for those who just anonymous downvote *s*: you may start thinking first

Down voting is a sign of defeat

- you can of course up vote or you do nothing, but down voting is a defensive position when you do not have a scientific argument!

further: 

the mentioned author of the crtical remakrs in CELL, Sir Adrian Bird, CBE, FRS, FRSE is a British geneticist and Buchanan Professor of Genetics at the University of Edinburgh is one of “the” leading world experts in Genomics, Epigenomics, at least to my understanding

http://en.wikipedia.org/wiki/Adrian_Bird

It is quite interesting, many look up a discussion and wait what is happening *big laugh*

very honorable and recognized scientists, who as well reject 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 a critical thinking of a human being.

http://www.sciencedirect.com/science/article/pii/S0092867413010040

for those who just anonymous downvote *s*: you may start thinking first

Down voting is a sign of defeat

- you can of course up vote or you do nothing, but down voting is a defensive position when you do not have a scientific argument!

further: 

the mentioned author of the crtical remakrs in CELL, Sir Adrian Bird, CBE, FRS, FRSE is a British geneticist and Buchanan Professor of Genetics at the University of Edinburgh is one of “the” leading world experts in Genomics, Epigenomics, at least to my understanding

http://en.wikipedia.org/wiki/Adrian_Bird

Much the same thing can be recognized in cancer metabolism research. Otto Warburg told that cancer cells favorably synthesize ATP via aerobic glycolysis several decades ago, however, recent study has revealed that cancer stem-like cells depend on mitochondria for ATP synthesis and ROS scavenger via TCA cycle orchestrated with glutaminolysis and pentose-phosphate pathway to induce enough amount of NADPH.

If ROS plays an important role in cancer metabolism as Youshida suggests, why have none of the clinical trials with antioxidants shown any success? Ultimately, the goal of research is to help cancer patients not cells in petri dishes or laboratory animals.

If someone wants getting down from the ride on horse's, tiger's and elephant's, here the actual findings by Mehryar et al. WORLD GASTROENTEROL 2015:

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

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.

Independent of the support of the recent published new cancer paradigm, this could be a very useful approach for future peri-operative application in cancer surgery.

- and that is what we are here for.

http://www.pnas.org/content/112/13/4086.abstract.html?etoc

I apologize but I am still curious about Go J Yoshida's answer to Ijaz question:

If ROS plays an important role in cancer metabolism as Youshida suggests, why have none of the clinical trials with antioxidants shown any success? 

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.

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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

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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.

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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.

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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.

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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):213-43], 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.

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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.

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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.

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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)

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/1471-2407/14/331

quite interesting and maybe something to think:

Gene loss can be compensated / Rossi and Kontarakis et al. Nature 2015

Scientists from the Max Planck Institute scientists observed that other genes take over the functions of deactivated genes and mitigate the impact or even can completely compensate this situation.

Abstract

Cells sense their environment and adapt to it by fine-tuning their transcriptome. Wired into this network of gene expression control are mechanisms to compensate for gene dosage. The increasing use of reverse genetics in zebrafish, and other model systems, has revealed profound differences between the phenotypes caused by genetic mutations and those caused by gene knockdowns at many loci1, 2, 3, an observation previously reported in mouse and Arabidopsis4, 5, 6, 7. To identify the reasons underlying the phenotypic differences between mutants and knockdowns, we generated mutations in zebrafish egfl7, an endothelial extracellular matrix gene of therapeutic interest, as well as in vegfaa. Here we show that egfl7 mutants do not show any obvious phenotypes while animals injected with egfl7 morpholino (morphants) exhibit severe vascular defects. We further observe that egfl7 mutants are less sensitive than their wild-type siblings to Egfl7 knockdown, arguing against residual protein function in the mutants or significant off-target effects of the morpholinos when used at a moderate dose. Comparing egfl7 mutant and morphant proteomes and transcriptomes, we identify a set of proteins and genes that are upregulated in mutants but not in morphants. Among them are extracellular matrix genes that can rescue egfl7 morphants, indicating that they could be compensating for the loss of Egfl7 function in the phenotypically wild-type egfl7 mutants. Moreover, egfl7 CRISPR interference, which obstructs transcript elongation and causes severe vascular defects, does not cause the upregulation of these genes. Similarly,vegfaa mutants but not morphants show an upregulation of vegfab. Taken together, these data reveal the activation of a compensatory network to buffer against deleterious mutations, which was not observed after translational or transcriptional knockdown.

http://www.nature.com/nature/journal/vaop/ncurrent/full/nature14580.html

@Mr. Rohani Chaubal: Showing something in vitro and not being able to demonstrate in vivo or in a clinical setting is why cancer research has squandered trillions of dollars in the past 70 years with a overall life extension for most sporadic cancers of 4 weeks to 4 months. That speaks volumes since the ultimate goal of any basic research is to be able to use it in the clinic.The example you cite of BCR-ABL is a perfect case.

