Skip to main content

Advertisement

SpringerLink
Log in

Caffeine suppresses metastasis in a transgenic mouse model: a prototype molecule for prophylaxis of metastasis

  • Published:
Clinical & Experimental Metastasis Aims and scope Submit manuscript

Abstract

A significant fraction of cancer patients have occult disseminated tumors at the time of primary diagnosis, which usually progress to become clinically relevant lesions. Since the majority of cancer mortality is associated with metastatic disease, the ability to inhibit the growth of the secondary tumors would significantly reduce cancer-related morbidity and mortality. We have investigated whether caffeine, which has been shown to suppress tumor cell invasiveness and experimental metastasis, can suppress metastasis in a spontaneous transgene-induced mammary tumor model. Chronic exposure to caffeine prior to the appearance of palpable mammary tumors significantly reduced both tumor burden and metastatic colonization. However, when caffeine exposure began after the appearance of frank tumors, caffeine suppressed metastasis without changing primary tumor burden. The means by which caffeine suppressed metastatic activity may be associated with inhibition of malignant transformation of mammary epithelial cells, inhibition of conversion of dormant tumor cells to micrometastases, micrometastases to macrometastases, or inhibition of tumor cell adhesion and motility. Gene and protein expression patterns resulting from caffeine treatment showed that metastasis suppression may be associated with up-regulation the mRNA expression of multiple extracellular matrix genes, including Fbln1, Bgn, Sparc, Fbn1, Loxl1, Col1a1, Col3a1, Col5a1, Col5a2, Col5a3, Col6a1, Col6a2, and Col6a3. These data suggested that caffeine or other methyl xanthine derivatives may improve the clinical outcome in patients prior to and following the diagnosis of metastatic disease, and could potentially reduce the morbidity and mortality associated with disseminated tumors.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Subscribe and save

Springer+ Basic
$34.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or eBook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

Abbreviations

2-DE:

two-dimensional gel electrophoresis

caffeine21:

caffeine given at weaning

caffeine60:

caffeine given at 60 days of age

CID:

collision-induced dissociation

CK:

cytokeratin

ECM:

extracellular matrix

IT:

ion trap

PCNA:

proliferating cell nuclear antigen

PI3K:

phosphatidylinositol-3-kinase

pyMT:

polyoma middle T

References

  1. AB Al Mehdi K Tozawa AB Fisher et al. (2000) ArticleTitleIntravascular origin of metastasis from the proliferation of endothelium-attached tumor cells: A new model for metastasis Clinical & Experimental Metastasis 6 IssueID1 100–2

    Google Scholar 

  2. LA Liotta WG. Stetler-Stevenson (1993) Principles of molecular cell biology of cancer: Cancer metastasis SHV DeVita SA Rosenberg (Eds) Cancer: Principles & Practice of Oncology EditionNumber4 J.B. Lippincott Philadelphia, PA 134–49

    Google Scholar 

  3. O Schmidt-Kittler T Ragg A Daskalakis et al. (2003) ArticleTitleFrom latent disseminated cells to overt metastasis: Genetic analysis of systemic breast cancer progression Clinical & Experimental Metastasis 100 IssueID13 7737–42

    Google Scholar 

  4. R Heimann F Lan R McBride et al. (2000) ArticleTitleSeparating favorable from unfavorable prognostic markers in breast cancer: The role of E-cadherin Clinical & Experimental Metastasis 60 IssueID2 298–304

    Google Scholar 

  5. R Heimann S. Hellman (2000) ArticleTitleClinical progression of breast cancer malignant behavior: What to expect and when to expect it Clinical & Experimental Metastasis 18 IssueID3 591–9

    Google Scholar 

  6. R Grossarth-Maticek HJ. Eysenck (1991) ArticleTitleCoca-Cola, cancers, and coronaries: Personality and stress as mediating factors Clinical & Experimental Metastasis 68 1083–7

    Google Scholar 

  7. RP Gude LG Menon SG. Rao (2001) ArticleTitleEffect of caffeine, a xanthine derivative, in the inhibition of experimental lung metastasis induced by B16F10 melanoma cells Clinical & Experimental Metastasis 20 IssueID2 287–92

