#PAGE_PARAMS# #ADS_HEAD_SCRIPTS# #MICRODATA#

Is a Metastasis Susceptibility Gene That Suppresses Metastasis by Modifying Tumor Interaction with the Cell-Mediated Immunity


Metastasis is a complex process utilizing both tumor-cell-autonomous properties and host-derived factors, including cellular immunity. We have previously shown that germline polymorphisms can modify tumor cell metastatic capabilities through cell-autonomous mechanisms. However, how metastasis susceptibility genes interact with the tumor stroma is incompletely understood. Here, we employ a complex genetic screen to identify Cadm1 as a novel modifier of metastasis. We demonstrate that Cadm1 can specifically suppress metastasis without affecting primary tumor growth. Unexpectedly, Cadm1 did not alter tumor-cell-autonomous properties such as proliferation or invasion, but required the host's adaptive immune system to affect metastasis. The metastasis-suppressing effect of Cadm1 was lost in mice lacking T cell–mediated immunity, which was partially phenocopied by depleting CD8+ T cells in immune-competent mice. Our data show a novel function for Cadm1 in suppressing metastasis by sensitizing tumor cells to immune surveillance mechanisms, and this is the first report of a heritable metastasis susceptibility gene engaging tumor non-autonomous factors.


Vyšlo v časopise: Is a Metastasis Susceptibility Gene That Suppresses Metastasis by Modifying Tumor Interaction with the Cell-Mediated Immunity. PLoS Genet 8(9): e32767. doi:10.1371/journal.pgen.1002926
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1002926

Souhrn

Metastasis is a complex process utilizing both tumor-cell-autonomous properties and host-derived factors, including cellular immunity. We have previously shown that germline polymorphisms can modify tumor cell metastatic capabilities through cell-autonomous mechanisms. However, how metastasis susceptibility genes interact with the tumor stroma is incompletely understood. Here, we employ a complex genetic screen to identify Cadm1 as a novel modifier of metastasis. We demonstrate that Cadm1 can specifically suppress metastasis without affecting primary tumor growth. Unexpectedly, Cadm1 did not alter tumor-cell-autonomous properties such as proliferation or invasion, but required the host's adaptive immune system to affect metastasis. The metastasis-suppressing effect of Cadm1 was lost in mice lacking T cell–mediated immunity, which was partially phenocopied by depleting CD8+ T cells in immune-competent mice. Our data show a novel function for Cadm1 in suppressing metastasis by sensitizing tumor cells to immune surveillance mechanisms, and this is the first report of a heritable metastasis susceptibility gene engaging tumor non-autonomous factors.


Zdroje

1. SteegPS, TheodorescuD (2008) Metastasis: a therapeutic target for cancer. Nat Clin Pract Oncol 5: 206–219.

2. ChafferCL, WeinbergRA (2011) A perspective on cancer cell metastasis. Science 331: 1559–1564.

3. ValastyanS, WeinbergRA (2011) Tumor metastasis: molecular insights and evolving paradigms. Cell 147: 275–292.

4. ParkYG, ZhaoX, LesueurF, LowyDR, LancasterM, et al. (2005) Sipa1 is a candidate for underlying the metastasis efficiency modifier locus Mtes1. Nat Genet 37: 1055–1062.

5. CrawfordNP, AlsarrajJ, LukesL, WalkerRC, OfficewalaJS, et al. (2008) Bromodomain 4 activation predicts breast cancer survival. Proc Natl Acad Sci U S A 105: 6380–6385.

6. CrawfordNP, QianX, ZiogasA, PapageorgeAG, BoersmaBJ, et al. (2007) Rrp1b, a new candidate susceptibility gene for breast cancer progression and metastasis. PLoS Genet 3: e214 doi:10.1371/journal.pgen.0030214.

7. HunterK (2004) Genetic, genomic, and bioinformatic tools for studying breast cancer progression. Breast Dis 19: 83–91.