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

Dear Björn,

I actually do not understand the point to which you want to "arrive" ...

No researcher studying cancer is wrong our right. Everyone makes her / his best efforts to contribute a small piece of knowledge to this dramatic disease and some clinical progresses have actually been accomplished (leukemia, testicular cancer, and many others).

The mutation theory is one theory that has been validated by thousands of top level scientific publications. Same think for the embryonal theory.

You speak about "stepback", which is a more than negative message to young scientists. I understand therefore that some RG members have voted "S".

It seems to me that you like "history in science". I am fascinating by the progresses that are made in a CONTINUOUS manner in the cancer research field since more than a century.

For you who likes "original" (you have to take the French translation of this word ...), I am offering you as gift the attached articles that can enrich your library ...

Best regards

Robert

Now coming back to the severe criticisms raised not only by BJORN but also by IJAZ, I say that I am happy to be a biologist and not an oncologist who must face this disaster that is named a cancer. My wife is neuosurgeon and in charge of the neuro-oncology in a big hospital and she is not coming back every evening with great smiles ...

As a biologist, I am fascinating by the constant progresses that are made by researchers to understand this extraordinary complexicity of cancer biology. I think that you should read carefully the attached articles, which could dilute may be a little bit your criticisms about anticancer treatment failures.

What is also fascinating in cancer research is that each time a treatment results in a more or less failure, scientists indeed have the courage to step back to understand why, and they always come back with new ideas.

And to try to make as short as possible a potential long response, I will conclude by asking both of you to explain me (and sharing this info with the RG community) how YOU will treat (and even maybe save?) the patients whose cancer bring them a dismal prognosis.

With very best regards

Robert

Dear Robert,

we deeply apologize answering late and maybe not in the way you demand, we both are finishing some further important work and by this only occasionally check out the Blogs at RG,

however the following at the post scriptum maybe of interest to you or others, and for your convinience the web link and the paper

Kind regards

Björn

PS.

attached a recent published paper, entitled "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

Ad Conclusion:

„….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...."

http://link.springer.com/article/10.1007/s13277-016-4997-y

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

I would assume, that an Insinuation may be better posted in social instead of scientific media. 

Going back to the title of this question, the following may be of relevance

Somatic Mutation Theory - Why it's Wrong for Most Cancers.

Cell Physiol Biochem. 2016;38(5):1663-1680.

doi: 10.1159/000443106.

Article Somatic Mutation Theory - Why it's Wrong for Most Cancers

The following paper was brought 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

As proposed in BMC Cancer 2014, 14, 331.

DOI: 10.1186/1471-2407-14-331.

Stimulation TNF-α plus TGF-β1 downregulates E‑cadherin & promote Cell Transition via NF‑κB path / Li et al. Oncol Letters 2018

https://www.spandidos-publications.com/10.3892/ol.2018.8230

Precancerous niche (PCN) with its remodeled fibrosis predicts immunotherapy response / Chakravarthy at al. Nat Com 2018

https://www.nature.com/articles/s41467-018-06654-8

It seems scientists start to recognize the significance of the precancerous niche which was originary published in BMC Cancer 2014 :

https://www.researchgate.net/publication/262215307_Epistemology_of_the_origin_of_cancer_A_new_paradigm

Mutation Theory unlikely inducing carcinogenesis / Cicarelli Nature 2019

High level of genetic alterations -sequenced in cancer-associated genes in 844 esophagus tissue samples (normal and cancer cells) - arises as people age, BUT yet does not usually result into cancer

Thanks to Ijaz S. Jamall bringing this up

https://www.nature.com/articles/d41586-018-07737-8

Getting closer to reality:

BRCA1/2 mutation prevalence in 5,122 unselected Swedish breast cancer patients < 2% / Li et al. Int J Cancer 2019

Article Prevalence of BRCA1 and BRCA2 pathogenic variants in a large...

