Creating new paradigms is a prerequisite of scientific progress. But this way is the most difficult. The number of new technology far exceeds the number of new ideas. Lots of tables and graphs, but little explanation in the scientific literature.
Article Epistemology of the origin of cancer: A new paradigm
Over 20 years ago I screened some brain tumor samples for p53 mutations. Against the strong wish of my supervisor(s) to only focus on highly-malignant glioblastomas samples (WHO grade IV) which were already known to have mutations in the hotspots of the tumor suppressor gene p53, I decided to focus on something new, i.e. I asked the question whether some related, but diagnostically less malignant astrocytic brain tumors, astrocytoma WHO grades II and III (as well as biologically unrelated astrocytoma WHO grade I), could also have p53 mutations. At those days there was the model out for colon carcinoma and many scientists believed in p53 mutations as a "late event". To the best of my knowledge I was the first to find many p53 mutations already in WHO grade II astrocytomas, a finding which I shared with a colleague coming from Harvard for a visit to reproduce my results (von Deimling, Eibl et al. 1992). Since I had developed a striking animal model for medulloblastoma-like PNETs (primitive neuroectodermal tumors) using a virus gene which besides other functions also could inactivate p53, I also checked human medulloblastoma samples for such p53 mutations - and found to the best of my knowledge the first one in a human tumor sample; I shared and combined that finding with the finding of p53 in other non-astrocytic brain tumors (Ohgaki, Eibl et al. 1992). At the same time the Vogelstein-group also found a p53 mutations, but only in a cultured cell line of a medulloblastoma - but many cell cultures acquire such mutations. Now, 2 decades later, the rare subgroup of medulloblastomas seem to be in the focus of current medulloblastoma research in Germany with funding of 100 mio. EUR/dollars.
Nevertheless, shortly after my findings I realized that such point mutations are the wrong way cancer research should go. Of course, mutations can describe many subgroups of tumors, so the molecular pathologist can help to get the best tumor diagnosis.
But to be honest, I think all the genetics analyses are very boring for really bright scientists, and may not lead to the real understanding of cancer we may have in 10 or 20 years. Most cancer researchers still believe that the molecular genetics is the solution for all the cancer problems, but it becomes more and more clear, much of the last 3 decades of research was heavily overrated.
My estimated guess is: immunology is in many ways the solution ...
This includes all the inflammations which may support cancer development and many later stages, but also when it comes to an individual therapy of cancer. Genetics may help, but it should not be such a focus of billions of research money.
Agree.
Retrospectively some (to me) necessary points for such an endeavor:
•Thinking = more important than overtaking opinions, even they became dogmas.
•Understanding of findings in science as the primary intent.
•Reviewing scientific literature in detail, plus analyzing its pro’s and con’s.
•Discussing literature with an independent colleague.
•There are no stupid questions or answers.
•Having a colleague without “hidden envy” is of help.
•Search- / Reading of the primary references.
•Understanding history can change own thinking and future.
•Credit those, who deserve it.
•Accepting being often lost (mass of results found on science).
•Re-starting again (increase frustration tolerance).
•Re-scrutinize yourself (be aware of own bias).
•Accepting if own thinking was wrong.
•Accepting finding wrong conclusions in literature.
•Accepting shocks: realizing, that mutations had been suggested some 85y ago, but never been proven for the majority of cancers (just some 5 to 10%) was a shock.
•Don’t take yourself too important and stay down-to-earth.
•Be thankful for Eureka experiences: write them down.
•Try explaining it as simple as possible.
•Write everything down for getting re-scrutinized by the scientific community.
•Be aware about the “hidden envy” of many
•But don’t care about that.
@ Bjorn
There is one point that needs clarification before I go further on your theory: why do you say that mutations have never been proven for the majority of cancers? Most of the cancers harbor not only one, but several somatic mutations.
@Daniel: thank you; may I suggest to read the paper or if less time the section mutations and polymorphism; mutations had been first proposed in 1928; observed in many advanced cancers; that does not mean they had been proven causing or triggering cancer despite a minority of some 5 to 10% of cancers. It seems, that the observation that mutations were found in advanced cancers translated or mutated to statements, that they trigger cancer.
http://www.biomedcentral.com/1471-2407/14/331
or
http://www.biomedcentral.com/content/pdf/1471-2407-14-331.pdf
As you can see in this paper, almost all breast cancers have at least one somatic mutation in a cancer gene.
http://www.ncbi.nlm.nih.gov./pmc/articles/PMC3428862/
There are clearly cases of cancer where mutation is a critical early event. This includes all of the hereditary cancers such as breast or ovarian cancers in women who are BRCA1 and BRCA2 positive, hereditary non-polyposis colorectal cancer (HNPCC), also known as Lynch syndrome, retinoblastomas, Li-Fraumeni syndrome and some cancers of early childhood (http://www.cancer.org/cancer/cancercauses/geneticsandcancer/heredity-and-cancer).
However, these hereditary cancers account for about 5-10% of all human cancers and the vast majority of cancers are referred to as ‘sporadic” or of unknown etiology.
What about the 80% of sporadic cancers?
We allow ourselves addressing the section ‘Mutation and Polymorphism’ within the manuscript.
Much of the basis for the mutation theory of cancer originates from the observation that a cancer cell multiplies clonally and mutations have been observed in cancerous cells in culture and in animal models. However, given the tumor heterogeneity and the hundreds of thousands of mutations observed in a given human cancerous tissue (the available numbers had been addressed within the MS), the mutation theory as presently enunciated, does not account for the vast number of mutations actually observed and – to our knowledge - no studies have done to demonstrate that a single mutated cell becomes a cancer in vivo.
If mutations would serve as the central explanation for cancers in humans, then it would be unclear why only about 10% of smokers develop lung cancer and not 70-100%.
Only between 5 to 10% of breast and ovarian cancer are hereditary in etiology [Tomlinson IP et al.: The mutation rate and cancer. Proc Natl Acad Sci U S A 1996, 93(25): 14800-14803] and this number is an even lower 3-5% for colorectal cancer.
Despite infection-caused cancers, which are thought to occur in about 15% [Blattner WA: Human retroviruses: their role in cancer. Proc Assoc Am Physicians 1999, 111(6): 563-572] of cancers, the remainder of 72-77% (or even more) is determined as being “sporadic” or essentially where the etiology is unknown.
Somatic mutations are increasingly being questioned as drivers of carcinogenesis [Rosenfeld S: Are the somatic mutation and tissue organization field theories of carcinogenesis incompatible? Cancer Inform 2013, 12: 221-229; Versteeg R: Cancer: Tumours outside the mutation box. Nature 2014, 506(7489): 438-439].
This is underlined by actual publications in Nature (February 27, 2014) which revealed that certain cancers in humans (malignant ependymomas) are not associated with mutations [Mack SC et al.: Epigenomic alterations define lethal CIMP-positive ependymomas of infancy. Nature 2014, 506(7489): 445-450 & Parker et al.: C11orf95-RELA fusions drive oncogenic NF-κB signalling in ependymoma. Nature 2014, 506(7489): 451-455].
Actually, if you read carefully Versteeg's paper, you will see that cancers without driver mutations are the exception rather than the rule. And in these cases, extensive chromosomal defects or epigenetic modifications seem to be involved. It is known for long (see Beatrice Mintz and teratocarcinomas) that non mutational changes can play a major role in cancer. However, all the data indicate that the majority of cancers harbor driver somatic mutations.
