Loss of p53 in enterocytes generates an inflammatory microenvironment enabling invasion and lymph node metastasis of carcinogen-induced colorectal tumors
Open accessAbstract
Loss of p53 is considered to allow progression of colorectal tumors from the adenoma to the carcinoma stage. Using mice with an intestinal epithelial cell (IEC)-specific p53 deletion, we demonstrate that loss of p53 alone is insufficient to initiate intestinal tumorigenesis but markedly enhances carcinogen-induced tumor incidence and leads to invasive cancer and lymph node metastasis. Whereas p53 controls DNA damage and IEC survival during the initiation stage, loss of p53 during tumor progression is associated with increased intestinal permeability, causing formation of an NF-κB-dependent inflammatory microenvironment and the induction of epithelial-mesenchymal transition. Thus, we propose a p53-controlled tumor-suppressive function that is independent of its well-established role in cell-cycle regulation, apoptosis, and senescence.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Loss of p53 alone is insufficient to initiate intestinal tumorigenesis but markedly enhances carcinogen-induced tumor incidence, the progression of which is associated with increased intestinal permeability, causing the formation of a NF-κB-dependent inflammatory microenvironment.
“The loss of p53 alone is insufficient to initiate intestinal tumorigenesis but markedly enhances carcinogen-induced tumor incidence, the progression of which is associated with increased intestinal permeability, causing the formation of a NF-κB-dependent inflammatory microenvironment (322).”
From IL-6 in inflammation, autoimmunity and cancer (2021) · cites this paper as [322]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
Part of this paper’s reference list could not be split into single entries.
Tumorigenesis and the angiogenic switch
Bergers, G., & Benjamin, L. E. (2003) · Nature reviews. Cancer · doi:10.1038/nrc1093 · Cited by 3,559 · see citing works
The first 30 years of p53: growing ever more complex.
Levine, A. J., & Oren, M. (2009) · Nature Reviews Cancer · doi:10.1038/nrc2723 · Cited by 1,967 · see citing works
Transcriptional control of human p53-regulated genes
Riley, T., Sontag, E., Chen, P., & Levine, A. (2008) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm2395 · Cited by 1,921 · see citing works
Transcriptional Cross Talk between NF-κB and p53
Webster, G. A., & Perkins, N. D. (1999) · Molecular and Cellular Biology · doi:10.1128/mcb.19.5.3485 · Cited by 598 · see citing works
The pathological response to DNA damage does not contribute to p53-mediated tumour suppression
Christophorou, M. A., Ringshausen, I., Finch, A. J., Swigart, L. B., & Evan, G. I. (2006) · Nature · doi:10.1038/nature05077 · Cited by 382 · see citing works
Bennecke, M., Kriegl, L., Bajbouj, M., Retzlaff, K., Robine, S., Jung, A., Arkan, M. C., Kirchner, T., & Greten, F. R. (2010) · Cancer Cell · doi:10.1016/j.ccr.2010.06.013 · Cited by 186 · see citing works
Self-citation
Flagged first, then by citations
Research works printed but not linked: 38
- [1]1. Becker, C. ∙ Fantini, M.C. ∙ Neurath, M.F. High resolution colonoscopy in live mice Nat. Protoc. 2006; 1:2900-2904 Crossref Scopus (284) PubMed Google Scholar
