it is really quite interesting: if someone looks at the scientific writer blogs and comments, anyone concentrates on the fact, how anti-EGFR therapy could be improved.
But:
If someone looks in detail at the methods and results, it clearly comes up, that
"Stroma and remodeled ECM (precancerous niche) rather than the cancer cell itself triggers cancer development (carcinogenesis)"
Abstract
Background & Aims
Inhibitors of the epidermal growth factor receptor (EGFR) are the first-line therapy for patients with metastatic colorectal tumors without RAS mutations. However, EGFR inhibitors are ineffective in these patients, and tumor level of EGFR does not associate with response to therapy. We screened human colorectal tumors for EGFR-positive myeloid cells and investigated their association with patient outcome. We also performed studies in mice to evaluate how EGFR expression in tumor cells and myeloid cells contributes to development of colitis-associated cancer and ApcMin-dependent intestinal tumorigenesis.
Methods
We performed immunohistochemical and immunofluorescent analyses of 116 colorectal tumor biopsies to determine levels of EGFR in tumor and stroma; we also collected information on tumor stage and patient features and outcomes. We used the Mann-Whitney U and Kruskal-Wallis test to correlate tumor levels of EGFR with tumor stage, and the Kaplan-Meier method to estimate patients’ median survival time. We performed experiments in mice lacking EGFR in intestinal epithelial cells (Vil-Cre;Egfrfl/fl and Vil-CreERT2;Egfrfl/fl mice) or myeloid cells (LysM-Cre;Egfrfl/fl mice) on a mixed background. These mice were bred with ApcMin/+ mice; colitis and colitis-associated cancer were induced by administration of dextran sodium sulfate (DSS), with or without azoxymethane (AOM), respectively. Vil-CreERT2 was activated in developed tumors by administration of tamoxifen to mice. Littermates that expressed full-length EGFR were used as controls. Intestinal tissues were collected; severity of colitis, numbers and size of tumors, and intestinal barrier integrity were assessed by histologic, immunohistochemical, quantitative reverse transcription PCR, and flow cytometry analyses.
Results
We detected EGFR in myeloid cells in the stroma of human colorectal tumors; myeloid cell expression of EGFR associated with tumor metastasis and shorter patient survival time. Mice with deletion of EGFR from myeloid cells formed significantly fewer and smaller tumors than the respective EGFR-expressing controls in an ApcMin/+ background as well as after administration of AOM and DSS. Deletion of EGFR from intestinal epithelial cells did not affect tumor growth. Furthermore, tamoxifen-induced deletion of EGFR from epithelial cells of established intestinal tumors in given AOM and DSS did not reduce tumor size. EGFR signaling in myeloid cells promoted activation of STAT3 and expression of survivin in intestinal tumor cells. Mice with deletion of EGFR from myeloid cells developed more severe colitis after DSS administration, characterized by increased intestinal inflammation and intestinal barrier disruption, than control mice or mice with deletion of EGFR from intestinal epithelial cells. EGFR-deficient myeloid cells in the colon of DSS-treated LysM-Cre;Egfrfl/fl mice had reduced expression of interleukin 6 (IL6), and epithelial STAT3 activation was reduced compared to controls. Administration of recombinant IL6 to LysM-Cre;Egfrfl/fl mice given DSS protected them from weight loss and restored epithelial proliferation and STAT3 activation, compared with administration of DSS alone to these mice.
Conclusions
Increased expression of EGFR in myeloid cells from the colorectal tumor stroma associates with tumor progression and reduced survival time of patients with metastatic colorectal cancer. Deletion of EGFR from myeloid cells, but not intestinal epithelial cells, protects mice from colitis-induced intestinal cancer and ApcMin-dependent intestinal tumorigenesis. Myeloid cell expression of EGFR increases activation of STAT3 and expression of survivin in intestinal epithelial cells and expression of IL6 in colon tissues. These findings indicate that expression of EGFR by myeloid cells of the colorectal tumor stroma, rather than the cancer cells themselves, contributes to tumor development.
