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-...

you raised a good question,at present time ,it seems that we can not easily find out what is /are the drivers of humam cancers.Cancer is so heterogeneous and our researches about cancer mostly from the final stage,as we face a battlefield,the soldiers have been kilked,it is hard to find out who Provoke the war.so ,our reseaches about cancer are partly correct at least.maybe there is no universally applicable paradigm.

Dr Eibl, thank you very much for bringing this interesting article for discussion at this forum. RG. The association of chronic inflammatory states and cancer has been extensively considered, and is the subject of a spate of scientific articles, and continues to be an area of ongoing interest. . This may be relevant to the role of oxidative stress induced tissue damage in chronic inflammatory states.

Quite precisely! There is a very long distinct latency period in the development of pleural mesothelial cancers. Mesothelioma development may take about 25-50 years after exposure. A prolonged period of chronic inflammation may precede. Asbestos induced pulmonary fibrosis has extensively studied. Inflammatory cells are thought to have a significant role in asbestos induced cancers. Another important issue is the striking surface adsorption potentiality of asbestos particulate. Onset of inflammation may depend on the kind of fibers in question. Chrysotile asbestos has been shown to be predominantly active. Incomplete phagocytosis by pulmonary alveolar macrophages (PAMs) also results in the release of inflammatory mediators. Acute inflammatory response following the exposure of PAMs is the initial event. Inflammatory mediators include a multitude of factors such as arachidonate metabolites (leukotrienes), oxidants, etc. Free radical pathology in asbestos induced cancer has been extensively dealt with.

The number of mesothelioma cases reported annually in the USA is about 3,000. Bronchogenic carcinoma, where cigarette smoking is involved, is the major form of asbestos caused tumors. Asbestos fibers possess tremendous adsorptive capacity for environmental carcinogens such as the procarcinogenic polynuclear aromatic and nitrogen heterocyclic hydrocarbons (PAHs), components of cigarette smoke and ambient air; these carcinogens are indirectly acting, that is, they need to be metabolically activated to their proximate and ultimate carcinogenic forms by mixed-function oxygenases. The presence of PAHs and other cocarcinogens, which may be involved in tumor initiation/promotion confounds this issue of non-carcinogen involvement in asbestos induced cancers.

Dr Eibl: This could be of interest:

Oncogenes and tumor-suppressor genes in mesothelioma--a synopsis

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1470150/

Greetings!

Lipid peroxidation in rat alveolar macrophages exposed to chrysotile fibres.

Kandaswami C, Morin G, Sirois P.

Toxicol In Vitro. 1988;2(2):117-20.

Oncogenes and tumor-suppressor genes in mesothelioma--a synopsis

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1470150/

MECHANISMS OF ASBESTOS-INDUCED

CARCINOGENESIS

http://www.med.nagoya-u.ac.jp/medlib/nagoya_j_med_sci/7112/p001-010_Toyokuni.pdf

I may cite a section on Page 6 out of the paper 'Epistemology of the origin of cancer: a new paradigm':

http://www.biomedcentral.com/1471-2407/14/331

Perhaps the distinctive feature in the inflammation that promotes the conversion of

a normal cell to a cancerous one is its ability to trigger the onset of fibrosis. For example, pulmonary mesothelioma, known to be caused by exposure to

asbestos, generally presents decades after exposure. Its appearance is always preceded by inflammation and by severe fibrosis [114]. No increase in the number somatic mutations has been associated with asbestos carcinogenesis.

and on Page 9:

Asbestos leads to pulmonary mesothelioma decades after the exposure reveals fibrosis and, although no increase in somatic mutations has been reported in asbestos caused carcinogenesis, chronic inflammation has been observed in every instance of asbestos-induced mesothelioma.

http://www.nature.com/nature/journal/v517/n7536/full/517563a.html#comments

Very good - and fast - online comment on yesterday's issue of Nature - I could log in, but not leave a comment there (yet)...

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

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

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 all are 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

This would appear to be the first "substantive" evidence for what Bjorn and I have been suggesting for a few years now- the fact that mutations are observed in cancers does not mean they cause the cancers! Moreover, these data in humans also challenges the models used by IARC and other regulatory agencies regarding how some chemicals cause cancer. It takes us back to the vexing question: If somatic mutations occur routinely and do not cause cancer, what does?