Well, the reality seems being different, but of course may be related to our bias - you may read the following papers:
Measurements of mutagenesis of cells grown in culture yield values of approximately 2 x 10-10 single base substitutions per nucleotide in DNA per cell division or 1 x 10-7 mutations/gene/cell division. An even lower number has been demonstrated in stem cells in culture [Loeb LA: A mutator phenotype in cancer. Cancer Res 2001, 61: 3230-3239; Cervantes RB et al.: Embryonic stem cells and somatic cells differ in mutation frequency and type. Proc Natl Acad Sci U S A 2002, 99(6):3586-3590].
Taking into account this very low mutation frequency, it seems reasonable to question whether or not the spontaneous mutation rate in normal cells is sufficient to generate the large numbers of genetic alterations observed in human cancer cells.
If one were to assume that a cancer arises in a single stem cell, then the spontaneous mutation rate would only be adequate to account for less than one mutation per tumor which led to the hypothesis of the need for a “mutator phenotype”, which might induce many more mutations through the induction of genetic instability-a hypothesis not yet proven [Wogan GN et al.: Environmental and chemical carcinogenesis. Semin Cancer Biol 2004, 14(6): 473-486].
The question seems not whether mutations occur or do not occur.
Rather when these occur and whether they are the critical biochemical lesion even in the transformation of a normal cell to a cancer cell is the question.
We would assume that the arguments within Epistemology provide the evidence that it is time to question the prevailing paradigm. We are very aware, that this might not be easy for some.
The fact that the naked blind mole rat, Spalax, lives for about 30 years and does not develop cancer, even when exposed to known chemical carcinogens suggests that in the absence of the pre-cancerous niche, no cancer cells can form.
Thanks again for the talk, cheers.
"The question seems not whether mutations occur or do not occur." This is precisely the question. You have written: mutations have never been proven for the majority of cancers. When I show you evidence that it is a wrong statement, you say that it is not the question. I will not go further in trying to read your paper. Cheers.
@Daniel, The fact that somatic mutations are observed in a number of cancers is a fact. What is not proven is whether these are initial transformative events that cause a normal cell to convert to a cancerous" cell. It is helpful to not conflate the issue of causality with that of an association. And, of course, mutations do cause some small fraction of cancers such as hereditary cancers and radiation-induced cancers but not the vast majority of cancers as we understand them today. Cheers
Hi Ijaz.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3428862/
In this paper, the mutations, in more than 95% of tumors that have been analyzed, involve cancer genes.
Hi Daniel. I have no arguments with the presence of mutations or cancer genes in tumors. If cancer cells are clonal, this is absolutely necessary. My issue is what is the primal event in the transformation of a normal cell to a cancer cell? Cheers
Mutations are frequent. Correct.
Mutations had been only proven for less than 5% being "the cause" - Correct.
We are not question that mutations are not found in cancer.
We question, that it is the major cause - this is something different.
The primal event is a change in the behavior of the cell. As everything in biology, it depends on the interaction of genetics (or epigenetics) with environment. In almost all cases, teratocarcinomas being a striking exception, genetic changes are necessary.
True. But as we know "behavior" can encompass a vast array of sins! Cheers
Bjorn, if you mean to say that if you find a p53 or a ras mutation in a cancer, it is not causal, I cannot follow you.
Daniel, thank you for your comment(s).
We are not questioning, that mutations occur during carcinogenesis and - of course - we find mutations increasingly in advanced tumor categories.
We are also not questioning, that some hereditary cancers are directly triggered by mutations: the percentage rate for those is between 5 to 10%. But, still, the majority of cancers, some 80% are sporadic meaning their etiology is unknown (since a very long time).
For those (majority of cancers) it seems making sense, that mutations are not the cause (etiology), otherwise it would have been already proven. We both know, there are tons of papers which found mutations in advanced cancers. This is an observation and not a synonym for a prove being the etiologic reason– this is something different.
By this, we question mutations as being the etiology for the mass of cancers and not as associated observations, which occur during carcinogenesis.
Scientists have discovered a gene that motivates researchers to look for genes. :)
Once again, there is strong evidence that most cancers harbor mutations that are causative. Many of the mutations observed have been tested for their effects on cells. In addition, as the large majority of cancers do not display hyper-mutability in terms of point mutation, any recurring point mutation means a selective advantage.
@Daniel, Could you please cite examples of somatic mutations that are causative in human cancers in vivo? Even in ionizing radiation induced cancers (in the study of survivors from the A-bomb blasts in Hiroshima and Nagasaki) we find evidence of non-linear effects- i.e. sigmoidal dose-response curves that are indicative of rDNA epair even of known mutations in that instance. Also, in our study of children with Xeroderma pigmentosum (XP-C), we found mutations within skin cancer tissues but no mutations in nearby non-cancerous tissue. The "central causative" role of mutations is being questioned for non-hereditary cancers in our recent paper, not that there are no mutations in cancerous tissues.
http://www.ncbi.nlm.nih.gov/pubmed/?term=k-ras+mutation+colorectal
http://www.ncbi.nlm.nih.gov/pubmed/?term=myc+translocation+human+lymphoma
to quote only two examples. If I understand well, you find mutations in skin cancer but not in normal tissue of XP-C patients, and you conclude that mutations do not cause cancer. Hard to follow.
I may be of course wrong, but to my knowledge of history and Darwin:
Darwin was puzzled, that some made out of arguments a religion, and was even more puzzled about arguments about religion.
We are aware about the kras & myc examples.
They are not proof of being causative in human cancers in vivo – they are observations and thus with regard to causality hard to follow.
Causation is demonstrated in the mouse. What do you want? Human experimentation?
Still missing citing of any human cancer mutation examples that are not hereditary. Hard to follow.
@Daniel- From your lack of a response, it would appear that you have not examined the the history of cancer in humans to see if their is evidence of causality vis-à-vis mutations? You do not have to make an extreme statement such as "What evidence do you want, human experimentation" cigarette smoking causes cancer, exposure to benzene causes leukemia, ionizing radiation causes cancer, asbestos causes mesothelioma, etc. etc. All these were determined by epidemiological studies which show "associations" but when associations are repeatedly observed in large populations and repeatedly, then there is a strong suggestion of causality which can be tested experimentally in an animal model (but not in cell culture). So, I repeat my question, "where is the evidence that mutations are the causes of the vast majority of human cancers?"
Let's imagine that we do not yet know the cause of scurvy. Is it possible in this case, raise the question on some mutation as the cause of scurvy? Why not? Why lack of an important metabolit can not be a cause of cancer arising from corresponding metabolic disturbance? From this perspective, some gene dictates not cancer directly but a need in some substance that is necessary for normal metabolism. If you have this substance in sufficient quantity, you will not get cancer. So we need to talk about genetics of a deficit, not about genetics of a cancer. I hope that this approach is valid with respect to certain types of cancer.
In complete agreement with Prof. Matveev, genes are merely codes, how the codes are read determine their products or metabolites. Therefore, instead of accepting a mutation as causative of cancer, one would need a sufficient quality and quantity of mutations so that the resulting biochemical lesions (derangement of metabolites) could alter the way cells behave resulting in cancer. No such mechanism has been established for the vast majority of human cancers-- and it is not for lack of effort or monetary resources..
It was very forward thinking that mutations were proposed as being a cause for cancer in 1928. Since then some 5 to 10% hereditary tumors have been shown to be caused by mutations but some 80% of all human cancer are labeled as being “sporadic”- meaning they are of an unknown etiology. There are measurable mutation rates in different cancers cited correctly by @Daniel, but these observations are associations and not so far shown to be causative-which in science means being synonymous with proof of etiology.
As pointed out by Professor Matleev, genes are of importance for metabolism and changes of those would need a sufficient quantity of mutations. Even the clonal theory which is proposed to explain the rapid proliferation of cancer cells cannot account for the number of mutations observed in human cancers.
