Loss of the Lkb1 tumour suppressor provokes intestinal polyposis but resistance to transformation

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Abstract

Germline mutations in LKB1 (also known as STK11) are associated with Peutz–Jeghers syndrome (PJS), a disorder with predisposition to gastrointestinal polyposis and cancer1. PJS polyps are unusual neoplasms characterized by marked epithelial and stromal overgrowth but have limited malignant potential2. Here we show that Lkb1+/- mice develop intestinal polyps identical to those seen in individuals affected with PJS. Consistent with this in vivo tumour suppressor function, Lkb1 deficiency prevents culture-induced senescence without loss of Ink4a/Arf or p53. Despite compromised mortality, Lkb1-/- mouse embryonic fibroblasts show resistance to transformation by activated Ha-Ras either alone or with immortalizing oncogenes. This phenotype is in agreement with the paucity of mutations in Ras seen in PJS polyps3,4 and suggests that loss of Lkb1 function as an early neoplastic event renders cells resistant to subsequent oncogene-induced transformation. In addition, the Lkb1 transcriptome shows modulation of factors linked to angiogenesis, extracellular matrix remodelling, cell adhesion and inhibition of Ras transformation. Together, our data rationalize several features of PJS polyposis—notably its peculiar histopathological presentation and limited malignant potential—and place Lkb1 in a distinct class of tumour suppressors.

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Figure 1: Targeting strategy and analysis of Lkb1.
Figure 2: Gastrointestinal polyps in Lkb1+/- mice.
Figure 3: Lkb1-/- MEF immortalization studies.
Figure 4: Lkb1-/- cells are resistant to oncogenic transformation.
Figure 5: Lkb1-/- expression profile.

References

  1. 1

    Hemminki, A. et al. A serine/threonine kinase gene defective in Peutz–Jeghers syndrome. Nature 391, 184–187 (1998)

  2. 2

    Cooper, H. S. Pathology of the Gastrointestinal Tract (eds Ming, S.-C. & Goldman, H.) 819–853 (Wiliams & Wilkens, Baltimore, 1998)

  3. 3

    Entius, M. M. et al. Molecular genetic alterations in hamartomatous polyps and carcinomas of patients with Peutz–Jeghers syndrome. J. Clin. Pathol. 54, 126–131 (2001)

  4. 4

    Gruber, S. B. et al. Pathogenesis of adenocarcinoma in Peutz–Jeghers syndrome. Cancer Res. 58, 5267–5270 (1998)

  5. 5

    Giardiello, F. M. et al. Very high risk of cancer in familial Peutz–Jeghers syndrome. Gastroenterology 119, 1447–1453 (2000)

  6. 6

    Avizienyte, E. et al. Somatic mutations in LKB1 are rare in sporadic colorectal and testicular tumors. Cancer Res. 58, 2087–2090 (1998)

  7. 7

    Avizienyte, E. et al. LKB1 somatic mutations in sporadic tumors. Am. J. Pathol. 154, 677–681 (1999)

  8. 8

    Esteller, M. et al. Epigenetic inactivation of LKB1 in primary tumors associated with the Peutz–Jeghers syndrome. Oncogene 19, 164–168 (2000)

  9. 9

    Lakso, M. et al. Efficient in vivo manipulation of mouse genomic sequences at the zygote stage. Proc. Natl Acad. Sci. USA 93, 5860–5865 (1996)

  10. 10

    Rodriguez, C. I. et al. High-efficiency deleter mice show that FLPe is an alternative to CreloxP. Nature Genet. 25, 139–140 (2000)

  11. 11

    Ylikorkala, A. et al. Vascular abnormalities and deregulation of VEGF in Lkb1-deficient mice. Science 293, 1323–1326 (2001)

  12. 12

    Hemminki, A. et al. Localization of a susceptibility locus for Peutz–Jeghers syndrome to 19p using comparative genomic hybridization and targeted linkage analysis. Nature Genet. 15, 87–90 (1997)

  13. 13

    Ramirez, R. D. et al. Putative telomere-independent mechanisms of replicative aging reflect inadequate growth conditions. Genes Dev. 15, 398–403 (2001)

  14. 14

    Sherr, C. J. & DePinho, R. A. Cellular senescence: mitotic clock or culture shock? Cell 102, 407–410 (2000)