#StayTuned

- next week 4open by EDP Sciences will release the first peer-reviewed papers of an expensive Special Issue dealing with "carcinogenesis" consisting of

-pathogenic stimuli

-chronic inflammation

-fibrosis with its

-remodeling into precancerous niche PCN plus

-eicosanoids

-ubiquitous proteins

-microbiome

-morbid obesity

-metformin

Thanks to our great Guest Editor Obul Reddy Bandapalli - great work !

Happy Easter around the Globe with Peace and Happyness !

https://www.youtube.com/watch?v=IPg_W8VJdqE

Ijaz S. Jamall

Obul Reddy Bandapalli

In case of interest:

4open: Special issue first 7 out of 10 papers are out

Disruption of homeostasis-induced signaling and crosstalk in the carcinogenesis paradigm “Epistemology of the origin of cancer”

Obul R. Bandapalli (Guest Editor) - DKFZ Heidelberg, Germany

KEY SUMMARIES https://www.4open-sciences.org/key-summaries/306-new-research-challenges-current-thinking-on-cancer

Ijaz S. Jamall

The 8th out of 10 papers dealing with carcinogenesis is out:

NF-κB signaling and crosstalk during carcinogenesis

https://www.4open-sciences.org/articles/fopen/full_html/2019/01/fopen180043/fopen180043.html

Ijaz S. Jamall and @Florian Lang

Maybe something to think:

In vitro: antibacterial salinomycin decrease cancer cell growth, proliferation and metastasis in CDDP resistant breast cancer cells via NF-kB deregulation / Tyagi and Patro in Toxicol In Vitro 2019

https://www.sciencedirect.com/science/article/pii/S0887233319300347

#StayTuned

soon the 9th costly paper entitled

"Transition from normal to cancerous cell by precancerous niche (PCN) induced chronic cell-matrix stress "

of the 4open Special Issue

Disruption of homeostasis-induced signaling and crosstalk in the carcinogenesis paradigm “Epistemology of the origin of cancer”

https://www.4open-sciences.org/component/toc/?task=topic&id=1080 will be released

Ijaz S. Jamall

9th out of 10 papers is out

Transition from normal to cancerous cell by precancerous niche (PCN) induced chronic cell-matrix stress

https://www.4open-sciences.org/articles/fopen/full_html/2019/01/fopen180010/fopen180010.html

Ijaz S. Jamall

Thank you Gene Levinson for your outstanding independent judgement as a recognized molecular geneticist scientist

We are deeply humbled

https://bit.ly/2Vyplll

Interesting that we since some 100 years – from the very courageous proposals “for that time” by Boveri (1914) and Bauer (1928) – still - in accordance to Vogelstein and the Biotech branch (proposers of the Mutation dogma) - search for mutations. We may ask ourselves: who – in this case - has the most benefit from it? –patients?

We may continue to drive a blind alley – but this increasingly gets an ethical (and not just a scientific) question – and each cancer scientists in the near future will be judged by it by the public.

Attached the newest (frightening) data of consistently increase of CRC incidence in young patients - reality hurts:

Europe

COLON RECTAL Cancer 'consistently' rises among young European Adults aged 20–29 years AND aged 30–39 and 40–49 years / BMJ 2019

https://gut.bmj.com/content/early/2019/04/16/gutjnl-2018-317592

USA

CRC among US adults < 50 y (with greatest increase in cM1-disease) increased with 2.9% increase per year / JAMA 2019

https://jamanetwork.com/journals/jama/fullarticle/10.1001/jama.2019.3076

If riding on horses does not work, maybe riding on a tiger or an elephant?

Tumor metastasis to lymph nodes requires YAP-dependent metabolic adaptation / Lee et al. Science 2019

https://science.sciencemag.org/content/363/6427/644.long

The findings are in accordance to

(1)

https://bit.ly/2JcpGaL and

(2)

https://bit.ly/2J3CUGZ published in

@4open by @EDP_Sciences

Attached the modified illustration in accordance to Disruption of homeostasis-induced signaling and crosstalk in the carcinogenesis paradigm “Epistemology of the origin of cancer”

Alternative fatty acid desaturation pathway independent from SCD1 / Vriens et al. Nature 2019

Article Evidence for an alternative fatty acid desaturation pathway ...