If someone does not accept also a kind of genetic metabolism pathway, and would say that these control everything, why has it been now proven, that genes are controlled from the outside (epigenetics)? We know the mechanism of gene control by long non-coding RNA (lncRNAs) mediated repressor occlusion; this group also identified the COX-2-lncRNA, PACER, as a new potential target for COX-2-modulation in inflammation and cancer [Kramczyk et al. Elife. 2014 Apr 29;3:e01776].
http://elifesciences.org/content/3/e01776
If we want to make progress in cancer patient treatment and cancer prevention, and that is the reason we work in this field, we should cease handling the mutation theory as a Holy Grail or dogma or worse by including religion or Darwin or getting personal.
Thank you.
Over 20 years ago I screened some brain tumor samples for p53 mutations. Against the strong wish of my supervisor(s) to only focus on highly-malignant glioblastomas samples (WHO grade IV) which were already known to have mutations in the hotspots of the tumor suppressor gene p53, I decided to focus on something new, i.e. I asked the question whether some related, but diagnostically less malignant astrocytic brain tumors, astrocytoma WHO grades II and III (as well as biologically unrelated astrocytoma WHO grade I), could also have p53 mutations. At those days there was the model out for colon carcinoma and many scientists believed in p53 mutations as a "late event". To the best of my knowledge I was the first to find many p53 mutations already in WHO grade II astrocytomas, a finding which I shared with a colleague coming from Harvard for a visit to reproduce my results (von Deimling, Eibl et al. 1992). Since I had developed a striking animal model for medulloblastoma-like PNETs (primitive neuroectodermal tumors) using a virus gene which besides other functions also could inactivate p53, I also checked human medulloblastoma samples for such p53 mutations - and found to the best of my knowledge the first one in a human tumor sample; I shared and combined that finding with the finding of p53 in other non-astrocytic brain tumors (Ohgaki, Eibl et al. 1992). At the same time the Vogelstein-group also found a p53 mutations, but only in a cultured cell line of a medulloblastoma - but many cell cultures acquire such mutations. Now, 2 decades later, the rare subgroup of medulloblastomas seem to be in the focus of current medulloblastoma research in Germany with funding of 100 mio. EUR/dollars.
Nevertheless, shortly after my findings I realized that such point mutations are the wrong way cancer research should go. Of course, mutations can describe many subgroups of tumors, so the molecular pathologist can help to get the best tumor diagnosis.
But to be honest, I think all the genetics analyses are very boring for really bright scientists, and may not lead to the real understanding of cancer we may have in 10 or 20 years. Most cancer researchers still believe that the molecular genetics is the solution for all the cancer problems, but it becomes more and more clear, much of the last 3 decades of research was heavily overrated.
My estimated guess is: immunology is in many ways the solution ...
This includes all the inflammations which may support cancer development and many later stages, but also when it comes to an individual therapy of cancer. Genetics may help, but it should not be such a focus of billions of research money.
attached more explanation from Ijaz and myself: 'Cell-Cell Communication in the Tumor Microenvironment, Carcinogenesis, and Anticancer Treatment' Cell Physiol Biochem 2014;34(2):213-243. http://t.co/WtaoKUYVcd
Individuals not biologically related resemble each other genetically & influence their genetic constitution.
So, how about the dogma genetics cause everything?
Should we even may decline calling it a paradigm anymore?
Christakisa NA, Fowlerd JH: Friendship and natural selection, PNAS 2014; http://www.pnas.org/cgi/doi/10.1073/pnas.1400825111
Thanks @Ijaz bringing this up:
Attached another piece of prove:
Lysyl oxidase-like 2 is critical to tumor microenvironment and metastatic niche formation in hepatocellular carcinoma
Abstract:
Poor prognosis of cancers, including hepatocellular carcinoma (HCC), is mainly associated with metastasis; however, the underlying mechanisms remain poorly understood. This article investigates the role of lysyl oxidase-like 2 (LOXL-2) in the biology of HCC metastasis. First, we showed that HCC metastasis relies on a collagen-modifying enzyme, LOXL2, which was significantly overexpressed in tumorous tissues and sera of HCC patients, indicating that LOXL2 may be a good diagnostic marker for HCC patients. Second, we delineated a complex, interlinked signaling network that involves multiple regulators, including hypoxia, transforming growth factor beta (TGF-β), and microRNAs (miRNAs), converging to control the expression of LOXL2. We found not only that LOXL2 was regulated by hypoxia/hypoxia-inducible factor 1 alpha (HIF-1α), but also that TGF-β activated LOXL2 transcription through mothers against decapentaplegic homolog 4 (Smad4), whereas two frequently underexpressed miRNA families, miR-26 and miR-29, cooperatively suppressed LOXL2 transcription through interacting with the 3' untranslated region of LOXL2. Third, we demonstrated the imperative roles of LOXL2 in modifying the extracellular matrix components in the tumor microenvironment and metastatic niche of HCC. LOXL2 promoted intrahepatic metastasis by increasing tissue stiffness, thereby enhancing the cytoskeletal reorganization of HCC cells. Furthermore, LOXL2 facilitated extrahepatic metastasis by enhancing recruitment of bone-marrow–derived cells to the metastatic site. Conclusion: These findings integrate the clinical relevance, molecular regulation, and functional implications of LOXL2 in HCC metastasis. (Hepatology 2014;60:1645–1658)
here another piece:
Scientists from Istanbul used a copper chelator Tetrathiomolybdate in pulmonary fibrosis mice investigating its effect on LOX, as well as on MMP’s and TIMP1. The expression of all were significantly reduced.
Ovet H, Oztay F: The Copper Chelator Tetrahiomolybdate Regresed Bleiómycin-Induced Pulmonary Fibrosis in Mice, by Reducing Lysyl Oxidase Expressions. Biol Trace Elem Res 2014. 2014 Oct 28. [Epub ahead of print]
http://www.ncbi.nlm.nih.gov/pubmed/25349139
Interesting, we both, Ijaz and myself, thought it would take longer:
one significant step of the proposed sequences of the new cancer paradigm 'Epistemology of the origin of Cancer: a new paradigm'
http://www.biomedcentral.com/1471-2407/14/331
is already proven since today:
"The tumor microenvironment is the main source of IL-6 for plasma cell tumor development in mice". Nature 2015.
http://www.nature.com/leu/journal/v29/n1/full/leu2014260a.html?WT.ec_id=LEU-201501
The public may have been misinformed about the real impact of observed / measured mutations / genetics due to wrongly mixing up observations and conclusions.
If I may be allowed, reminding us: it nearly seems that this had been in a comparable way, as cholesterol and heart disease were for decades wrongly be connected, and as we already had been thought by the primary results of the Framingham Heart Study, which to date is the longest-running and most comprehensive study on heart disease, it was clearly demonstrated that cholesterol intake in the diet had no correlation with heart disease. Interestingly, those scientists who reminded colleagues about the possibility abou a wrong direction were - before the results came up - ignored.
However, as above mentioned by this, some generations of scientists may have been misleaded into the wrong direction.
Contrary to the popular opinion, mutations and the majority of findings in cancer genetics so far reported are either late events or epiphenomena that occurs after the appearance of the pre-cancerous niche.
http://www.nature.com/nature/journal/v517/n7536/full/517563a.html#comments
NORMAL CELL TRANSITION INTO CANCER CELL – http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0117986 - Prove of 6th sequence of new cancer paradigm http://www.biomedcentral.com/1471-2407/14/331
attached below the actual prove of the 6th sequence of the new proposed cancer paradigm:
The transition from one cell function to another, as well as the transition of one cell type to another seems to be a routine event rather than a rare one. It has been shown that an epithelial mesenchymal transition (EMT) in embryogenesis/morphogenesis acts in a direction opposite to that of a mesenchymal-epithelial transition (MET) [Cell 2009, 139(5):871–890]. Furthermore, EMT can induce non-cancer stem cells to become cancer stem cells [Cell 2008, 133(4):704–715 & PLoS One 2008, 3(8):e2888].