- [4]4. Bollrath, J. ∙ Greten, F.R. IKK/NF-κB and STAT3 pathways: central signalling hubs in inflammation-mediated tumour promotion and metastasis EMBO Rep. 2009; 10:1314-1319 Crossref Scopus (346) PubMed Google Scholar
- [5]5. Bollrath, J. ∙ Phesse, T.J. ∙ von Burstin, V.A. ... gp130-mediated Stat3 activation in enterocytes regulates cell survival and cell-cycle progression during colitis-associated tumorigenesis Cancer Cell. 2009; 15:91-102 Full Text Full Text (PDF) Scopus (820) PubMed Google Scholar
- [7]7. Clarke, A.R. ∙ Cummings, M.C. ∙ Harrison, D.J. Interaction between murine germline mutations in p53 and APC predisposes to pancreatic neoplasia but not to increased intestinal malignancy Oncogene. 1995; 11:1913-1920 PubMed Google Scholar
- [8]8. Egan, L.J. ∙ Eckmann, L. ∙ Greten, F.R. ... IκB-kinaseβ-dependent NF-κB activation provides radioprotection to the intestinal epithelium Proc. Natl. Acad. Sci. USA. 2004; 101:2452-2457 Crossref Scopus (182) PubMed Google Scholar
- [9]9. el Marjou, F. ∙ Janssen, K.P. ∙ Chang, B.H. ... Tissue-specific and inducible Cre-mediated recombination in the gut epithelium Genesis. 2004; 39:186-193 Crossref Scopus (803) PubMed Google Scholar
- [10]10. Elyada, E. ∙ Pribluda, A. ∙ Goldstein, R.E. ... CKIα ablation highlights a critical role for p53 in invasiveness control Nature. 2011; 470:409-413 Crossref Scopus (158) PubMed Google Scholar
- [11]11. Fazeli, A. ∙ Steen, R.G. ∙ Dickinson, S.L. ... Effects of p53 mutations on apoptosis in mouse intestinal and human colonic adenomas Proc. Natl. Acad. Sci. USA. 1997; 94:10199-10204 Crossref Scopus (68) PubMed Google Scholar
- [12]12. Fearon, E.R. ∙ Vogelstein, B. A genetic model for colorectal tumorigenesis Cell. 1990; 61:759-767 Full Text (PDF) Scopus (10629) PubMed Google Scholar
- [13]13. Fodde, R. ∙ Smits, R. ∙ Clevers, H. APC, signal transduction and genetic instability in colorectal cancer Nat. Rev. Cancer. 2001; 1:55-67 Crossref Scopus (795) PubMed Google Scholar
- [14]14. Greten, F.R. ∙ Eckmann, L. ∙ Greten, T.F. ... IKKβ links inflammation and tumorigenesis in a mouse model of colitis-associated cancer Cell. 2004; 118:285-296 Full Text Full Text (PDF) Scopus (2185) PubMed Google Scholar
- [15]15. Grivennikov, S.I. ∙ Greten, F.R. ∙ Karin, M. Immunity, inflammation, and cancer Cell. 2010; 140:883-899 Full Text Full Text (PDF) Scopus (8482) PubMed Google Scholar
- [16]16. Hahn, W.C. ∙ Weinberg, R.A. Rules for making human tumor cells N. Engl. J. Med. 2002; 347:1593-1603 Crossref Scopus (813) PubMed Google Scholar
- [17]17. Halberg, R.B. ∙ Katzung, D.S. ∙ Hoff, P.D. ... Tumorigenesis in the multiple intestinal neoplasia mouse: redundancy of negative regulators and specificity of modifiers Proc. Natl. Acad. Sci. USA. 2000; 97:3461-3466 Crossref Scopus (117) PubMed Google Scholar
- [18]18. Hanahan, D. ∙ Weinberg, R.A. Hallmarks of cancer: the next generation Cell. 2011; 144:646-674 Full Text Full Text (PDF) Scopus (49668) PubMed Google Scholar
- [19]19. Hill, D.A. ∙ Artis, D. Intestinal bacteria and the regulation of immune cell homeostasis Annu. Rev. Immunol. 2010; 28:623-667 Crossref Scopus (475) PubMed Google Scholar
