Cytokinesis failure due to derailed integrin traffic induces aneuploidy and oncogenic transformation in vitro and in vivo

Gunilla Högnäs, Saara Tuomi, Stefan Veltel, Elina Mattila, A. Murumägi, Henrik Edgren, Olli Kallioniemi, Johanna Ivaska (Corresponding Author)

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Abstract

Aneuploidy is frequently detected in solid tumors but the mechanisms regulating the generation of aneuploidy and their relevance in cancer initiation remain under debate and are incompletely characterized. Spatial and temporal regulation of integrin traffic is critical for cell migration and cytokinesis. Impaired integrin endocytosis, because of the loss of Rab21 small GTPase or mutations in the integrin β-subunit cytoplasmic tail, induces failure of cytokinesis in vitro. Here, we describe that repeatedly failed cytokinesis, because of impaired traffic, is sufficient to trigger the generation of aneuploid cells, which display characteristics of oncogenic transformation in vitro and are tumorigenic in vivo. Furthermore, in an in vivo mouse xenograft model, non-transformed cells with impaired integrin traffic formed tumors with a long latency. More detailed investigation of these tumors revealed that the tumor cells were aneuploid. Therefore, abnormal integrin traffic was linked with generation of aneuploidy and cell transformation also in vivo. In human prostate and ovarian cancer samples, downregulation of Rab21 correlates with increased malignancy. Loss-of-function experiments demonstrate that long-term depletion of Rab21 is sufficient to induce chromosome number aberrations in normal human epithelial cells. These data are the first to demonstrate that impaired integrin traffic is sufficient to induce conversion of non-transformed cells to tumorigenic cells in vitro and in vivo.
Original languageEnglish
Number of pages10
JournalOncogene
DOIs
Publication statusPublished - 2011
MoE publication typeA1 Journal article-refereed

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Cytokinesis
Aneuploidy
Integrins
Neoplasms
Monomeric GTP-Binding Proteins
Endocytosis
Heterografts
Chromosome Aberrations
Ovarian Neoplasms
Cell Movement
In Vitro Techniques
Tail
Prostatic Neoplasms
Down-Regulation
Epithelial Cells
Mutation

Cite this

Högnäs, Gunilla ; Tuomi, Saara ; Veltel, Stefan ; Mattila, Elina ; Murumägi, A. ; Edgren, Henrik ; Kallioniemi, Olli ; Ivaska, Johanna. / Cytokinesis failure due to derailed integrin traffic induces aneuploidy and oncogenic transformation in vitro and in vivo. In: Oncogene. 2011.
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abstract = "Aneuploidy is frequently detected in solid tumors but the mechanisms regulating the generation of aneuploidy and their relevance in cancer initiation remain under debate and are incompletely characterized. Spatial and temporal regulation of integrin traffic is critical for cell migration and cytokinesis. Impaired integrin endocytosis, because of the loss of Rab21 small GTPase or mutations in the integrin β-subunit cytoplasmic tail, induces failure of cytokinesis in vitro. Here, we describe that repeatedly failed cytokinesis, because of impaired traffic, is sufficient to trigger the generation of aneuploid cells, which display characteristics of oncogenic transformation in vitro and are tumorigenic in vivo. Furthermore, in an in vivo mouse xenograft model, non-transformed cells with impaired integrin traffic formed tumors with a long latency. More detailed investigation of these tumors revealed that the tumor cells were aneuploid. Therefore, abnormal integrin traffic was linked with generation of aneuploidy and cell transformation also in vivo. In human prostate and ovarian cancer samples, downregulation of Rab21 correlates with increased malignancy. Loss-of-function experiments demonstrate that long-term depletion of Rab21 is sufficient to induce chromosome number aberrations in normal human epithelial cells. These data are the first to demonstrate that impaired integrin traffic is sufficient to induce conversion of non-transformed cells to tumorigenic cells in vitro and in vivo.",
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Högnäs, G, Tuomi, S, Veltel, S, Mattila, E, Murumägi, A, Edgren, H, Kallioniemi, O & Ivaska, J 2011, 'Cytokinesis failure due to derailed integrin traffic induces aneuploidy and oncogenic transformation in vitro and in vivo', Oncogene. https://doi.org/10.1038/onc.2011.527

Cytokinesis failure due to derailed integrin traffic induces aneuploidy and oncogenic transformation in vitro and in vivo. / Högnäs, Gunilla; Tuomi, Saara; Veltel, Stefan; Mattila, Elina; Murumägi, A.; Edgren, Henrik; Kallioniemi, Olli; Ivaska, Johanna (Corresponding Author).

In: Oncogene, 2011.

Research output: Contribution to journalArticleScientificpeer-review

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AU - Högnäs, Gunilla

AU - Tuomi, Saara

AU - Veltel, Stefan

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AU - Murumägi, A.

AU - Edgren, Henrik

AU - Kallioniemi, Olli

AU - Ivaska, Johanna

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