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

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-...

To start with i am a molecular biologist by training(no PhD yet)

According to my theory immortality is a natural inevitable consequence of evolution. And according to me cancer is really not a disease at all, it is evolution in process. The cell (which will later extend to organism level) is "searching" the "mutational-space" (i.e. space representing all possible mutations in humans) for the right combinations of mutations under different aspects like telomere-lengthening, apoptosis, tumour-suppressor, metabolism etc. which will make the cell grow forever in a controlled manner rather than the uncontrollable form we see now as the cancer disease. We are directing our own evolution and speeding it with anti-cancer drugs. Cancer develops resistance thereby taking another path in the mutational space. The longevity will result in brain size development and opening up other higher level functioning phenomenon of the brain. Coalescing of consciousness will take place. We will have hive mind. If One knows and every one else will know  immediately. Renewable energy resource and technology like mnemonics and the likes will help advance our species in leaps and bounds. Knowledge based society will prevail. We would have moved by the time our sun becomes a red giant., maybe to Mars first and then rest of the galaxy, universe. All this will take millions of years, of course. We will know everthing there is to know. And we will realize that sum of all knowledge - EVERYTHING and NOTHING is the same!....and then the cycle starts all over again. Like in Isaac Asimov's The last question. Try to read the Vedas if you can. Get hold of Sir Penrose's Cycles of time and Endless Universe by Steinhardt and Turok. You will see a lot of things matches. The ancient vedic texts even have quantum physics and string theory described in them. Even the noble laureate Schrödinger acknowledged the fact that the ancient Indians knew about Quantum physics and that we are just re-discovering it.

Coming back to cancer. You could argue that cancer is somatic and not a germline affecting disease which is passed on to the offsprings. Well. I have searched through literature and i have it in my hard disk (data which i searched through from countless entries from Sanger Research Institute's database)  that some oncogenes (cancer causing genes) are selected in the germline! Now why would nature select these terrible mutations to be passed on. If it is detrimental to the population, how is it selected in the germline??!!!  no one is able to come up with a convincing answer.

So basically we are headed there - immortality i mean, slowly but steadily. And i don't think future posthuman species will look anything like us.

it might sound like science fiction now but i thorougly believe that this is what is going to happen. today's science fiction is tomorrow's science. based on all the physics, biology, natural philosophy, sci&tech etc. i have come to this conclusion about life.  i just wanted this cancer/evolution idea to be "out there" so that people can think about it, know about it, spread the knowledge. I have searched for many people (scientists/biologists) who have ideas like me and have indeed come across a few people. I have done a lot of thought experiments in physics and biology and philosophy and develop theory and then i check if anybody else have come up with it. lots of it have already been published by other people. so i pat myself in the back saying "well if they came up with a accepted hypothesis, your thinking is on the right track"...so with similar belief i have confidence on the theory how human life is going to develop in the future.

I Thank you and RG for giving me an opportunity to put my idea out there and thank you for asking a question and letting me answer it.

Thanks for your answer!

One could argue: mortalitiy of higher lifes is a prerequisite of life - on the one hand side bacteria and single cell organisms divide and are more or less already immortal, but can adapt to changing environments by fast division and some mutations. But higher organisms like mammals have longer generations - they need for several reasons the mortality - to allow a next generation by restricted ressources, so the optimization by evolution should be fast death after reproduction... cancer cells won't make it into the next generation, but genetic accumulation of activated cancer genes may promote even faster generations. The evolutionary advantage of populations with many activated cancer genes may be an early death of the parental generation - leaving more ressources untouched for the next generation. Well, evolution doesn't seem to be too social to the individual human.

I agree with your sentence, "Evolution does not seem to be too social to the individual human". Getting back to the origin of Cancer, 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

Thank You, Björn, for your comment and the link. With my little publications in the field of (onco)gene transfer into neuronal precursor cells in an animal model 25 years ago, and with the proof of similar genetic pathways in human (finding the first p53 mutation in a medulloblastoma, which appears to define today one subtype of medulloblastomas) - it seems to be state-of-the-art to base personal medicine and tumor diagnostics on more and more defined genetic and lineage-defined pathways. Nevertheless, I am still very critical about such (boring) pure genetic views, since I could also confirm my postulates of metastatic pathways, involving activation states of cell adhesion receptors, which can be influenced by the environment, i.e. not (only) by the genetic profile of a metastatic stem cell. Therefore, I still hope to get some day the support to finish my sabotaged (Palo Alto) and plagiarized (Munich) experiments.