    Google Scholar 

  8. MC Cohen M Bereta J. Bereta (1997) ArticleTitleEffect of cytokines on tumour cell-endothelial interactions Clinical & Experimental Metastasis 1997 IssueID34(1–2 199–204

    Google Scholar 

  9. M Bereta J Bereta I Georgoff et al. (1994) ArticleTitleMethylxanthines and calcium-mobilizing agents inhibit the expression of cytokine-inducible nitric oxide synthase and vascular cell adhesion molecule-1 in murine microvascular endothelial cells Clinical & Experimental Metastasis 212 IssueID2 230–42

    Google Scholar 

  10. BE Bang C Ericsen J. Aarbakke (1994) ArticleTitleEffects of cAMP and cGMP elevating agents on HL-60 cell differentiation Clinical & Experimental Metastasis 75 IssueID2 108–12

    Google Scholar 

  11. CW. Welsch (1994) ArticleTitleCaffeine and the development of the normal and neoplastic mammary gland Clinical & Experimental Metastasis 207 IssueID1 1–12

    Google Scholar 

  12. SH Shafer SH Phelps CL. Williams (1998) ArticleTitleReduced DNA synthesis and cell viability in small cell lung carcinoma by treatment with cyclic AMP phosphodiesterase inhibitors Clinical & Experimental Metastasis 56 IssueID9 1229–36

    Google Scholar 

  13. JP Minton MK Foecking DJ Webster et al. (1979) ArticleTitleResponse of fibrocystic disease to caffeine withdrawal and correlation of cyclic nucleotides with breast disease Clinical & Experimental Metastasis 135 IssueID1 157–8

    Google Scholar 

  14. JP Minton MK Foecking DJ Webster et al. (1979) ArticleTitleCaffeine, cyclic nucleotides, and breast disease Clinical & Experimental Metastasis 86 IssueID1 105–9

    Google Scholar 

  15. CT Guy RD Cardiff WJ. Muller (1992) ArticleTitleInduction of mammary tumors by expression of polyomavirus middle T oncogene: A transgenic mouse model for metastatic disease Clinical & Experimental Metastasis 12 IssueID3 954–61

    Google Scholar 

  16. T Le Voyer Z Lu J Babb et al. (2000) ArticleTitleAn epistatic interaction controls the latency of a transgene-induced mammary tumor Clinical & Experimental Metastasis 11 IssueID10 883–9

    Google Scholar 

  17. YP Lu YR Lou Y Lin et al. (2001) ArticleTitleInhibitory effects of orally administered green tea, black tea, and caffeine on skin carcinogenesis in mice previously treated with ultraviolet B light (high-risk mice): relationship to decreased tissue fat Clinical & Experimental Metastasis 61 IssueID13 5002–9

    Google Scholar 

  18. T Lifsted T Le Voyer M Williams et al. (1998) ArticleTitleIdentification of inbred mouse strains harboring genetic modifiers of mammary tumor age of onset and metastatic progression Clinical & Experimental Metastasis 77 IssueID4 640–4

    Google Scholar 

  19. M Wilm A Shevchenko T Houthaeve et al. (1996) ArticleTitleFemtomole sequencing of proteins from polyacrylamide gels by nano-electrospray mass spectrometry Clinical & Experimental Metastasis 379 IssueID6564 466–9

    Google Scholar 

  20. A Labedzki J Buters W Jabrane et al. (2002) ArticleTitleDifferences in caffeine and paraxanthine metabolism between human and murine CYP1A2 Clinical & Experimental Metastasis 63 IssueID12 2159–67

    Google Scholar 

  21. RM. Gilbert (1976) Caffeine as a drug abuse RJ Gibbins Y Israll H Kolant (Eds) et al. Recent Advances in Alcohol and Drug Problems John Wiley New York 49–75

    Google Scholar 

  22. ML Bunker M. McWilliams (1979) ArticleTitleCaffeine content of common beverages Clinical & Experimental Metastasis 74 IssueID1 28–32

    Google Scholar 

  23. E Browaeys-Poly K Cailliau JP. Vilain (2001) ArticleTitleTransduction cascades initiated by fibroblast growth factor 1 on Xenopus oocytes expressing MDA-MB-231 mRNAs. Role of Grb, phosphatidylinositol 3-kinase, Src tyrosine kinase, and phospholipase Cgamma Clinical & Experimental Metastasis 13 IssueID5 363–8