The findings are in accordance to

(1)

https://bit.ly/2JcpGaL and

(2)

https://bit.ly/2J3CUGZ

published in @4open by @EDP_Sciences

Attached the modified illustration in accordance to Disruption of homeostasis-induced signaling and crosstalk in the carcinogenesis paradigm “Epistemology of the origin of cancer”

"Mutant BRCA is an indispensable founding event for 'some' tumours, but in a considerable proportion of other cancers, it appears to be biologically neutral"

Jonsson et al. Nature 2019

https://www.nature.com/articles/s41586-019-1382-1

Dependence of initial conditions.

Every tumor have specific trajectory.

As Professor Marjan Slak Rupnik pointed out wisely

"That means hundreds of other markers could be indispensable founding events."

Mice with abrupt involution induce chronic inflammation, fibrosis, remodeling (which someone may call Precancerous Niche) followed by ductal hyperplasia and metaplasia and cancer

Basree et al. Breast Cancer Rev 2019

https://breast-cancer-research.biomedcentral.com/articles/10.1186/s13058-019-1163-7

Increasing Evidence for cancer paradigm “Epistemology of the Origin of Cancer”

https://bit.ly/2IW7Icx

https://bit.ly/2LavqnP

Something to think - maybe even to re-think

Genomic variability with Aneuploidy often physiological (not pathogenic)

Spectral karyotype analysis reveals ≈33% of neuroblasts as aneuploid

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC60876/

Please allow me to provide another point which (from my perspective) may be even of high significance in this regard:

We know – although many might not being aware – that in case someone analyzes databases, that a recent simulation database trial of Multiple Sclerosis (MS) patients revealed, that the percentage of false positive findings can exceed 20%, depending on variable selection [BMC Medical Research Methodology 2008, 8, 18, DOI: 10.1186/1471-2288-8-18 ]. Besides: Martin Daumer’s research led to the fact, that MRT for predicting MS (which was during that time a dogma) was cancelled.

Meaning for here:

At least “that” potential false bias (knowing the paradigm) was here not available, as the distinguished scientists of Breast Cancer Res 2019 proved our paradigm independently from us ‘without’ being aware about our paradigm (but of course of their own results) [as you can see, it was not cited]:

https://breast-cancer-research.biomedcentral.com/articles/10.1186/s13058-019-1163-7

However, at this potential bias was ‘not’ existing. This may even be of significance.

Last (missing) paper of Special Issue finalized and re-submitted with

-n=5 Figures

-n=355 References

The fall-out did not result into cancer incidences as declared (feared)

"National trends in cancer incidence rates for the nation of Ukraine are comparable to those observed in its neighbor country, Belarus, and are mostly comparable to those of the United States, with the exception of decreasing colon and cervical cancer rates in the United States"

"...calculated AAPC for thyroid cancer incidence rates in the nation of Ukraine from 1999 to 2016 was 4.2, which was not particularly different from the 3% to 4% observed in the United States SEER registry over a similar time interval"

Meaning:

Less likely induced 'double-strand-breaks'

Trends in Solid Tumor Incidence in Ukraine 30 Years After Chernobyl

https://ascopubs.org/doi/full/10.1200/JGO.19.00099

Someone may read in very detail the paper below as this explains the distinguished reader 

(1) 

the actual Ukraine Data

(2) 

why different radiation resulted into different effects (lower in Nagasaki than Hiroshima)

(3)

and as its whole while the somatic mutation theory cannot explain more than some 5-to-10% of cancers

https://www.researchgate.net/publication/301787378_Somatic_Mutation_Theory_-_Why_it's_Wrong_for_Most_Cancers

thanks to Ijaz S. Jamall for this piece

Peptostreptococcus anaerobius promotes colorectal carcinogenesis and modulates tumour immunity