- [20]20. Horst, D. ∙ Budczies, J. ∙ Brabletz, T. ... Invasion associated up-regulation of nuclear factor κB target genes in colorectal cancer Cancer. 2009; 115:4946-4958 Crossref Scopus (41) PubMed Google Scholar
- [21]21. Hung, K.E. ∙ Maricevich, M.A. ∙ Richard, L.G. ... Development of a mouse model for sporadic and metastatic colon tumors and its use in assessing drug treatment Proc. Natl. Acad. Sci. USA. 2010; 107:1565-1570 Crossref Scopus (167) PubMed Google Scholar
- [22]22. Jang, K.T. ∙ Chae, S.W. ∙ Sohn, J.H. ... Coexpression of MUC1 with p53 or MUC2 correlates with lymph node metastasis in colorectal carcinomas J. Korean Med. Sci. 2002; 17:29-33 Crossref Scopus (18) PubMed Google Scholar
- [23]23. Jonkers, J. ∙ Meuwissen, R. ∙ van der Gulden, H. ... Synergistic tumor suppressor activity of BRCA2 and p53 in a conditional mouse model for breast cancer Nat. Genet. 2001; 29:418-425 Crossref Scopus (853) PubMed Google Scholar
- [24]24. Joyce, J.A. ∙ Pollard, J.W. Microenvironmental regulation of metastasis Nat. Rev. Cancer. 2009; 9:239-252 Crossref Scopus (2975) PubMed Google Scholar
- [25]25. Kawauchi, K. ∙ Araki, K. ∙ Tobiume, K. ... p53 regulates glucose metabolism through an IKK-NF-κB pathway and inhibits cell transformation Nat. Cell Biol. 2008; 10:611-618 Crossref Scopus (527) PubMed Google Scholar
- [26]26. Kusaba, T. ∙ Nakayama, T. ∙ Yamazumi, K. ... Expression of p-STAT3 in human colorectal adenocarcinoma and adenoma; correlation with clinicopathological factors J. Clin. Pathol. 2005; 58:833-838 Crossref Scopus (153) PubMed Google Scholar
- [28]28. Madison, B.B. ∙ Dunbar, L. ∙ Qiao, X.T. ... cis elements of the villin gene control expression in restricted domains of the vertical (crypt) and horizontal (duodenum, cecum) axes of the intestine J. Biol. Chem. 2002; 277:33275-33283 Crossref Scopus (623) PubMed Google Scholar
- [29]29. Mantovani, A. ∙ Allavena, P. ∙ Sica, A. ... Cancer-related inflammation Nature. 2008; 454:436-444 Crossref Scopus (8867) PubMed Google Scholar
- [30]30. Meek, D.W. Tumour suppression by p53: a role for the DNA damage response? Nat. Rev. Cancer. 2009; 9:714-723 Crossref Scopus (521) PubMed Google Scholar
- [31]31. Meining, A. ∙ Frimberger, E. ∙ Becker, V. ... Detection of cholangiocarcinoma in vivo using miniprobe-based confocal fluorescence microscopy Clin. Gastroenterol. Hepatol. 2008; 6:1057-1060 Full Text Full Text (PDF) Scopus (127) PubMed Google Scholar
- [32]32. Murdoch, C. ∙ Muthana, M. ∙ Coffelt, S.B. ... The role of myeloid cells in the promotion of tumour angiogenesis Nat. Rev. Cancer. 2008; 8:618-631 Crossref Scopus (1323) PubMed Google Scholar
- [33]33. Ogata, H. ∙ Sekikawa, A. ∙ Yamagishi, H. ... GROα promotes invasion of colorectal cancer cells Oncol. Rep. 2010; 24:1479-1486 PubMed Google Scholar
- [34]34. Pohl, H. ∙ Rösch, T. ∙ Vieth, M. ... Miniprobe confocal laser microscopy for the detection of invisible neoplasia in patients with Barrett’s oesophagus Gut. 2008; 57:1648-1653 Crossref Scopus (194) PubMed Google Scholar
- [35]35. Polyak, K. ∙ Weinberg, R.A. Transitions between epithelial and mesenchymal states: acquisition of malignant and stem cell traits Nat. Rev. Cancer. 2009; 9:265-273 Crossref Scopus (2803) PubMed Google Scholar
- [36]36. Qiu, W. ∙ Carson-Walter, E.B. ∙ Kuan, S.F. ... PUMA suppresses intestinal tumorigenesis in mice Cancer Res. 2009; 69:4999-5006 Crossref Scopus (42) PubMed Google Scholar