  15. 15

    Kamijo, T. et al. Tumor suppression at the mouse INK4a locus mediated by the alternative reading frame product p19ARF. Cell 91, 649–659 (1997)

  16. 16

    Serrano, M. et al. Role of the INK4a locus in tumour suppression and cell mortality. Cell 85, 27–37 (1996)

  17. 17

    Sage, J. et al. Targeted disruption of the three Rb-related genes leads to loss of G1 control and immortalization. Genes Dev. 14, 3037–3050 (2000)

  18. 18

    Dannenberg, J. H., van Rossum, A., Schuijff, L. & te Riele, H. Ablation of the retinoblastoma gene family deregulates G1 control causing immortalization and increased cell turnover under growth- restricting conditions. Genes Dev. 14, 3051–3064 (2000)

  19. 19

    Serrano, M., Lin, A. W., McCurrach, M. E., Beach, D. & Lowe, S. W. Oncogenic ras provokes premature cell senescence associated with accumulation of p53 and p16INK4a. Cell 88, 593–602 (1997)

  20. 20

    Whitehead, I. P. et al. Dependence of Dbl and Dbs transformation on MEK and NF-κB activation. Mol. Cell. Biol. 19, 7759–7770 (1999)

  21. 21

    Yoshioka, N. et al. Isolation of transformation suppressor genes by cDNA subtraction: lumican suppresses transformation induced by v-src and v-K-ras. J. Virol. 74, 1008–1013 (2000)

  22. 22

    Qing, J. et al. Suppression of anchorage-independent growth and matrigel invasion and delayed tumour formation by elevated expression of fibulin-1D in human fibrosarcoma-derived cell lines. Oncogene 15, 2159–2168 (1997)

  23. 23

    Reeve, J. G., Guadano, A., Xiong, J., Morgan, J. & Bleehen, N. M. Diminished expression of insulin-like growth factor (IGF) binding protein-5 and activation of IGF-I-mediated autocrine growth in simian virus 40-transformed human fibroblasts. J. Biol. Chem. 270, 135–142 (1995)

  24. 24

    Vasseur, S. et al. p8 is critical for tumour development induced by rasV12 mutated protein and E1A oncogene. EMBO Rep. 3, 165–170 (2002)

  25. 25

    Bergers, G. et al. Matrix metalloproteinase-9 triggers the angiogenic switch during carcinogenesis. Nature Cell Biol. 2, 737–744 (2000)

  26. 26

    Silver, D. P. & Livingston, D. M. Self-excising retroviral vectors encoding the Cre recombinase overcome Cre-mediated cellular toxicity. Mol. Cell 8, 233–243 (2001)

  27. 27

    Sharpless, N. E. et al. Loss of p16Ink4a with retention of p19Arf predisposes mice to tumorigenesis. Nature 413, 86–91 (2001)

  28. 28

    Carrasco, D., Weih, F. & Bravo, R. Developmental expression of the mouse c-rel proto-oncogene in hematopoietic organs. Development 120, 2991–3004 (1994)

  29. 29

    Miyoshi, H. et al. Gastrointestinal hamartomatous polyposis in Lkb1 heterozygous knockout mice. Cancer Res. 62, 2261–2266 (2002)

  30. 30

    Jishage, K. et al. Role of Lkb1, the causative gene of Peutz-Jegher's syndrome, in embryogenesis and polyposis. Proc. Natl Acad. Sci. USA 99, 8903–8908 (2002)

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Acknowledgements

We thank L. Ritchie and J. Horner of DFCI mouse core for advice and assistance; S. Dymecki, H. Westphal, M. Oren, S. Lowe, D. Silver, C. Der & J. DeCaprio for advice and reagents; and D. Livingston, J. DeCaprio and W. Kaelin for comments on the manuscript. N.B. is supported by the ACS John Peter Hoffman Award and the Liss Family Fund grant for research in pancreatic cancer. R.A.D. is an American Cancer Society Professor and recipient of the Steven and Michele Kirsch Foundation Investigator Award. This work was supported by grants from the NCI (National Cancer Institute) and ACS (American Cancer Society).

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Correspondence to Ronald A. DePinho.

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Bardeesy, N., Sinha, M., Hezel, A. et al. Loss of the Lkb1 tumour suppressor provokes intestinal polyposis but resistance to transformation. Nature 419, 162–167 (2002) doi:10.1038/nature01045

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