Braun recognized some 60 y ago that a gram negative bacterium Agrobacterium tumefaciens could initiate the in vitro transformation of normal plant cells into tumor cells; he showed that transformation occurs in a short time period, resulting in tumor cells with slower growth and less progression [Am J Biol 1947, 34(4):234–240 & Proc Natl Acad Sci U S A 1958, 44(4):344–349 & Phytopathology 1951, 41:963–966]. Zaenen et al. revealed, and Mary-Ann Chilton’s group subsequently proved, that a small DNA plasmid within A. tumefaciens was responsible for the transformation [J Mol Biol 1974, 86(1):109–127.]: tumor inducing DNA (Ti-DNA), after infection, was integrated into the plant genome in tobacco plants [Cell 1977, 11(2):263–271]. Chilton also showed that Braun’s findings were based on the same principle: although the T-DNA from the A. tumefaciens Ti-plasmids was not at first detected [Proc Natl Acad Sci U S A 1974, 71(9):3672–3676], it was later proven to be in the nuclear DNA fraction of crown-gall tumors [Proc Natl Acad Sci U S A 1980, 77(7):4060–4064]. More evidence comes from research on mesothelial cells. In 1966, Eskeland, based on silver-staining electron microscopy studies, first suggested that injured or destroyed mesothelial cells are replaced in location and function by free-floating “peritoneal macrophages,” which are transformed from their original role to that of mesothelial cells [Acta Pathol Microbiol Scand 1966, 68(3):379–395 & Acta Pathol Microbiol Scand 1966, 68(3):353–378.].
As a consequence of a pathogenic stimulus such as inflammation or wound healing, EMT can change MCs into cells with mesenchymal or epithelial characteristics [Int J Biochem Cell Biol 1997, 29(1):5–17]. Recently it was reported that the transition from one cell function to another, as well as the transition of one cell type to another seems to be a routine event rather than a rare one [BMC Cancer. 2014 May 10;14:331] AND due to the above findings within the human, animal and plant kingdom it was proposed that carcinogenesis occurs by a multistep sequence and that its last step is a transition of a normal cell into a cancer cell. The actual paper in PLoS ONE 2015 proves the proposed 6th sequence of the new cancer paradigm http://www.biomedcentral.com/1471-2407/14/331 as chronic lung injury results into a transition of a normal cell into a cancer cell: http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0117986
In case someone is interested that increasingly very honorable and recognized scientists reject as well such hype trains, such as mutations, epigenetics, and many others start getting on stage:
leading biologist, Adrian Bird, Edinburgh University:
he recently compared epigenetics with Lamarckian evolution and presented extensive discussion on why epigenetics is bad science and the claims are hyped up - you may want reading it (weblink below):
These views are not alone and had been echoed by Eric Davidson, Mark Ptashne and many others.
Of course those who earn money with hype trains will at first declare it as minor opinions, but I would assume they completely underestimate what is real going on, as if someone is awake, hecan see it nearly at every corner of the streets.
Of course my views may be biased as critical thinking by a human being.
http://www.sciencedirect.com/science/article/pii/S0092867413010040
Here some more evidence:
Actual findings by Mehryar et al. WORLD GASTROENTEROL 2015 strongly supporting the new cancer hypothesis: DNA of high-risk Human Papillomavirus (HPV) types 16 and 18 is present in 80% of esophageal squamous cell carcinoma (ESCC):
http://www.wjgnet.com/1007-9327/full/v21/i10/2905.htm
This indicates in terms of ESCC a strong epidemiological indication and in terms of the mass of cancers one strong important Domino stone for the paradigm of subclinical inflammation, an infectious agent and cancer genesis proposed in ‘Epistemology of the Origin of Cancer’ in BMC CANCER 2014:
http://www.biomedcentral.com/1471-2407/14/331
http://www.wjgnet.com/1007-9327/full/v21/i10/2905.htm
http://www.biomedcentral.com/1471-2407/14/331
Since probably most or all of the so-called tumor viruses contain an oncoGENE, I think, one should consider transferring an oncogene into a cell as a genetic event - and not just speculate on the inflammation. At least there is no need to establish here the view of an immune or inflammatory response as the origin of some cancers. Maybe this is the reasone why some scientists differ in the percentage how many cancers can be explained by genetics. Of course I would consider pleural mesothelioma induced by asbestos fibres, but also the gastric cancers induced by bacteria not such a genetic event due to the lack of a transmitted oncogene, but I would count HPV induced cancers as more genetically induced cancers. In my animal experiment from 1990 (publ. 1994) with gene transfer of SV40LT I could induce medulloblastoma-like tumors. There was no inflammation necessary to induce those tumors after long latency periods of 5-11 months - but probably other genetic mutations had to appear (only half of the animals developed such tumors). These findings made my supervisor from staff physician directly to full professor.
Thank you @Robert.
The association of HPV with cancer of the cervix was discovered in 1983 and, by 1999,was proven to cause nearly all cervical cancers. Harald zurHausen published his paper in PNAS [PNAS 1983 Jun;80(12):3812-3815] reporting that HPV 16 was present in 11 out of 18 cancer patients; further, they found it in samples from Kenya and Brazil, and in vulva and penile cancer biopsy samples, but only rarely in condylomataacuminata (2/33). Sixteen years later it was reported that HPV was observed in 93% of invasive cervical cancers [Walboomers et al. J Pathol1999 Sep;189(1):12-19]. About 45% of US females between the age of 20 and 24 yearsare HPVinfected and it is well known that many HPV infections are subclinical (with chronic inflammation) without becoming clinically evident as was shown in cervix carcinoma [PNAS 1995;92(7):2840-2844], and also seen in HPV associated middle ear carcinoma [Am J Pathol. 1997 Apr;150(4):1327-1333], penile carcinomas [Oncol Lett 2010;1(2):267-272] by activation of different cytokines, such as TGF, interleukins, interferon’s and nuclear factor-κB (NF-κB). A different approach was published 5 years ago [Carcinogenesis 2010;31(11): 1905-1912]. And now we see it in esophageal squamous cell carcinoma (ESCC) as well.
Moreover, it bears being repeated here that the sensitivity of a PCR can be less than optimal--meaning just because HPV is not proven by PCR does not mean there is no HPV.
In 1986, an Asian group revealed that cases of condylomatous dysplasia with severe stromal inflammation were negative for HPV more frequently than those with mild stromal inflammation [GynecolObstet Invest 1986;22(2):97-101]. This was later discussed as the basis (as an explanation) for spontaneous regression. In such cases a T-cell phenotype assessed inflammation was observed. Furthermore, this investigation revealed that T-cell mediated immune reaction against cells and not HPV antigen induced a systemic spontaneous regression of numerous flat warts in humans before a cancer could develop.
Therefore Ijaz and myself would assume that it is not correct suggesting a non-inflammatory association of HPV-induced cancers, although – and that point is right by @Robert – that there are cases reported, in which no inflammation was reported (not the same as not present).
However, we do not know how many scientists in this regard did not concentrate at all reporting inflammation (?).
Putting this together reveals to us, that the speculation inflammation might not be prerequisite is not correct.