/ Long et al. Nat Microbiol 2019

https://www.nature.com/articles/s41564-019-0541-3

in this regard

Chronic inflammation evoked by pathogenic stimulus during carcinogenesis

https://bit.ly/2YfZV22

Microbiome and morbid obesity increase pathogenic stimulus diversity

https://bit.ly/2YxxpEC

NF-κB signaling and crosstalk during carcinogenesis

https://bit.ly/2SONi8c

Caveat Emptor: The Perils of Panel Testing in Hereditary Breast Cancer

Thanks to Amy Taylor and Marc Tischkowitz for this piece – highly appreciated

https://ascopubs.org/doi/10.1200/JCO.19.00122

both shortly review the paper by Beitsch et al. (2019) J Clin Oncol 37, 453-460,

only reading one paragraph (as below) just makes me shaking my head - despite questioning the Beitsch' et al. interpretation

“Lastly, we note that at least one third of the 27 authors of the work by Beitsch et al1 are employees of or receive honoraria, research funding, or indirect support from diagnostic laboratories that are heavily involved in marketing gene panels, which could result in a significant conflict of interest when interpreting of the results of the study.”

Thanks to Gudrun Schüler for this piece

First of all, it is important to note that relatively fluid geographic variation and the fact that incidence rates vary over time within phenotype, indicate that there are still unidentified non-genetic mechanisms related to cancer risk, etiology, and progression that urgently need to be addressed. The reason epigenetics has become so important in cancer is the role of environmental influences (whether they be health behaviors such as smoking or carcinogenic toxins). Genome-wide expression changes can precede tumor manifestation and are an important indication of host susceptibility. We get many mutations daily but the majority do not result in cancer. The reason is that we have multiple DNA repair mechanisms to fix them, an immune system to destroy cancer cells and other defense mechanisms such as apoptosis. Genetic risk is one issue but it is not the only one.

"We get many mutations daily but the majority do not result in cancer."

Do you have any proof that some mutations do result in cancer?

There are many laboratory experiments that show that if you insert a cancer cell into an animal, they will develop tumors. But there is also research from the Levin lab at Tufts that hyperpolarization of membrane potential in a cancer cell inserted into a tadpole embryo can prevent tumors. We are beginning to do cell work in our lab testing whether depolarization of normal cells without mutation can cause proliferation and gene expression changes indicative of cancer.

"There are many laboratory experiments that show that if you insert a cancer cell into an animal, they will develop tumors."

It doesn't follow that mutations cause cancer, does it?

Maybe your work will show that the cause is depolarization not mutations, am I right? If so you will put one more nail in the coffin of the Somatic Mutation theory of cancer. And in that of the Bad Luck theory as well.

Our work does not show that mutations cause cancer but the work of many others does show that. It is quite well established that certain types of mutations are causally associated with cancer. A mutation of the Agouti gene in genetically identical mice is associated with a significantly increased risk of breast cancer. Female BALB/c transgenic mice with an activated rat HER-2/neu gene mimic the progression and gene expression profiles of human breast cancer (Atolfi 2005). A well-known example is p53 mutations, which cause tumor suppressor properties to malfunction.

How do you know that that is causality? According to my information, the association indeed exists: there are data that confirm that the number of particular mutations is correlated with the incidence of particular cancer. Thus there three opportunities:

- mutation cause cancer

- cancer causes mutations

- mutations and cancer don't cause each other but are associated in some other, more complicated manner - for example, both of them are correlated with some third variable.

Why are you sure that the first variant takes place?

Correlation doesn't imply causation, that is a golden rule in statistics.

There are a lot of examples of so called "spurious correlations", one can find them just by googling "spurious correlations".

Sorry for the typo: the first opportunity is "mutations cause cancer."

The only way somatic mutations could be shown to cause cancer would be to do a time series study that shows first a mutation, then more mutations, and ultimately cancer. The "risk of developing cancer" is a mathematical construct and certainly an association, but not causal.

BaljaevaMaria@ As a person doing chemical carcinogenesis in animal models I can assure you, that chemical mutagenesis can induce cancer. In my animal model during the last 15 years no spontaneous tumors have occured. After treatment with chemical carcinogene, this model nicely develops tumors. As a spectrum of mutations induced by this mutagene (DMBA) is well known, one can point out that there is a causation and not only correlation present here. One can try to contests that, saying that maybe DMBA just changes microenvironment in tissues, or influences immune cells, so the cancer can develop. However, as the cancer develops (in my model) ab. 6 months after the last dose of DMBA (a very long time in a mouse's life), the problem should lay with some more stable changes, e.g., genomic changes such as mutations.

Ijaz S. Jamall@ And maybe the problem with antioxidatns in tumor treatment is their bioavaliability in vivo? So the other factors muddle simple, straightforward solution to the problem.