http://www.gastrojournal.org/article/S0016-5085(17)35414-8/abstract
http://www.gastrojournal.org/article/S0016-5085(17)35414-8/abstract
Dvorak et al. proposed the theory that a “tumor is a wound that never heals” I agree. This is also in assosiacition with your findings. I daily deal with ovarian cancer and peritoneal carcinomatosis, observing thickened inflamatory peritoneal tissue. I think more studies investigating inflamattion, tumor microenviroment and cancer associated fibroblast should be undertaken.CAF and CAF secreted growth factors (such as EGF) also seems critical in colorectal cancer. I would like to be involved or help in projects regarding tumor enviroment. All the best, Evrim
Our (Brucher and Jamall--- https://www.ncbi.nlm.nih.gov/pubmed/24885752) thinking is consistent with the paper cited above and with those from Erler's lab:
https://www.ncbi.nlm.nih.gov/pubmed/28303905
https://www.ncbi.nlm.nih.gov/pubmed/27761366
Thanks for pointing me to this abstract; it will be very interesting to read the full paper later.
This is very interesting and also very likely. "Precancerous niche" is a very important factor for cancer development.
So, EGFR expression in tumor stromal cells contributes to tumor development, yet, EGFR inhibitors are not effective in certain patients and do not correlate with response to therapy (see abstract). Then what am I missing?
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
Dvorak et al. proposed the theory that a “tumor is a wound that never heals” I agree. This is also in assosiacition with your findings. I daily deal with ovarian cancer and peritoneal carcinomatosis, observing thickened inflamatory peritoneal tissue. I think more studies investigating inflamattion, tumor microenviroment and cancer associated fibroblast should be undertaken.CAF and CAF secreted growth factors (such as EGF) also seems critical in colorectal cancer. I would like to be involved or help in projects regarding tumor enviroment. All the best, Evrim
See also http://stke.sciencemag.org/content/10/491/eaao5803.full about two papers demonstrating protein profiles changing in direct vicinity of tumour.
I have read letter from scienceletter and now reading your article Biotechnologie und Krebs
Die chronische Inflammation ist eine „der“ wichtigen
Sequenzen eines schrittweisen Karzinogenese-Prozesses
Thank you
is it correct naming fibroblasts "cancer associated Fibroblast" just because being engaged in carcinogenesis.
should we therefore call any Kind of cell "Cancer associated XYZ"?
Isn't it traditional for the medical world to call things by their appearance, rather than by their biology?
Dear Brucher, very interesting and coincided with a research results we concluded at Lymphoma and H. Pylori as specific Ab against certain cell (Keratinocytes) transduct gene through attachment to EGFR expressing certain diseases as dermatitis and CIU, MALT lymphoma and Langerhans cell histiocytosis. H. Pylori eradication will revert the condition to normal.
Regards
Adil Bashir
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
Article Simultaneous stimulation with tumor necrosis factor-α and tr...
if you want to see a different approach to ECM, please read this:
Extracellular matrix and its role in conveying glial/neural interactions in health and disease
- February 2017
- Journal of Integrative Neuroscience 16(1):93-106
- DOI
- 10.3233/JIN-170012
thanks - the term "pre-cancerous niche" makes more sense - an own paper will come, thanks b
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
Dear Brücher, happy New Year although it’s late,
Trigger Hypothesis proposed in one of papers we published;
American Journal of Dermatology and Venereology 2013, 2(3): 27-30 DOI: 10.5923/j.ajdv.20130203.03
Primary Cutaneous Follicular Lymphoma Associated with Helicobacter pylori Infection
A. H. Bashir1,6,*, S M Yousif2, Lamyaa A M EL Hassan3, W M Elamin4, Ameera Adam5, M. E. Ibrahim5, K. O. Alfarouk5,6, A. K. Muddathir7, A M EL Hassan5
When we saw him first we diagnosed his skin lesions as Xanthogranuloma. After the demonstration of CD 1a positive cells by immunohistochemistry we changed our initial diagnosis to Langerhans histiocytosis. A complex overlap exists between Xanthogranuloma and Langerhans cell histiocytosis, with lesions showing clinical and/or pathological features of both disorders. A year later he developed nodular lesions in a different part of the skin. This proved to be a follicular lymphoma. The tumor was expressing H pylori antigen. Primary cutaneous lymphomas are usually regarded to represent the cutaneous counterpart of extranodal marginal zone lymphoma of the mucosa-associated lymphoid tissue (MALT).