Thanks, Björn, for elaborating on this aspect, I fully support your view here. But to support your view even stronger, it would be ideal to find some viruses, bacteria or other inflammation inducing agents, which do not contain or directly activate an oncogene, but can induce cancer.
Here another piece of evidence:
HPV – PROINFLAMMATORY MICROENVIRONMENT – CARCINOGENESIS in COLORECTAL CANCER / Li et al. PLoS ONE 2015
Someone may call the "proinflammatory microenviornment": precancerous niche
Abstract
BACKGROUND:
Colorectal cancer (CRC) is a major burden of public health and healthcare worldwide. Microbiota has been suggested in promoting chronic inflammation in the intestine which, in turn, promotes tumor development. This study focuses on possible correlations of human papillomavirus (HPV) infection with proinflammatory Stat3 signaling activities and the resulting levels of its downstream proinflammatory cytokine IL-17 in CRC patients.
METHODS:
HPV was examined using HPV Genotyping Chip technology and constitutively active Stat3 (p-Stat3) and IL-17 levels were tested using immunohistochemistry (IHC) in paraffin-embedded cancerous and adjacent normal tissues (ANT) from a cohort of 95 CRC patients. Correlation analyses were performed between HPV infection and clinicopathological characteristics, Stat3 activities and IL-17 levels among these CRC patients.
RESULTS:
Three major findings were observed: (1) HPV infection existed in a high rate of CRC cases (48.4%, 46/95), of which 45 cases (45/46, 97.8%) were high-risk HPV16-positive and only one case was HPV53-positive. (2) HPV infection correlated with poorer clinical stages (III+IV) of CRC. (3) HPV infection strongly correlated with both constitutively higher Stat3 activities (P
Please find below strong evidence supporting the new cancer hypothesis:
Japanese scientists treat lung cancer patients with anti-inflammatory and –fibrotic atrial natruretic peptide and show that patients have by this lower recurrence rates
Personal summary:
Interesting approach from Japanese scientists: the authors published in 2011 a paper in which they could show, that circulating tumor cells in pulmonary veins during the manipulation of lung cancer surgery could be a prognostic indicator for early recurrence [Funaki et al. Eur J Cardiothorac Surg 2011;40(2):322–327]. Further this group showed, that ANP downregulates inflammatory response and having a prophylactic effect on postoperative complications due to lung surgery [Njiri et al. J Thorac Cardiovasc Surg 2012; 143(2): 488–494 Nojiri et al. Eur J Cardiothorac Surg 2013; 44(1):98–103; Eur J Cardiothorac Surg 2012; 41(6):1330–1334]. It is important to mention that ANP - besides an inhibition of the renin-angiotesin-aldosteron path through specific binding to the guanylyl cyclase-A (GC-A) receptor - has an anti-fibrotic effect (!) [Li et al. Curr Cardiol Rev 2001; 5(1):45–51 and Kishimoto et al. Curr Cardiol Rev 2009; 5(1):45–51]. Now the authors combined these findings and applicated ANP during curative lung cancer surgery and found that the recurrence rate (versus control) was lower.
Nojiri T et al.: Atrial natriuretic peptide prevents cancer metastasis through vascularendothelial cells. Proc Natl Acad Sci U S A. 2015 Mar 16. pii: 201417273. [Epub ahead of print]
http://www.pnas.org/content/112/13/4086.abstract.html?etoc
Independent of the strong support of the recent published new cancer paradigm, this could be a very useful and important approach for future peri-operative application in cancer surgery - as that is what we here for.
http://www.pnas.org/content/112/13/4086.abstract.html?etoc
Inflammation & Gastric cancer: MMP 7 restrains H pylori-induced gastric inflammation and premalignant lesions in the stomach by altering macrophage polarization. Krakowiak MS, et al. Manager's ChoiceIjaz Jamall, Ph.D., DABTRisk-Based Decisions, Inc.
Helicobacter pylori is the strongest risk factor for the development of gastric cancer. Although the specific mechanisms by which this pathogen induces carcinogenesis have not been fully elucidated, high-expression interleukin (IL)-1β alleles are associated with increased gastric cancer risk among H. pylori-infected persons. In addition, loss of matrix metalloproteinase 7 (MMP7) increases mucosal inflammation in mouse models of epithelial injury, and we have shown that gastric inflammation is increased in H. pylori-infected MMP7−/− C57BL/6 mice. In this report, we define mechanisms that underpin such responses and extend these results into a genetic model of MMP7 deficiency and gastric cancer. Wild-type (WT) or MMP7−/− C57BL/6 mice were challenged with broth alone as an uninfected control or the H. pylori strain PMSS1. All H. pylori-challenged mice were successfully colonized. As expected, H. pylori-infected MMP7−/− C57BL/6 mice exhibited a significant increase in gastric inflammation compared with uninfected or infected WT C57BL/6 animals. Loss of MMP7 resulted in M1 macrophage polarization within H. pylori-infected stomachs, as assessed by Luminex technology and immunohistochemistry, and macrophages isolated from infected MMP7-deficient mice expressed significantly higher levels of the M1 macrophage marker IL-1β compared with macrophages isolated from WT mice. To extend these findings into a model of gastric cancer, hypergastrinemic WT INS-GAS or MMP7−/− INS-GAS mice were challenged with H. pylori strain PMSS1. Consistent with findings in the C57BL/6 model, H. pylori-infected MMP7-deficient INS-GAS mice exhibited a significant increase in gastric inflammation compared with either uninfected or infected WT INS-GAS mice. In addition, the incidence of gastric hyperplasia and dysplasia was significantly increased in H. pylori-infected MMP7−/− INS-GAS mice compared with infected WT INS-GAS mice, and loss of MMP7 promoted M1 macrophage polarization. These results suggest that MMP7 exerts a restrictive role on H. pylori-induced gastric injury and the development of premalignant lesions by suppressing M1 macrophage polarization.
http://www.nature.com/onc/journal/v34/n14/abs/onc2014135a.html?WT.ec_id=ONC-201504
Short Communication nature.com
Please let me try adding some explanation of the paper @Ijaz commented above.
We assume it is necessary to present it in a stepwise fashion to make it more comprehensible and why – from our perspective – this paper is of some significance. If you take your time you may uncover that it is another important step supporting our proposed cancer hypothesis published in BMC Cancer 2014. We are aware that the theme is complex and, therefore, the following is subdivided into 7 parts.
------------------------------------------------------------------
Part 1 - MMP
Matrix metalloproteinases (MMP) are zinc-dependent endopeptidases and understood regulating tumor suppression [Overall et al. Nat Rev Cancer 2006] and expression profiles of some MMPs have been correlated with poor clinical prognosis for several human tumor types [Egeblad et al. Nat Rev Cancer 2002]. Historically MMPs are thought to exert proinvasive and prometastatic activity by mere ECM remodeling [Overall et al. Nat Rev Cancer 2002]. It was shown, that - under certain experimental circumstances -overexpression of the endogenous broad-spectrum metalloproteinase [including a disintegrin and metalloproteinase-10 (ADAM-10)[Amour et al. FEBS Lett 2000] and tissue inhibitor of metalloproteinases-1 (TIMP-1) [Chircho et al. Cancer Metastasis Rev 2006] can reduce tumor cell invasion [Elezkurtai et al. J Gene Med 2004; Brand in Curr Gene Ther 2002].
References- Part 1:
Overall CM, Kleifeld O. Tumour microenvironment—opinion: validating matrix metalloproteinases as drug targets and anti-targets for cancer therapy. Nat Rev Cancer 2006;6:227–239.
Egeblad M, Werb Z. New functions for the matrix metalloproteinases in cancer progression. Nat Rev Cancer 2002;2:161–174.