8. HunterKW, BromanKW, VoyerTL, LukesL, CozmaD, et al. (2001) Predisposition to efficient mammary tumor metastatic progression is linked to the breast cancer metastasis suppressor gene Brms1. Cancer Res 61: 8866–8872.

9. LancasterM, RouseJ, HunterKW (2005) Modifiers of mammary tumor progression and metastasis on mouse chromosomes 7, 9, and 17. Mamm Genome 16: 120–126.

10. ItoT, ShimadaY, HashimotoY, KaganoiJ, KanT, et al. (2003) Involvement of TSLC1 in progression of esophageal squamous cell carcinoma. Cancer Res 63: 6320–6326.

11. KikuchiS, YamadaD, FukamiT, MaruyamaT, ItoA, et al. (2006) Hypermethylation of the TSLC1/IGSF4 promoter is associated with tobacco smoking and a poor prognosis in primary nonsmall cell lung carcinoma. Cancer 106: 1751–1758.

12. YangG, HeW, CaiM, LuoF, KungH, et al. (2011) Loss/Down-regulation of tumor suppressor in lung cancer 1 expression is associated with tumor progression and is a biomarker of poor prognosis in ovarian carcinoma. Int J Gynecol Cancer 21: 486–493.

13. YouY, MaL, YouM, LiX, WangS, et al. (2010) TSLC1 gene silencing in cutaneous melanoma. Melanoma Res 20: 179–183.

14. SuraceEI, LusisE, MurakamiY, ScheithauerBW, PerryA, et al. (2004) Loss of tumor suppressor in lung cancer-1 (TSLC1) expression in meningioma correlates with increased malignancy grade and reduced patient survival. J Neuropathol Exp Neurol 63: 1015–1027.

15. KuramochiM, FukuharaH, NobukuniT, KanbeT, MaruyamaT, et al. (2001) TSLC1 is a tumor-suppressor gene in human non-small-cell lung cancer. Nat Genet 27: 427–430.

16. WatabeK, ItoA, KomaYI, KitamuraY (2003) IGSF4: a new intercellular adhesion molecule that is called by three names, TSLC1, SgIGSF and SynCAM, by virtue of its diverse function. Histol Histopathol 18: 1321–1329.

17. PeiXF, NobleMS, DavoliMA, RosfjordE, TilliMT, et al. (2004) ExplanT cell culture of primary mammary tumors from MMTV-c-Myc transgenic mice. In Vitro Cell Dev Biol Anim 40: 14–21.

18. SussanTE, PletcherMT, MurakamiY, ReevesRH (2005) Tumor suppressor in lung cancer 1 (TSLC1) alters tumorigenic growth properties and gene expression. Mol Cancer 4: 28.

19. GalibertL, DiemerGS, LiuZ, JohnsonRS, SmithJL, et al. (2005) Nectin-like protein 2 defines a subset of T cell zone dendritic cells and is a ligand for class-I-restricted T cell-associated molecule. J Biol Chem 280: 21955–21964.

20. BolesKS, BarchetW, DiacovoT, CellaM, ColonnaM (2005) The tumor suppressor TSLC1/NECL-2 triggers NK-cell and CD8+ T cell responses through the cell-surface receptor CRTAM. Blood 106: 779–786.

21. GiangrecoA, HosteE, TakaiY, RosewellI, WattFM (2012) Epidermal Cadm1 expression promotes autoimmune alopecia via enhanced T cell adhesion and cytotoxicity. J Immunol 188: 1514–1522.

22. HellerG, GeradtsJ, ZieglerB, NewshamI, FilipitsM, et al. (2007) Downregulation of TSLC1 and DAL-1 expression occurs frequently in breast cancer. Breast Cancer Res Treat 103: 283–291.

