Intestinal tumorigenesis initiated by dedifferentiation and acquisition of stem-cell-like properties

S. Schwitalla; A.A. Fingerle; P. Cammareri; T. Nebelsiek; S.I. Goktuna; P.K. Ziegler; O. Canli; J. Heijmans; D.J. Huels; G. Moreaux; R.A. Rupec; M. Gerhard; R. Schmid; N. Barker; H. Clevers; R. Lang; J. Neumann; T. Kirchner; M.M. Taketo; G.R. van den Brink; O.J. Sansom; M.C. Arkan; F.R. Greten

doi:10.1016/j.cell.2012.12.012

Intestinal tumorigenesis initiated by dedifferentiation and acquisition of stem-cell-like properties

S. Schwitalla, A.A. Fingerle, P. Cammareri, T. Nebelsiek, S.I. Goktuna, P.K. Ziegler, O. Canli, J. Heijmans, D.J. Huels, G. Moreaux, R.A. Rupec, M. Gerhard, R. Schmid, N. Barker, H. Clevers, R. Lang, J. Neumann, T. Kirchner, M.M. Taketo, G.R. van den BrinkO.J. Sansom, M.C. Arkan, F.R. Greten

Hubrecht Institute

Research output: Contribution to journal/periodical › Article › Scientific › peer-review

860 Citations (Scopus)

Abstract

Cell-type plasticity within a tumor has recently been suggested to cause a bidirectional conversion between tumor-initiating stem cells and nonstem cells triggered by an inflammatory stroma. NF-kappaB represents a key transcription factor within the inflammatory tumor microenvironment. However, NF-kappaB's function in tumor-initiating cells has not been examined yet. Using a genetic model of intestinal epithelial cell (IEC)-restricted constitutive Wnt-activation, which comprises the most common event in the initiation of colon cancer, we demonstrate that NF-kappaB modulates Wnt signaling and show that IEC-specific ablation of RelA/p65 retards crypt stem cell expansion. In contrast, elevated NF-kappaB signaling enhances Wnt activation and induces dedifferentiation of nonstem cells that acquire tumor-initiating capacity. Thus, our data support the concept of bidirectional conversion and highlight the importance of inflammatory signaling for dedifferentiation and generation of tumor-initiating cells in vivo.

Original language	English
Pages (from-to)	25-38
Journal	Cell
Volume	152
Issue number	1-2
DOIs	https://doi.org/10.1016/j.cell.2012.12.012
Publication status	Published - 2013

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Schwitalla, S., Fingerle, A. A., Cammareri, P., Nebelsiek, T., Goktuna, S. I., Ziegler, P. K., Canli, O., Heijmans, J., Huels, D. J., Moreaux, G., Rupec, R. A., Gerhard, M., Schmid, R., Barker, N., Clevers, H., Lang, R., Neumann, J., Kirchner, T., Taketo, M. M., ... Greten, F. R. (2013). Intestinal tumorigenesis initiated by dedifferentiation and acquisition of stem-cell-like properties. Cell, 152(1-2), 25-38. https://doi.org/10.1016/j.cell.2012.12.012

@article{0dec931d9e2b451e9347c8130f19c4fc,

title = "Intestinal tumorigenesis initiated by dedifferentiation and acquisition of stem-cell-like properties",

abstract = "Cell-type plasticity within a tumor has recently been suggested to cause a bidirectional conversion between tumor-initiating stem cells and nonstem cells triggered by an inflammatory stroma. NF-kappaB represents a key transcription factor within the inflammatory tumor microenvironment. However, NF-kappaB's function in tumor-initiating cells has not been examined yet. Using a genetic model of intestinal epithelial cell (IEC)-restricted constitutive Wnt-activation, which comprises the most common event in the initiation of colon cancer, we demonstrate that NF-kappaB modulates Wnt signaling and show that IEC-specific ablation of RelA/p65 retards crypt stem cell expansion. In contrast, elevated NF-kappaB signaling enhances Wnt activation and induces dedifferentiation of nonstem cells that acquire tumor-initiating capacity. Thus, our data support the concept of bidirectional conversion and highlight the importance of inflammatory signaling for dedifferentiation and generation of tumor-initiating cells in vivo.",