Overall CM, Lopez-Otin C. Strategies for MMP inhibition in cancer: innovations for the post-trial era. Nat Rev Cancer 2002;2:657–672.
Amour A, Knight CG, Webster A, et al. The in vitro activity of ADAM-10 is inhibited by TIMP-1 and TIMP-3. FEBS Lett 2000;473:275–279.
Chirco R, Liu XW, Jung KK, Kim HR. Novel functions of TIMPs in cell signaling. Cancer Metastasis Rev 2006;25: 99–113.
Elezkurtaj S, Kopitz C, Baker AH, et al. Adenovirusmediated overexpression of tissue inhibitor of metalloproteinases-1 in the liver: efficient protection against T-cell lymphoma and colon carcinoma metastasis. J Gene Med 2004;6:1228–1237.
Brand K. Cancer gene therapy with tissue inhibitors of metalloproteinases (TIMPs).Curr Gene Ther 2002;2: 255–271
------------------------------------------------------------------
Part 2 - MMP7
Matrix metalloproteinase-7 (MMP7; synonym: pump-1 protease (PUMP1 or uterine metalloproeteinase or Matrilysn) was discovered in 1988 in the uterus by Woessner [Woessner J BiolChem 1988]. MMP7 breaks down the extracellular matrix (ECM) by degrading casein, Fibronectin, or type I, II, IV and V [YokomamaClin Cancer Res 2008]. It has been shown that lower MMP7 activity is associated with an increase of mucosal inflammation.
References- Part 2:
Woessner JF, Taplin CJ (November 1988). "Purification and properties of a small latent matrix metalloproteinase of the rat uterus".J. Biol. Chem. 263 (32): 16918–216925
Yokoyama Y, Grünebach F, Schmidt SM, Heine A, Häntschel M, Stevanovic S, Rammensee HG, Brossart P (2008). "Matrilysin (MMP-7) is a novel broadly expressed tumor antigen recognized by antigen-specific T cells". Clin. Cancer Res. 14 (17): 5503–5511.
------------------------------------------------------------------
Part 3 - Prior experiment
The group showed in 2008 that MMP7 is overexpressed in gastric pre- and cancerous tissue and that Helicobacter cytotoxin-associated gene (+) selectively increases MMP7 in vitro and in vivo [Ogden et al. Mol Cell Biol 2008].
References Part 3:
Ogden SR, Wroblewski LE, Weydig C, Romero-Gallo J, O'Brien DP, Israel DA, Krishna US, Fingleton B, Reynolds AB, Wessler S, Peek RM Jr: p120 and Kaiso regulate Helicobacter pylori-induced expression of matrix metalloproteinase-7. MolBiol Cell. 2008 Oct;19(10):4110-4121.
------------------------------------------------------------------
Part 4 - This paper [Krakowiak et al. Oncogene 2015]
The authors [Krakowiak et al. Oncogene 2015] showed that MMP7 knockdown mice (less MMP7) reveal increasedHpylori- induced gastric inflammation. After the group established the animal model, all knockdown mice showed increased gastric inflammation and the decreased MMP7 levels were associated with increased M1 macrophage markers. This was afterwards scrutinized by transfection of H.pylori strain PMSS1. Another finding was that even hyperplasia and dysplasia was increased in these knockdown mice and also the M1 macrophage polarization. Therefore, the authors concluded that the suppressing of M1 macrophage polarization could be of benefit.
References - Part 4:
KrakowiakMS, NotoJM, PiazueloMB, HardbowerDM, Romero-GalloJ, Delgado A, Chaturvedi R, Correa P, Wilson KT, Peek Jr RM: Matrix metalloproteinase 7 restrains Helicobacter pylori-induced gastric inflammation and premalignant lesions in the stomach by altering macrophage polarization. Oncogene 2015;34, 1865–187.
------------------------------------------------------------------
Part 5 - Connection to the cancer hypothesis [BMC Cancer 2014]
One important aspect of our hypothesis is the chronic inflammation which clearly has been shown in precancerous states. Another aspect is the knowledge, that the expression of MMP7 is regulated by the Wnt/ β catenin pathway, and mediated by transforming growth factor-beta(TGF-β) as it stimulates ECM and suppresses the steady-state level of MMP7. If someone read the following two papers it will be clear that the researchers of this paper made significant experiments which explain the proposed sequences [BMC Cancer. 2014 May 10;14:331: 1-8 and Cell PhysiolBiochem. 2014;34(2):213-243], because we also know that TGF-β usually stimulates MMP7 (mRNA and proteins) facilitating invasive behavior – shown in glioma cells [Gaide et al. BiochimBiophysActa 2012]. For further reading of the induction and effects of chronic inflammation please read here [BMC Cancer 2014 May 10;14:331: 1-8 and Cell Physiol Biochem 2014;34(2):213-243]
References- Part 5
Brücher BLDM, Jamal IS: Epistemology of the origin of cancer: a new paradigm. BMC Cancer 2014 May 10;14:331: 1-8.
Brücher BLDM, Jamal IS: Cell-cell communication in the tumor microenvironment, carcinogenesis, and anticancer treatment.Cell Physiol Biochem 2014;34(2):213-243.
GaideChevronnay HP, Selvais C, Emonard H, Galant C, Marbaix E, Henriet P: Regulation of matrix metalloproteinases activity studied in human endometrium as a paradigm of cyclic tissue breakdown and regeneration. Biochim Biophys Acta 2012;1824 (1):146–156.
------------------------------------------------------------------
Part 6 - Deeper explanation and connection 1 –to: [BMC Cancer 2014]:
The continuous release of TGFβ that is triggered by chronic inflammation has many effects:
(1) TGFβ represses E-cadherin and occludin, increasing theadherens junction disassembly [Hurst et al. Am J Physiol 1999]. Inhibiting TGFβ receptor type-I has been shown to decrease its invasiveness [Shinto et al. Br J Cancer 2010].
(2) TGFβ induces miR21, akey regulator of mesenchymal phenotype transition [Wang et al. Int J Biochem Cell Biol 2012], but increased levels also have been observedin early chronic fibrosis in COPD patients [Xie et al. MolBiosyst 2014].
(3)TGFβ activates protein kinase B (AKT or PKB) through phosphoinositide-3 kinase (PI3K) [Vinals et al. Mol Cell Biol 2001], activating the mechanistic targets of rapamycin complex 1 (mTORC1) and mTORC2 [Zeng et al. Blood 2007]. Furthermore, TORC activates the translation of proteins important for cell growth and development, and the PI3K/TmTORC1 pathway has recently been shown both essential for cancer-associated inflammation [Thiem et al. Blood 2007].
(4)LOX and matrix metalloproteinase (MMPs) are induced by TGFβ [Xie et al. J Biomech 2013], and
(5) LOX activates PI3K [Pez et al. Cancer Res 2011].
(6) The phosphorylation of glycogen synthasekinase-3beta (GSK3beta) by AKT stabilizes SNAIL [Schlessinger et al. Nat Cell Biol 2004], which leads to an increase of TGFβ-induced SNAIL [Peinado et al. J BiolChem 2003].
(7) SNAIL stability and activity, furthermore, are activated by LOX [Peinado et al. Nat Rev Cancer 2007].
(8) TGFβ effects the dissociation of the long isoform of p120 from the membrane and its accumulation in the cytoplasm [Noren et al. J Cell Biol 2000] and Figure two B in [Yilmaz et al. Mol Cancer Res 2010].
The chronic release of TGFβ and the continuousLOX activation triggers an accumulation of p120 in the cytoplasm, inducing remodeling of the ECM,which forms the pre-cancerous niche (PCN). This process may be seen as the starting point for the chronic-stress escape strategy as proposed [BMC Cancer 2014].