 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

Thank you Björn (and Ijaz) for pointing and linking to this sophisticated animal model.

What strikes me most is that lack of p53 in combination with chronic inflammation was able to lead to so many, histologically different subsets of tumors. On the other hand, the model can not serve for the many tumors associated with K-ras.

To understand this model better, it might be interesting to fully sequence the different tumors (on the isogenic background of the mouse strain) and look specifically, which mutations and fingerprint of mutations are associated with each type of those histologically quite different tumors. Perhaps this will lead to new classification of tumors.

How certain are we that either p53 or kras act in the same fashion in every situation- both in vitro and, importantly, in vivo?

Good point, Ijaz. As you know, each model has its limitations, but they usually help to understand important parts of more complex systems - and this is the challenge for the experimental scientist to design the right experiments and then to convince others of the right interpretation; of course, there can be so many, sometimes opposite functions of certain gene products, that it is important to look very closely to all circumstances, like differentiation stage of a cell, genetic background of the animal, inflammation. Using isogenic (incl. transgenig/knockout and similar) mouse strains, helps to eliminate all the different possible genetic backgrounds.

As known since over 20 years for some histologically identical tumor, some common mutations can exclude themselves (mutual exclusion), i.e. if a histologically definde tumor type has a mutation or loss of a specific chromosome, it does not have the loss of a specific, but also commonly lost other chromosome - and vice versa.

Therefore, the animal model mentioned above may serve as a model for inflammation induced tumors, and be mutually exclusive for other tumors associated (or caused) by K-ras mutations.

Thank you, Robert. For example, if one sampled the same tumor at 20 different time points in its growth, would be get the same mutation each time? What of the proportion of different mutations in that same thought experiment? How reliable are mutation data over time? 

It is well accepted that an accumulation of mutations over time contributes to the evolution and changing behaviour of a tumor, explaining the developing resistance after initial response, but then relapse to many therapeutical approaches. I think there are more and more examples clearly documenting the overgrowth of new subclones with just one or two new mutations within a primary tumor, but also generations of metastases. The analysis of mutations in different parts and time points of a tumor and its metastases allows clear evolution lines of an individual tumor within a patient. Of course, it is a multi-billion dollar market with an enormous potential to increase I think from 70 to 140 billion dollar per year with all those new immune therapeuticals, but there is a chance that the investments into real research over the decades will be good for the next generations of patients - if the societies can afford it. But it seems still to be a lot of work with all the new compounds in the pipeline addressing the different set of mutations and testing the best therapy (or even cure)...

So, in the animal model cited above it might help to find the new mutations (in addition to the obviously necessary lack of p53) in the many different histological types of tumors. It may be the same mutation in different stages of stem cell development, up to different mutations in different cells of origin. In any way a full sequence analysis will show what mutations contribute to which tumor type - or what compounds, chemicals, smoke in the environment or natural radioactivity might have caused the additional (postulated) mutations to use the extra proliferation of the inflammation to accumulate cancer mutations. I think the example serves as a model that inflammation is one possibility to develop a tumor out of a mutated cell, in this case, p53, which is know to be mutated in half of the cancers.

1) "It is well accepted that an accumulation of mutations over time contributes to the evolution and changing behaviour of a tumor."

2) "clearly documenting the overgrowth of new subclones with just one or two new mutations within a primary tumor"

3) "The analysis of mutations in different parts and time points of a tumor and its metastases allows clear evolution lines of an individual tumor within a patient."

Robert, your answers come from within the "existing paradigm" which has not helped in clinical studies despite such optimism. To my knowledge, the time series of mutations from a normal cell to a malignant cell has not been demonstrated and neither am I aware of the "homogeneity" of mutations within a cancer cell over time, notwithstanding clonal proliferation.  