- [38]38. Soler, A.P. ∙ Miller, R.D. ∙ Laughlin, K.V. ... Increased tight junctional permeability is associated with the development of colon cancer Carcinogenesis. 1999; 20:1425-1431 Crossref Scopus (304) PubMed Google Scholar
- [39]39. Toft, N.J. ∙ Winton, D.J. ∙ Kelly, J. ... Msh2 status modulates both apoptosis and mutation frequency in the murine small intestine Proc. Natl. Acad. Sci. USA. 1999; 96:3911-3915 Crossref Scopus (157) PubMed Google Scholar
- [40]40. Valdés-Mora, F. ∙ Gómez del Pulgar, T. ∙ Bandrés, E. ... TWIST1 overexpression is associated with nodal invasion and male sex in primary colorectal cancer Ann. Surg. Oncol. 2009; 16:78-87 Crossref Scopus (65) PubMed Google Scholar
- [41]41. Vogelstein, B. ∙ Fearon, E.R. ∙ Hamilton, S.R. ... Genetic alterations during colorectal-tumor development N. Engl. J. Med. 1988; 319:525-532 Crossref Scopus (6189) PubMed Google Scholar
- [42]42. Waldner, M.J. ∙ Wirtz, S. ∙ Neufert, C. ... Confocal laser endomicroscopy and narrow-band imaging-aided endoscopy for in vivo imaging of colitis and colon cancer in mice Nat. Protoc. 2011; 6:1471-1481 Crossref Scopus (49) PubMed Google Scholar
- [43]43. Wang, X. ∙ Tully, O. ∙ Ngo, B. ... Epithelial tight junctional changes in colorectal cancer tissues ScientificWorldJournal. 2011; 11:826-841 Crossref Scopus (41) PubMed Google Scholar
Cited by
Sorted by citations
Inflammation and cancer: triggers, mechanisms, and consequences
Greten, F. R., & Grivennikov, S. I. (2019) · Immunity · doi:10.1016/j.immuni.2019.06.025 · Cited by 3,806 · see citing works
Self-citationNF-κB, inflammation, immunity and cancer: coming of age
Taniguchi, K., & Karin, M. (2018) · Nature Reviews Immunology · doi:10.1038/nri.2017.142 · Cited by 2,679 · see citing works
IL-6 in inflammation, autoimmunity and cancer
Hirano, T. (2021) · International Immunology · doi:10.1093/intimm/dxaa078 · Cited by 1,453 · see citing works
“The loss of p53 alone is insufficient to initiate intestinal tumorigenesis but markedly enhances carcinogen-induced tumor incidence, the progression of which is associated with increased intestinal permeability, causing the formation of a NF-κ B-dependent inflammatory microenvironment (322).”
BackgroundIL-6R/STAT3/miR-34a feedback loop promotes EMT-mediated colorectal cancer invasion and metastasis
Rokavec, M., Öner, M. G., Li, H., Jackstadt, R., Jiang, L., Lodygin, D., Kaller, M., Horst, D., Ziegler, P. K., Schwitalla, S., et al. (2014) · Journal of Clinical Investigation · doi:10.1172/jci73531 · Cited by 753 · see citing works
Self-citationThe dynamic nature of senescence in cancer
Lee, S., & Schmitt, C. A. (2019) · Nature Cell Biology · doi:10.1038/s41556-018-0249-2 · Cited by 588 · see citing works
Vanharanta, S., & Massagué, J. (2013) · Cancer Cell · doi:10.1016/j.ccr.2013.09.007 · Cited by 563 · see citing works
Loss of p53 triggers WNT-dependent systemic inflammation to drive breast cancer metastasis
Wellenstein, M. D., Coffelt, S. B., Duits, D. E. M., van Miltenburg, M. H., Slagter, M., de Rink, I., Henneman, L., Kas, S. M., Prekovic, S., Hau, C.-S., et al. (2019) · Nature · doi:10.1038/s41586-019-1450-6 · Cited by 500 · see citing works
Interaction between the microbiome and TP53 in human lung cancer