8t~6�
thank you very much
it would have been interested to know some deeper information about the stroma reaction
You are right prof. in a recent study it was found that the matrix degradation process in cancer tissue is multifunctional: besides the involvement in cancer invasion and metastasis, the matrix degradation process is also involved in the tissue remodeling process and in the immune/inflammatory reaction occurring in the stroma. Besides such facilities are not available in underdeveloped countries as you know.
This paper will be orally presented at Madridge Dermatology European conference , 20-21 March 2019, Park Inn by Radisson Frankfurt Airport.
American Journal of Dermatology and Venereology 2013, 2(3): 27-30 DOI: 10.5923/j.ajdv.20130203.03
Primary Cutaneous Follicular Lymphoma Associated with Helicobacter pylori Infection
#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
I think the technical name given to these histological changes is desmoplasia; increased activation of fibroblastic stromal cells in the surrounding ECM of the tumour, which often favors tumour growth.
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”
If we take the 10,000 foot aerial view of the problem, there is no logical reason why metastatic lesions should only occur at locations distant to the primary tumor. The role of the stroma, LOXL2, and YAP signaling (as Prof. Brucher suggests) provides a coherent and plausible explanation in contrast to the more "magical" role of mutations.
"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
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.
Dear Brücher
This study confirming that any physiological process in our body if not given chance to perform it, it will develop disuse problem with time. Natural signaling to certain with no response proposal should be raised.
Last (missing) paper of Special Issue finalized and re-submitted with
-n=5 Figures
-n=355 References
There is a difference between those 5-to-10% of cancers which are proven being originated by germ line mutations and which we do not question.
The complexity below may be of significance.
In regard to the mass of cancers, we prefer a very differentiated view in this regard, which explains why we on purpose published n=5 peer-reviewed papers together with the cancer paradigm 2014-2016. [peer-review process duration: 8 months]
1. (2014), Epistemology of the origin of cancer: a new paradigm, BMC Cancer 14(186), 1-15.
Article Epistemology of the origin of cancer: A new paradigm
2. (2014), Cell-Cell communication in tumor microenvironment, carcinogenesis and anticancer treatment, Cell Physiol Biochem 34(2), 213-243.
Article Cell-Cell Communication in the Tumor Microenvironment, Carci...
3. (2014), Imagine a World without Cancer, BMC Cancer 14(186), 1-8.
Article Imagine a world without cancer.
4. (2016), Somatic Mutation Theory: Why it’s Wrong for Most Cancers, Cell Physiol Biochem 38(5), 1-18.
Article Somatic Mutation Theory - Why it's Wrong for Most Cancers
5. (2016), Genomics, microRNA, epigenetics, and proteomics for future diagnosis, treatment and monitoring response n upper GI cancers, Clin Transl Med 5, 1-16.
Article Genomics, microRNA, epigenetics, and proteomics for future d...
Afterwards we published (after peer-review of course) the Evidence of the 2014 cancer paradigm within a Special Issue recently
[peer-review process duration 12 months]
(1 paper, “Synopsis” will come up shortly)
1. (2019), Key Summaries Special Issue: Disruption of homeostasis-induced signaling and crosstalk in the carcinogenesis paradigm “Epistemology of the origin of cancer”
https://bit.ly/2W8mZea
2. (2019), Prelude and Premise to the Special Issue, 4open 2(6), 1-8.
Article Prelude and premise to the special issue: disruption of home...
3. (2019), Undervalued ubiquitous proteins, 4open 2(7), 1-13.
Article Undervalued ubiquitous proteins
4. (2019), Chronic inflammation evoked by pathogenic stimulus during carcinogenesis, 4open 2(8), 1-22.
Article Chronic inflammation evoked by pathogenic stimulus during ca...
5. (2019), Eicosanoids in carcinogenesis, 4open 2(9), 1-34.
Article Eicosanoids in carcinogenesis
6. (2019), Microbiome and morbid obesity increase pathogenic stimulus diversity, 4open 2(10), 1- 16.
Article Microbiome and morbid obesity increase pathogenic stimulus diversity
7. (2019), Precancerous niche (PCN), a product of fibrosis with remodeling by incessant chronic inflammation, 4open 2(11), 1-21.