Well, perhaps the existing paradigm really can explain most or even all of the things the best - and no additional, unknown factors are needed (which does not exclude the may be found - but I haven't seen any fundamental experiment for really supporting any better theory). I also can not imagine any self-renewing or stable tumor cell without any genetic difference to a normal cell it was derived from.

I compare it like someone drives in a car and makes, for example, a right turn; then, as a driver you easily postulate there must be a force pulling your body to the left, i.e. a centrifugal force --- but, as we all know, there is not such a force at all. Of course, postulating such a force can help to explain the drivers feeling of such a force. The observer from above would only see there is a lack of centripetal force and the body wants to go just straight at the speed of the car and is retracted by the closed door or the seat, i.e. the body wants to move just tangential to the circle, but not 90° away.

In the tumor model based on a fundamental mutation of the major tumor suppressor gene, and with inflammation aspects, one can easily explain inflammation as more cell divisions (under stress) which automatically augments the the chance of additional mutations.

In the medulloblastoma model in rats I had developed over a quarter of a century ago,  the SV40LT antigen might also have inactivated tumor suppressor proteins in the target cells, i.e. neuronal precurser cells. The model is, afaik cited in all editions of the WHO classification of brain tumors since then and seems to have intrigued neuropathologists to look closer in human medulloblastomas. At that time I wanted to check if the supposed mechanism in my rat medulloblastoma model (which was histologically indistinguishable from its human counterpart - in big contrast to many animal tumor models) I checked primary human medulloblastomas for mutations in the hotspot exons of p53 and found only few of them (about 10%), to the best of my knowledge today I was the first to ever find a p53 mutation in a medulloblastoma --- but nowadays this entity reflects even one of four in the newest classification brain tumors; this means: the mutational spectrum of a tumor is already above the pure histological classification of brain tumors. And this appears to be the new WHO standard. On the other hand, it means that classical histological diagnostics may have major drawbacks.

Perhaps we find more participants in the discussion?

Robert: to repeat the statements of "believe" and / or "this is cited everywhere" seems - at least to me - not being an intellectual argument of the failure assuming mutations would the major cause for the development of cancer - this had been done some 85y and if we are honest, only a marginal benefit resulted out of this thinking

Björn, it is of course OK to have an own view - but beleiving that mutations are not crucial for cancer development is (currently) not convincing to any leaders in the cancer research - expecially without any experimental approach, I can not see any approach to induce tumors without mutations. I think the progress of decades of cancer research is visible, one should not deny it.

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

Thanks, Björn, for pointing to this short commentary - I really may not get the point, or I may not have read it carefully enough - but all the argumentation appears to me a bit as with other argumentations in conspiracy theories...

I think it is just too trivial to not accept the experiments - and not being able to provide a mutation-less cancer cell.

As I tried to paint previously in driving with a car into a turn: one does not need to postulate a non-existing force, just because there is the feeling something pushes the driver away from the center of the circle... Although I am open for theoretical hypotheses, I can not deny my experiments and results which do not need anything instead of mutations. Of course, any carcinogenic factors leading to mutations will be interesting for prevention, like reducing cell divisions caused by inflammation, or toxic compounds reducing repair gene activity....

Dear Eibl

If you read attached paper and project , I will be very happy

https://www.researchgate.net/project/Testing-New-Cancer-Theory-Chaotic-Adaptation-TheoryCAT

Article Cancer is the chaotic search for adaptation to previously un...

Is cancer development Darwinian or Lamarkcian ?

It is the main question

Thank You, Dr. Tez, for providing your review paper; I am sorry, but I can not read it now.  But it is of course free for discussion here.

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

https://onlinelibrary.wiley.com/doi/full/10.1002/ijc.31841

When we talk about mutation in relation with genetics, we should not override epigenetics. Apart from its effect in progression of cancer, the role this plays during initiation has been considered a vital point.

I think it is both, genetics and epigenetics. In my opinion the proof that mutations can result in cancer is evidenced by very early onset of certain cancers like childhood leukemias and retinoblastomas. I agree with the notion that it might not be 100% mutations since it is known from genetics that epigenetics play important role even in the inheritance of certain metabolic syndromes (without the presence of genetic alterations). For example, it was shown, at least in mice, that the way parents are fed affects some metabolic phenotypes in offsprings.