References - Part 6:
Hurst V IV, Goldberg PL, Minnear FL, Heimark RL, Vincent PA:Rearrangement of adherens junctions by transforming growth factorbeta1:role of contraction. Am J Physiol 1999, 276(4Pt1):L582–L595.
Shinto O, Yashiro M, Kawajiri H, Shimizu K, Shimizu T, Miwa A, Hirakawa K:Inhibitory effect of a TGFbeta receptor type-I inhibitor, Ki26894, oninvasiveness of scirrhous gastric cancer cells. Br J Cancer 2010, 102(5):844–851.
Wang T, Zhang L, Shi C, Sun H, Wang J, Li R, Zou Z, Ran X, Su Y: TGF-β-induced miR-21 negatively regulates the antiproliferative activity but hasno effect on EMT of TGF-β in HaCaT cells. Int J Biochem Cell Biol 2012,44(2):366–376.
Xie L, Wu M, Lin H, Liu C, Yang H, Zhan J, Sun S: An increased ratio ofserum miR-21 to miR-181a levels is associated with the early pathogenicprocess of chronic obstructive pulmonary disease in asymptomaticheavy smokers. MolBiosyst 2014, Epub ahead of print.
Viñals F, Pouysségur J: Transforming growth factor beta1 (TGF-beta1)promotes endothelial cell survival during in vitro angiogenesis via anautocrine mechanism implicating TGF-alpha signaling. Mol Cell Biol 2001,21(21):7218–7230.
Zeng Z, dos Sarbassov D, Samudio IJ, Yee KW, Munsell MF, Ellen Jackson C,Giles FJ, Sabatini DM, Andreeff M, Konopleva M: Rapamycin derivativesreduce mTORC2 signaling and inhibit AKT activation in AML. Blood 2007,109(8):3509–3512.
Thiem S, Pierce TP, Palmieri M, Putoczki TL, Buchert M, Preaudet A, Farid RO,Love C, Catimel B, Lei Z, Rozen S, Gopalakrishnan V, Schaper F, Hallek M,Boussioutas A, Tan P, Jarnicki A, Ernst M: mTORC1 inhibition restrictsinflammation-associated gastrointestinal tumorigenesis in mice. J ClinInvest 2013, 123(2):767–781.
Xie J, Wang C, Huang DY, Zhang Y, Xu J, Kolesnikov SS, Sung KL, Zhao H:TGF-beta1 induces the different expressions of lysyl oxidases and matrixmetalloproteinases in anterior cruciate ligament and medial collateralligament fibroblasts after mechanical injury. J Biomech 2013, 46(5):890–898.
Pez F, Dayan F, Durivault J, Kaniewski B, Aimond G, Le Provost GS, Deux B,Clézardin P, Sommer P, Pouysségur J, Reynaud C: The HIF-1-inducible lysyloxidase activates HIF-1 via the Akt pathway in a positive regulation loopand synergizes with HIF-1 in promoting tumor cell growth. Cancer Res2011, 71(5):1647–1657.
Schlessinger K, Hall A: GSK-3beta sets Snail’s pace. Nat Cell Biol 2004,6(10):913–915.
Peinado H, Quintanilla M, Cano A: Transforming growth factor beta-1induces snail transcription factor in epithelial cell lines: mechanisms forepithelial mesenchymal transitions. J BiolChem 2003, 278(23):21113–21123.
Peinado H, Olmeda D, Cano A: Snail, Zeb and bHLH factors in tumourprogression: an alliance against the epithelial phenotype? Nat Rev Cancer2007, 7(6):415–428.
Noren NK, Liu BP, Burridge K, Kreft B: p120 catenin regulates the actincytoskeleton via Rho family GTPases. J Cell Biol 2000, 150(3):567–580.
Yilmaz M, Christofori G: Mechanisms of motility in metastasizing cells.Mol Cancer Res 2010, 8(5):629–642.
Brücher BLDM, Jamal IS: Epistemology of the origin of cancer: a new paradigm. BMC Cancer 2014 May 10;14:331: 1-8.
------------------------------------------------------------------
Part 7- Deeper explanation and connection 2 / fibrosis –to: [BMC Cancer 2014]:
The next aspect is fibrosis: it is known that VEGF promotesfibrogenesis as well as hepatic tissue repair and a resolution of fibrosis. The inhibition of VEGF by neutralizing antibodies (mcr84) abrogated (1) the chemokine (C-X-C motif) ligand 9 (CXCL9) on mRNA and protein levels and (2) the matrix metallopeptidase 13 (MMP13), both of which are necessary for triggering fibrosis [Yang et al. Gastroenterology 2014]. These models alsomight explain why obesity and dysbiosis are associated with cancer and carcinogenesis.Further,EGFR induces MMP7 and MMP13 for inducing progress in gastric cancer [Ye et al. TumourBiol 2014].
This may serve as an explanation how fibrosis is triggered after chronic inflammation resulted in the pre-cancerous niche (PCN) if the stimulus persists as proposed in the new cancer hypothesis [BMC Cancer 2014].
References - Part 7:
Yang L, Kwon J, Popov Y, Gajdos GB, Ordog T, Brekken RA, Mukhopadhyay D, Schuppan D, Bi Y, Simonetto D, Shah VH: Vascular endothelial growth factor promotes fibrosis resolution and repair in mice. Gastroenterology 2014;146:1339-1350.e1.
Ye Y, Zhou X, Li X, Tang Y, Sun Y, Fang J: Inhibition of epidermal growth factor receptor signaling prohibits metastasis of gastric cancer via downregulation of MMP7 and MMP13. Tumour Biol. 2014 Nov;35(11):10891-10896.
Brücher BLDM, Jamal IS: Epistemology of the origin of cancer: a new paradigm. BMC Cancer. 2014 May 10;14:331: 1-8.
------------------------------------------------------------------
------------------------------------------------------------------
The following aspect may be of relevance:
Recently a detailed view on the data of analysis of 31,717 cancer cases and 26,136 cancer-free controls (healthy controls) from 13 genome-wide association studies had been performed [Jacobs et al. Nat Genet 2012].
This revealed that “the vast majority, if not all, of aberrations that were observed in the cancer-affected cohort were also seen in cancer-free subjects, although at lower frequency”; it was recommended that the “weight should shift to the non-inherited component which, until now, has routinely been thought of as synonymous with environmental factors” [Forsberg J Med Genet 2013].
References:
Jacobs et al.: Detectable clonal mosaicism and its relationship to aging and cancer. Nat Genet 2012;44(6):651-8:
http://www.nature.com/ng/journal/v44/n6/full/ng.2270.html
Forsberg et al.: Non-heritable genetics of human disease: spotlight on post-zygotic genetic variation acquired during lifetime. J Med Genet 2013;50(1):1-10.
http://jmg.bmj.com/content/50/1/1.long
http://www.nature.com/ng/journal/v44/n6/full/ng.2270.html
http://jmg.bmj.com/content/50/1/1.long
The following attached paper [Kim et al. Pancreas 2015 Apr 18] reveals
http://journals.lww.com/pancreasjournal/Abstract/publishahead/The_Basic_Helix_Loop_Helix_Transcription_Factor.99027.aspx
(1)
Huge evidence that the recent proposed “NORMAL CELL – CANCER CELL TRANSITION (NCCCT)” in “Epistemology of the origin of cancer: a new paradigm” at BMC Cancer 2014;14(331):1-15 is real
(2)
a CANCER CELL TRANSITION can be reversed to NORMAL CELL and
(3)
It s unlikely that mutations are evolved in the development as the reverse does not affect such.
http://journals.lww.com/pancreasjournal/Abstract/publishahead/The_Basic_Helix_Loop_Helix_Transcription_Factor.99027.aspx
http://www.biomedcentral.com/content/pdf/1471-2407-14-331.pdf
Our article published in peer-reviewed Journal "Communicative & Integrative Biology". A few major points discussed in the paper:
(1) Brain is not the source of consciousness.
