only in a pathological way.
The tumours can access genes involved in embryogenesis and organ development but only in a chaotic fashion.
Dear Barry: chaotic, quasi-chaotic or semi-chaotic? In my opinion cancer development is not chaotic. This looks like semi-chaotic development, i.e. the response of cancer cells, to the chaotic destruction of DNA, is not chaotic. This mechanism is supported, among others, by clonal expansion and clonal selection, and as a result we get a monster consisting of set of unicellular beings. Each of these unicellular beings is potentially very dangerous.
Dear Andrej yes agreed at least in part maybe does not fit perfectly into chaos theory but certainly not stochastic. I would emphasize that most tumors are heterogenous from onset. Part of the tumor cell mass being clonal and well behaved in terms of human biology. Other portions of the tumor cell mass driven by chromosome breakage and reunion events with each turn of the cell cycle generate massively rearranged genomes and chaotic reprogramming of H sapiens developmental pathways. not as unicellular organisms but as parasitic (to the host) but symbiotic(to each other) cell populations.
this looks like semi-chaotic development Dear Barry: destruction of DNA (by ROS) is chaotic, but cancer cells are alive and for this reason their response to this destruction is very logical, it can be said that in a sense this response is preprogrammed.
Maybe, as I can imagine this all, symbiotic (to each other) behaviour - this is only our illusion...
we observe the most-adapted cancer cells that clone quickly (i.e. these aggressive cells). Other cells clone not so fast (or die) - in any case, they are dominated by aggressive ones. The impression may be that these most aggressive cells cooperate.
Yes agreed. The real breakthrough in our understanding of cancer will come from a description of the :Big Bang" event ie what happened in that first cell that opened the door into the darkness. By the time most tumors are diagnosed they are at least 100MM cells. Assuming a doubling time of approx 24h thats about 20 cell divisions over a month or so. Difficult to work backwards and figure out how the tumor mass started from the very first event. And as you say the most aggressive cells would be selected for in the diagnosed tumor and not necessarily represent the single cell of origin in any way.
Tumor growth seems following a 'Gompertz', curve, I was said, replication is high in early times, when the mass is heavy, multiplication rate flattens, but this may change from histology to histology, from a lump to another.
Genetic, mutational tumor landscape is quite stable in some pathologies, e.g, changes from primary to metastatic lumps, or inside same lump along space and time, appear 'only' in 10% of CRC tumors.
Some elementary probability calculations may help you ascertain what this mean for chances of an individual therapy being efficacious, and for how long, but numbers make me feel bad.
this single cell of origin probably died soon after cancer transformation and the first cloning (i.e. after cancer initialization).
We can only observe the light of this expired (evil) star...
But we have to remember that this has been the cell of our body. So, better to die than to be transformed - but unfortunately apoptosis does not always protect against transformation.
My view is that in early divisions extreme genomic and epigenomic instability is favored as it provides the variability upon which forces in the local microenvironment can act to favor tumor growth and progression. But later as Joe stated there is excess noise in the system so secondary events must damp this down to favor tumor survival ie angiogenesis glucose supply and normoxia.
Maybe in this way: after undergoing polyploidy by cancer cells (as a result of genome instability), these cells obtain a lot of new possibilities to adapt to environment. So, at the beginning of the cancer development, the cancer cells need a lot of changes to adapt. After time, process of undergoing polyploidy helps the cells to adapt, so such large changes are not needed anymore and the process of adaptive changes (in some cases) may slow down.
for example: https://www.researchgate.net/publication/322599783_Stress-induced_polyploidy_shifts_somatic_cells_towards_a_pro-tumourogenic_unicellular_gene_transcription_network
Dear Mesut,
from our today's point of view, we can have such an impression.
A result of cancer development is not chaotic, so from the point of view of the effects that occur at the microbiological level, this development is not chaotic, it looks like semi-chaotic.
The use of very fast computers (maybe in the future the use of quantum computers) and advanced programming algorithms, should in the future slowly, step-by-step reveal the pattern of cancer development.
for example:
"Pattern of cancer mutations" section in https://www.researchgate.net/publication/326302952_Bioenergetics_of_life_disease_and_death_phenomena
Somatic mutant clones colonize the human esophagus with age
Iñigo Martincorena1,*,†, et. al.
Science 23 Nov 2018: Vol. 362, Issue 6417, pp. 911-917 DOI: 10.1126/science.aau3879
The mutational burden of aging
As people age, they accumulate somatic mutations in healthy cells. About 25% of cells in normal, sun-exposed skin harbor cancer driver mutations. What about tissues not exposed to powerful mutagens like ultraviolet light? Martincorena et al. performed targeted gene sequencing of normal esophageal epithelium from nine human donors of varying age (see the Perspective by Chanock). The mutation rate was lower in esophagus than in skin, but there was a strong positive selection of clones carrying mutations in 14 cancer-associated genes. By middle age, more than half of the esophageal epithelium was colonized by mutant clones. Interestingly, mutations in the cancer driver gene NOTCH1 were more common in normal esophageal epithelium than in esophageal cancer.Science, this issue p. 911; see also p. 893
Abstract
The extent to which cells in normal tissues accumulate mutations throughout life is poorly understood. Some mutant cells expand into clones that can be detected by genome sequencing. We mapped mutant clones in normal esophageal epithelium from nine donors (age range, 20 to 75 years). Somatic mutations accumulated with age and were caused mainly by intrinsic mutational processes. We found strong positive selection of clones carrying mutations in 14 cancer genes, with tens to hundreds of clones per square centimeter. In middle-aged and elderly donors, clones with cancer-associated mutations covered much of the epithelium, with NOTCH1 and TP53 mutations affecting 12 to 80% and 2 to 37% of cells, respectively. Unexpectedly, the prevalence of NOTCH1 mutations in normal esophagus was several times higher than in esophageal cancers. These findings have implications for our understanding of cancer and aging.
I'd say mutant cancer cells revert to normal genotype rarely, if ever, but there are some malignancies where it revert
Mutations move in the foward direction at about the same rate as reversions do so about 10-6 to 10-7 per cell division per gene. In a palpable mass of 10-8 cells there will be about 10 to 100 cells that have reverted to wildtype wrt their histopathology and show up as normal by light microscopy.
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