author = "S. Schwitalla and A.A. Fingerle and P. Cammareri and T. Nebelsiek and S.I. Goktuna and P.K. Ziegler and O. Canli and J. Heijmans and D.J. Huels and G. Moreaux and R.A. Rupec and M. Gerhard and R. Schmid and N. Barker and H. Clevers and R. Lang and J. Neumann and T. Kirchner and M.M. Taketo and {van den Brink}, G.R. and O.J. Sansom and M.C. Arkan and F.R. Greten",

note = "Reporting year: 2013",

year = "2013",

doi = "10.1016/j.cell.2012.12.012",

language = "English",

volume = "152",

pages = "25--38",

journal = "Cell",

issn = "0092-8674",

publisher = "Elsevier B.V.",

number = "1-2",

}

Schwitalla, S, Fingerle, AA, Cammareri, P, Nebelsiek, T, Goktuna, SI, Ziegler, PK, Canli, O, Heijmans, J, Huels, DJ, Moreaux, G, Rupec, RA, Gerhard, M, Schmid, R, Barker, N, Clevers, H, Lang, R, Neumann, J, Kirchner, T, Taketo, MM, van den Brink, GR, Sansom, OJ, Arkan, MC & Greten, FR 2013, 'Intestinal tumorigenesis initiated by dedifferentiation and acquisition of stem-cell-like properties', Cell, vol. 152, no. 1-2, pp. 25-38. https://doi.org/10.1016/j.cell.2012.12.012

TY - JOUR

T1 - Intestinal tumorigenesis initiated by dedifferentiation and acquisition of stem-cell-like properties

AU - Schwitalla, S.

AU - Fingerle, A.A.

AU - Cammareri, P.

AU - Nebelsiek, T.

AU - Goktuna, S.I.

AU - Ziegler, P.K.

AU - Canli, O.

AU - Heijmans, J.

AU - Huels, D.J.

AU - Moreaux, G.

AU - Rupec, R.A.

AU - Gerhard, M.

AU - Schmid, R.

AU - Barker, N.

AU - Clevers, H.

AU - Lang, R.

AU - Neumann, J.

AU - Kirchner, T.

AU - Taketo, M.M.

AU - van den Brink, G.R.

AU - Sansom, O.J.

AU - Arkan, M.C.

AU - Greten, F.R.

N1 - Reporting year: 2013

PY - 2013

Y1 - 2013

N2 - Cell-type plasticity within a tumor has recently been suggested to cause a bidirectional conversion between tumor-initiating stem cells and nonstem cells triggered by an inflammatory stroma. NF-kappaB represents a key transcription factor within the inflammatory tumor microenvironment. However, NF-kappaB's function in tumor-initiating cells has not been examined yet. Using a genetic model of intestinal epithelial cell (IEC)-restricted constitutive Wnt-activation, which comprises the most common event in the initiation of colon cancer, we demonstrate that NF-kappaB modulates Wnt signaling and show that IEC-specific ablation of RelA/p65 retards crypt stem cell expansion. In contrast, elevated NF-kappaB signaling enhances Wnt activation and induces dedifferentiation of nonstem cells that acquire tumor-initiating capacity. Thus, our data support the concept of bidirectional conversion and highlight the importance of inflammatory signaling for dedifferentiation and generation of tumor-initiating cells in vivo.

AB - Cell-type plasticity within a tumor has recently been suggested to cause a bidirectional conversion between tumor-initiating stem cells and nonstem cells triggered by an inflammatory stroma. NF-kappaB represents a key transcription factor within the inflammatory tumor microenvironment. However, NF-kappaB's function in tumor-initiating cells has not been examined yet. Using a genetic model of intestinal epithelial cell (IEC)-restricted constitutive Wnt-activation, which comprises the most common event in the initiation of colon cancer, we demonstrate that NF-kappaB modulates Wnt signaling and show that IEC-specific ablation of RelA/p65 retards crypt stem cell expansion. In contrast, elevated NF-kappaB signaling enhances Wnt activation and induces dedifferentiation of nonstem cells that acquire tumor-initiating capacity. Thus, our data support the concept of bidirectional conversion and highlight the importance of inflammatory signaling for dedifferentiation and generation of tumor-initiating cells in vivo.

U2 - 10.1016/j.cell.2012.12.012

DO - 10.1016/j.cell.2012.12.012

M3 - Article

SN - 0092-8674

VL - 152

SP - 25

EP - 38

JO - Cell

JF - Cell

IS - 1-2

ER -

Intestinal tumorigenesis initiated by dedifferentiation and acquisition of stem-cell-like properties

Abstract

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