(2) Consciousness is ubiquitous in all living organisms, starting from bacteria to human beings.
(3) The individual cells in the multicellular organisms are also individually cognitive entities.
(4) Proposals like “artificial life”, “artificial intelligence”, “sentient machines” and so on are only fairytales because no designer can produce an artifact with the properties like internal teleology (Naturzweck) and formative force (bildende Kraft).
(5) The material origin of life and objective evolution are only misconceptions that biologists must overcome.
http://www.tandfonline.com/doi/full/10.1080/19420889.2015.1085138
I assume the following is of relevance:
It may be of interest, that increasing evidence is coming up, that HPV-16 seems initiating the multistep sequencing process of carcinogenesis. It was not by accident, that all the following papers were blogged at the web group of the Theodor-Billroth-Academy at LinkedIn (https://www.linkedin.com/groups/1884710).
Oropharyngeal [JAMA Oncol 2015],
Tongue [Br J Cancer 2015]
Colorectal [PLoS One 2015]
ESCC [World J Gastroenterol 2015]
Gastric cancer [World J Gastroenterol 2014]
Ijaz brought up a wise question “…would it not be prudent to extend vaccination against HPV (e.g., Gardasil) to males and females beyond the current recommended age of 26..”. As it was shown, that some 80% of ESCC (esophageal squamous cell cancers) seem being HPV-16 triggered, I would assume, it is not anymore a question of numbers, but my view could be of course biased. However, such a trial would be for sure less expansive compared to many unnecessary trials.
Ana Gradissimo was so kind bringing up the next one in head and neck cancers:
Agalliu et al. JAMA Oncol 2016. http://oncology.jamanetwork.com/article.aspx?articleid=2482916
I assume the following paper with ist onclusion may be of relevance:
Insight into the molecular basis of Schistosoma haematobium-induced bladder cancer through urine proteomics
Tumor Biol 2016
http://link.springer.com/article/10.1007/s13277-016-4997-y
...Interesting conclusion within the paper:
„….Our findings also support the hypothesis, as recently proposed [BMC Cancer. 2014;14:331], that most cancers originate from a biological or chemical stimulus and are followed by chronic inflammation, fibrosis, and a change in the tissue microenvironment that leads to a pre-cancerous niche...."
Article Insight into the molecular basis of Schistosoma haematobium-...
The following may be of relevance:
Prostate primary human basal and luminal epithelial cells are cells of origin of cancer / PNAS 2016
https://www.linkedin.com/groups/1884710/1884710-6123387419854200835
Abstract
The cell of origin for prostate cancer remains a subject of debate. Genetically engineered mouse models have demonstrated that both basal and luminal cells can serve as cells of origin for prostate cancer. Using a human prostate regeneration and transformation assay, our group previously demonstrated that basal cells can serve as efficient targets for transformation. Recently, a subpopulation of multipotent human luminal cells defined by CD26 expression that retains progenitor activity in a defined organoid culture was identified. We transduced primary human prostate basal and luminal cells with lentiviruses expressing c-Myc and activated AKT1 (myristoylated AKT1 or myrAKT1) to mimic the MYC amplification and PTEN loss commonly detected in human prostate cancer. These cells were propagated in organoid culture before being transplanted into immunodeficient mice. We found that c-Myc/myrAKT1–transduced luminal xenografts exhibited histological features of well-differentiated acinar adenocarcinoma, with strong androgen receptor (AR) and prostate-specific antigen (PSA) expression. In contrast, c-Myc/myrAKT1–transduced basal xenografts were histologically more aggressive, with a loss of acinar structures and low/absent AR and PSA expression. Our findings imply that distinct subtypes of prostate cancer may arise from luminal and basal epithelial cell types subjected to the same oncogenic insults. This study provides a platform for the functional evaluation of oncogenes in basal and luminal epithelial populations of the human prostate. Tumors derived in this fashion with defined genetics can be used in the preclinical development of targeted therapeutics.
Park et al. PNAS 2016:
http://www.pnas.org/content/pnas/early/2016/04/01/1603645113.abstract.html?collection
https://www.linkedin.com/groups/1884710/1884710-6123387419854200835
The following paper was brough up by Ijaz at the web Group of the Theodor-Billroth-Academy (TBA) at LinkedIn and it might be of importance for critical thinking:
Chronic inflammation initiates pancreatic carcinogenesis
- without K-ras mutations and
- in p53 absence
Oncogene 2017:
Abstract
Chronic inflammation (CI) is a risk factor for pancreatic cancer (PC) including the most common type, ductal adenocarcinoma (PDAC), but its role and the mechanisms involved are unclear. To investigate the role of CI in PC, we generated genetic mouse models with pancreatic specific CI in the presence or absence of TP53. Mice were engineered to express either cyclooxygenase-2 (COX-2) or IκB kinase-2 (IKK2), and TP53+/+ or TP53f/f specifically in adult pancreatic acinar cells by using a full-length pancreatic elastase promoter-driven Cre. Animals were followed for >80 weeks and pancreatic lesions were evaluated histologically and immunohistochemically. The presence of K-ras mutations was assessed by direct sequencing, locked nuclei acid (LNA)-based PCR, and immunohistochemistry. We observed that sustained COX-2/IKK2 expression caused histological abnormalities of pancreas, including increased immune cell infiltration, proliferation rate and DNA damage. A minority of animals with CI developed pre-neoplastic lesions, but cancer was not observed in any TP53+/+ animals within 84 weeks. In contrast, all animals with CI-lacking TP53 developed various subtypes of PC, including acinar cell carcinoma, ductal adenocarcinoma, sarcomatoid carcinoma and neuroendocrine tumors, and all died within 65 weeks. No evidence of K-ras mutations was observed. Variations in the activity of the Hippo, pERK and c-Myc pathways were found in the diverse cancer subtypes. In summary, chronic inflammation is extremely inefficient at inducing PC in the presence of TP53. However, in the absence of TP53, CI leads to the development of several rare K-ras-independent forms of PC, with infrequent PDAC. This may help explain the rarity of PDAC in persons with chronic inflammatory conditions.
http://www.nature.com/onc/journal/v36/n22/full/onc2016461a.html
http://www.nature.com/onc/journal/v36/n22/full/onc2016461a.html
Someone may be interested reading carefully the commentary written commentary by Dr. Stuart G. Baker, National Cancer Institute, Bethesda, MD, USA, which was brought up by Ijaz:
“The questionable premises underlying the search for cancer driver mutations and cancer susceptibility genes.”
Dr. Stuart G. Baker, National Cancer Institute, Bethesda, MD, USA
http://www.cognitivephilology.uniroma1.it/index.php/Organisms/article/view/13873/13628
http://www.cognitivephilology.uniroma1.it/index.php/Organisms/article/view/13873/13628
Cancer is very complex I read an excellent article that explain very well the aetiology of cancer by two terms: exposome and interactome.
Exposome include dietary, lifestyle, environmental, microbial, hormonal, and genetic factors from the embryonic life until the old age. Interactome represent all the interactions existing between all the exposome.
It was the best explication of cancer that I had ever read.
See this article :Etiologic field effect: reappraisal of the field effect concept in cancer predisposition and progression/doi:10.1038/modpathol.2014.81
- Badges
- Science topic