Greathouse, K. L., White, J. R., Vargas, A. J., Bliskovsky, V. V., Beck, J. A., von Muhlinen, N., Polley, E. C., Bowman, E. D., Khan, M. A., Robles, A. I., et al. (2018) · Genome Biology · doi:10.1186/s13059-018-1501-6 · Cited by 446 · see citing works
Guo, G., Yu, M., Xiao, W., Celis, E., & Cui, Y. (2017) · Cancer Research · doi:10.1158/0008-5472.can-16-2832 · Cited by 168 · see citing works
NF-κB: a double-edged sword controlling inflammation
Liu, D., Zhong, Z., & Karin, M. (2022) · Biomedicines · doi:10.3390/biomedicines10061250 · Cited by 157 · see citing works
Epigenetic remodelling shapes inflammatory renal cancer and neutrophil-dependent metastasis
Nishida, J., Momoi, Y., Miyakuni, K., Tamura, Y., Takahashi, K., Koinuma, D., Miyazono, K., & Ehata, S. (2020) · Nature Cell Biology · doi:10.1038/s41556-020-0491-2 · Cited by 135 · see citing works
Regulation of Metabolic Activity by p53
Flöter, J., Kaymak, I., & Schulze, A. (2017) · Metabolites · doi:10.3390/metabo7020021 · Cited by 81 · see citing works
McCubrey, J. A., Yang, L. V., Abrams, S. L., Steelman, L. S., Follo, M. Y., Cocco, L., Ratti, S., Martelli, A. M., Augello, G., & Cervello, M. (2022) · Cells · doi:10.3390/cells11142155 · Cited by 49 · see citing works
- Authors
- Schwitalla, S., Ziegler, P. K., Horst, D., Becker, V., Kerle, I., Begus-Nahrmann, Y., Lechel, A., Rudolph, K. L., Langer, R., Slotta-Huspenina, J., Bader, F. G., Prazeres da Costa, O., Neurath, M. F., Meining, A., Kirchner, T., & Greten, F. R.
- Affiliations
- TUM Klinikum (DE)
- Pathologisches Institut (DE)
- Universität Ulm (DE)
- Friedrich-Alexander-Universität Erlangen-Nürnberg (DE)
- Corresponding author
- Greten, Florian R.
- ORCID
- Venue
- Cancer Cell
- Publisher
- Elsevier BV
- Published
- 2013-01
- Volume
- 23
- Issue
- 1
- Pages
- 93-106
- ISSN
- 1535-6108 (ISSN-L)
- OpenAlex
- W2027266715
- Cited by
- 296
- References
- 6
- Citations by year
- 2026: 9 · 2025: 21 · 2024: 23 · 2023: 16 · 2022: 19 · 2021: 26 · 2020: 30 · 2019: 12 · 2018: 26 · 2017: 15 · 2016: 21 · 2015: 35 · 2014: 25 · 2013: 17
- FWCI
- 12.19
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cancer Cell (publishedVersion)
- PubMed (publishedVersion)
- Bern Open Repository and Information System (University of Bern) (submittedVersion)
- mediaTUM (Technical University of Munich) (submittedVersion)
- Funders
- Deutsche Forschungsgemeinschaft
- Deutsche Krebshilfe
- Topics
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Health Sciences › Medicine › Pathology and Forensic Medicine › Genetic factors in colorectal cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mechanisms of cancer metastasis
- Keywords
- p53 deficiency, colorectal cancer, enterocytes, intestinal epithelial cells, carcinogen-induced tumors, tumor invasion, lymph node metastasis, tumor microenvironment, NF-κB signaling, intestinal permeability, epithelial-mesenchymal transition, tumor progression, tumor suppression
- MeSH terms
- Adenoma, Animals, Carcinogens, Carcinoma, Disease Models, Animal, Lymph Nodes, Neoplasm Invasiveness, Neoplasm Metastasis, Colorectal Neoplasms, Tumor Suppressor Protein p53, Mutagenesis, Site-Directed, Mice, Tumor Microenvironment
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