Article Precancerous niche (PCN), a product of fibrosis with remodel...
8. (2019), Metformin alters signaling homeostasis, 4open 2(12), 1-17.
Article Metformin alters signaling induced crosstalk and homeostasis...
9. (2019), NF-κB signaling and crosstalk in carcinogenesis, 4open 2(13), 1-35.
Article NF-kB signaling and crosstalk during carcinogenesis
10. (2019), Transition from normal to cancerous cell by precancerous niche (PCN) induced chronic cell-matrix stress, 4open 2(14), 1-31.
Article Transition from normal to cancerous cell by precancerous nic...
Now (afterwards), the complexity of the 2014 peer-reviewed published cancer paradigm was independently from us proven here
"Breast Cancer Research, Volume 21, Article number: 80 (2019)"
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
Great discussion! I DO agree with Björn L.D.M. Brücher and Ijaz S. Jamall ! Thanks a lot for explaining very well these questions!
In living organisms, only death is determinative. Everything else comports itself based on its milieu. Broadly speaking, changes should be viewed as adaptive, chronologically and with respect to stresses imposed on organisms or cells. Viewed in this context, there is little reason, a priori, to assume that mutations in general should be aberrations of nature or necessarily pathogenic.
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
YES , This observations was seen in different types of cancer. In breast cancer the conclusion by Dr Wang : ECM remodeling was primarily mediated by matrix metalloproteinases (MMPs). This MMP activity caused profound structural and mechanical changes in the developing ECM, which then modified vascular endothelial growth factor (VEGF) secretion by CAFs and matrix sequestration. Collectively, these findings enhance the understanding of the mechanisms by which Fn and Col I synergistically interplay in promoting a sustained altered signaling cascade to remodel the breast tumor stroma for invasive breast tumor growth.
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
We've had much evidence for decades from Mina Bissell, Ph.D. and others that cancer is controlled by the ECM/microenvironment. Article Of Extracellular Matrix, Scaffolds, and Signaling: Tissue Ar...
If i may
It is a significant difference if we know that ECM controls cancer or - as here - triggers carcinogenesis - the onset of the first cancer cell - as proposed within
"Epistemology of the origin of cancer" As provided here within the pentology started with the cancer paradigm
https://www.researchgate.net/publication/262215307_Epistemology_of_the_origin_of_cancer_A_new_paradigm
And plus as deepened here in detail
https://www.4open-sciences.org/key-summaries/306-new-research-challenges-current-thinking-on-cancer
As Dr, Maguire suggests, Dr. Bissell did publish several papers early on about the ECM but these papers still focused on gene expression as in the paper cited by Maguire, "...The microenvironment influences gene expression so that the behavior of a cell is largely determined by its interactions with the extracellular matrix, neighboring cells, and soluble local and systemic cues..." We have gone beyond that body of work as cited by Prof. Brucher above.
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
The next study ripe for re-evaluation- risk of breast or ovarian cancers in BRCA 1/BRCA2 mutation carriers. Current risk values:
"
Of the 3,886 women eligible for the breast cancer risk analysis, 426 developed breast cancer during the study period. The peak incidence of breast cancer was seen in women 41–50 years old for BRCA1 mutation carriers and those 51–60 years old for BRCA2 mutation carriers. The cumulative risk estimates for developing breast cancer by age 80 were 72% for BRCA1 carriers and 69% for BRCA2 carriers.
Among the 5,066 women enrolled in the ovarian cancer risk analysis, 109 were diagnosed with ovarian cancer during follow-up. For mutations in both BRCA genes, the risk of ovarian cancer increased with increasing age, until women reached ages 61–70. The cumulative risk estimates for developing ovarian cancer by age 80 were 44% for BRCA1 mutation carriers and 17% for BRCA2 mutation carriers.
For the 2,213 women eligible for the contralateral breast cancer risk analysis, the cumulative risk of a contralateral breast cancer 20 years after a first breast cancer was 40% for BRCA1 mutation carriers and 26% for BRCA2 mutation carriers."
https://www.cancer.gov/news-events/cancer-currents-blog/2017/brca-mutation-cancer-risk
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
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