Nevertheless, this discussion is good for pointing out that tumor initiation is not a straightforward process.

Patrycja Koszałka , according to your description you've proved three things in your experiments:

first, the chemical carcinogene causes cancer; second, the same carcinogene causes mutations; third, mutations appear earlier than cancer.

That is not the proof of mutations being the cause of cancer as two effects caused by one process do not necessarily have a causal relationship with each other.

Let me suggest a simple example: when the warm season comes, both tulips and peonies bloom. Tulips bloom earlier than peonies. That doesn't mean that flowering tulips cause flowering peonies.

"...mutations in the DNA do occur and for a multitude of reasons but without necessarily causing cancer" here: https://www.researchgate.net/post/Are_there_any_experiments_confirming_that_driver_mutations_are_the_cause_of_cancer_not_merely_its_companions_or_consequences

Dr. Koszalka: I agree with you that DMBA treatment of animals results in cancer and that observations in those cancers show somatic mutations and this has been reported in hundreds of publications but I would not interpret those observations as being causal. Let's take a few different examples: 1) asbestos causes cancer but not through mutations. 2) HPV causes cancer but not through mutations 3) Hepatitic C causes cancer but not through mutations. How would you explain these? You might read through our 2016 paper which explains our thinking in much greater detail:

https://www.karger.com/Article/FullText/443106

In case of this may be of interest, the last (missing) paper is out

Synopsis: Special Issue on “Disruption of signaling homeostasis induced crosstalk in the carcinogenesis paradigm Epistemology of the origin of cancer”

4open 2(28), 1-30.

https://www.4open-sciences.org/articles/fopen/full_html/2019/01/fopen180008/fopen180008.html

The following may be of interest (some may call it disruption of homeostasis)

Endoscopically healed mucosa of ulcerative colitis (=precancerous condition) show persisting dysregulation in regard to cytokines, fibrosis-associated mediators

/ Gundersen et al. Clin Transl Gastroenterol 2019

https://bit.ly/30Pb2LS

Value of Genes triggering carcinogenesis due to familial risk in CRC had been overestimated

Weigl et al. Int J Cancer 2019 - DKFZ, Heidelberg, Germany

Until now, cancer centers worldwide overestimated (and still do) the value of genes in causing carcinogenesis.

The DKFZ in Heidelberg, Germany, starts now - as one of the (very) rare leading cancer centers in the world - to face reality in saying goodbye to these 'believes':

Familial risk in CRC by single nucleotide polymorphisms (SNPs) is 10% less:

between 5.4 -14.3%

Someone may look in detail about the HR with its 95% CI values

https://onlinelibrary.wiley.com/doi/abs/10.1002/ijc.32664

Attached the press release:

https://www.dkfz.de/en/presse/pressemitteilungen/2019/dkfz-pm-19-42-Familial-risk-of-colorectal-cancer-the-genes-only-tell-part-of-the-story.php

“…scientists …. conclude that the role of genes has been overestimated in patients with a higher familial risk of colorectal cancer..”

Maybe (hopefully) the time is right now, being proud enough to face reality and getting away from hypes, wishes, and believes

Although reality sometimes hurts

This means that the from some scientists felt heretical declaration of the reality in our paper in regard to SMT in 2016 of my distinguished coauthor and friend Ijaz S. Jamall and me was correct.

https://www.researchgate.net/publication/301787378_Somatic_Mutation_Theory_-_Why_it's_Wrong_for_Most_Cancers

CD95 activation in single cancer cells leads to apoptosis while in the composite (e.g. solid tumors) results into growth stimulus

Balta et al. Cell Rep 2019

Highlights

• Specific intermolecular spacing of CD95Ligand induces efficient CD95 clustering

• CD95 clustering triggers apoptotic and survival signaling

• CD95 signals survival in the presence of cell-cell contact

• Cell-cell contact increases levels of phosphotyrosinated proteins including CD95

Article 3D Cellular Architecture Modulates Tyrosine Kinase Activity,...

Spectral karyotype analysis reveals ≈33% of neuroblasts as aneuploid

Rehen et al. PNAS 2001

Genomic variability with aneuploidy often physiological (not pathogenic)

Something to think - maybe even to re-think

https://www.pnas.org/content/98/23/13361.long