23. TakahashiY, IwaiM, KawaiT, ArakawaA, ItoT, et al. (2011) Aberrant expression of tumor suppressors CADM1 and 4.1B in invasive lesions of primary breast cancer. Breast Cancer

24. BertoloC, GuerreroD, VicenteF, CordobaA, EstellerM, et al. (2008) Differences and molecular immunohistochemical parameters in the subtypes of infiltrating ductal breast cancer. Am J Clin Pathol 130: 414–424.

25. AllinenM, PeriL, KujalaS, Lahti-DomeniciJ, OutilaK, et al. (2002) Analysis of 11q21-24 loss of heterozygosity candidate target genes in breast cancer: indications of TSLC1 promoter hypermethylation. Genes Chromosomes Cancer 34: 384–389.

26. BoersmaBJ, ReimersM, YiM, LudwigJA, LukeBT, et al. (2008) A stromal gene signature associated with inflammatory breast cancer. Int J Cancer 122: 1324–1332.

27. DesmedtC, PietteF, LoiS, WangY, LallemandF, et al. (2007) Strong time dependence of the 76-gene prognostic signature for node-negative breast cancer patients in the TRANSBIG multicenter independent validation series. Clin Cancer Res 13: 3207–3214.

28. RingnerM, FredlundE, HakkinenJ, BorgA, StaafJ (2011) GOBO: gene expression-based outcome for breast cancer online. PLoS ONE 6: e17911 doi:10.1371/journal.pone.0017911.

29. OvermeerRM, HenkenFE, SnijdersPJ, Claassen-KramerD, BerkhofJ, et al. (2008) Association between dense CADM1 promoter methylation and reduced protein expression in high-grade CIN and cervical SCC. J Pathol 215: 388–397.

30. LungHL, CheungAK, XieD, ChengY, KwongFM, et al. (2006) TSLC1 is a tumor suppressor gene associated with metastasis in nasopharyngeal carcinoma. Cancer Res 66: 9385–9392.

31. SchreiberRD, OldLJ, SmythMJ (2011) Cancer immunoediting: integrating immunity's roles in cancer suppression and promotion. Science 331: 1565–1570.

32. DuPageM, MazumdarC, SchmidtLM, CheungAF, JacksT (2012) Expression of tumour-specific antigens underlies cancer immunoediting. Nature 482: 405–409.

33. KennedyJ, VicariAP, SaylorV, ZurawskiSM, CopelandNG, et al. (2000) A molecular analysis of NKT cells: identification of a class-I restricted T cell-associated molecule (CRTAM). J Leukoc Biol 67: 725–734.

34. ColesMC, RauletDH (2000) NK1.1+ T cells in the liver arise in the thymus and are selected by interactions with class I molecules on CD4+CD8+ cells. J Immunol 164: 2412–2418.

35. LifstedT, Le VoyerT, WilliamsM, MullerW, Klein-SzantoA, et al. (1998) Identification of inbred mouse strains harboring genetic modifiers of mammary tumor age of onset and metastatic progression. Int J Cancer 77: 640–644.

36. SmithR, SheppardK, DiPetrilloK, ChurchillG (2009) Quantitative trait locus analysis using J/qtl. Methods Mol Biol 573: 175–188.

Štítky
Genetika Reprodukčná medicína

Článok vyšiel v časopise

PLOS Genetics


2012 Číslo 9
Najčítanejšie tento týždeň
Najčítanejšie v tomto čísle
Kurzy

Zvýšte si kvalifikáciu online z pohodlia domova

Získaná hemofilie - Povědomí o nemoci a její diagnostika
nový kurz

Eozinofilní granulomatóza s polyangiitidou
Autori: doc. MUDr. Martina Doubková, Ph.D.

Všetky kurzy
Prihlásenie
Zabudnuté heslo

Zadajte e-mailovú adresu, s ktorou ste vytvárali účet. Budú Vám na ňu zasielané informácie k nastaveniu nového hesla.

Prihlásenie

Nemáte účet?  Registrujte sa

#ADS_BOTTOM_SCRIPTS#