    Google Scholar 

  24. LC Foukas N Daniele C Ktori et al. (2002) ArticleTitleDirect effects of caffeine and theophylline on p110 delta and other phosphoinositide 3-kinases Clinical & Experimental Metastasis 277 IssueID40 37124–30

    Google Scholar 

  25. BB Zhou P Chaturvedi K Spring et al. (2000) ArticleTitleCaffeine abolishes the mammalian G(2)/M DNA damage checkpoint by inhibiting ataxia-telangiectasia-mutated kinase activity Clinical & Experimental Metastasis 275 IssueID14 10342–8

    Google Scholar 

  26. KW Hunter KW Broman TL Voyer et al. (2001) ArticleTitlePredisposition to efficient mammary tumor metastatic progression is linked to the breast cancer metastasis suppressor Gene Brms1 Clinical & Experimental Metastasis 61 IssueID24 8866–72

    Google Scholar 

  27. OA Agapova CS Ricard M Salvador-Silva et al. (2001) ArticleTitleExpression of matrix metalloproteinases and tissue inhibitors of metalloproteinases in human optic nerve head astrocytes Clinical & Experimental Metastasis 33 IssueID3 205–16

    Google Scholar 

  28. RP Somerville KA Jungers SS. Apte (2004) ArticleTitleDiscovery and characterization of a novel, widely expressed metalloprotease, ADAMTS10, and its proteolytic activation Clinical & Experimental Metastasis 279 IssueID49 51208–17

    Google Scholar 

  29. H Baribault M Wilson-Heiner W Muller et al. (1997) ArticleTitleFunctional analysis of mouse keratin 8 in polyoma middle T-induced mammary gland tumours Clinical & Experimental Metastasis 6 IssueID6 359–67

    Google Scholar 

  30. RB Lichtner JA Julian SM North et al. (1991) ArticleTitleCoexpression of cytokeratins characteristic for myoepithelial and luminal cell lineages in rat 13762NF mammary adenocarcinoma tumors and their spontaneous metastases Clinical & Experimental Metastasis 51 IssueID21 5943–50

    Google Scholar 

  31. PJ. Wirth (1994) ArticleTitleTwo-dimensional polyacrylamide gel electrophoresis in experimental hepatocarcinogenesis studies Clinical & Experimental Metastasis 15 IssueID3–4 358–71

    Google Scholar 

  32. CA Neumann DS Krause CV Carman et al. (2003) ArticleTitleEssential role for the peroxiredoxin Prdx1 in erythrocyte antioxidant defence and tumour suppression Clinical & Experimental Metastasis 424 IssueID6948 561–5

    Google Scholar 

  33. D Jiang W Ying Y Lu et al. (2003) ArticleTitleIdentification of metastasis-associated proteins by proteomic analysis and functional exploration of interleukin-18 in metastasis Clinical & Experimental Metastasis 3 IssueID5 724–37

    Google Scholar 

  34. JD Wulfkuhle DC Sgroi H Krutzsch et al. (2002) ArticleTitleProteomics of human breast ductal carcinoma in situ Clinical & Experimental Metastasis 62 IssueID(22 6740–9

    Google Scholar 

  35. L Bini B Magi B Marzocchi et al. (1997) ArticleTitleProtein expression profiles in human breast ductal carcinoma and histologically normal tissue Clinical & Experimental Metastasis 18 IssueID15 2832–41

    Google Scholar 

  36. XF Pei MS Noble MA Davoli et al. (2004) ArticleTitleExplant-cell culture of primary mammary tumors from MMTV-c-Myc transgenic mice Clinical & Experimental Metastasis 40 IssueID1 14–21

    Google Scholar 

  37. A Lentini HK Kleinman P Mattioli et al. (1998) ArticleTitleInhibition of melanoma pulmonary metastasis by methylxanthines due to decreased invasion and proliferation Clinical & Experimental Metastasis 8 IssueID2 131–7

    Google Scholar 

  38. LA Liotta CN Rao SH. Barsky (1983) ArticleTitleTumor invasion and the extracellular matrix Clinical & Experimental Metastasis 49 IssueID6 636–49

    Google Scholar 

  39. WO Twal A Czirok B Hegedus et al. (2001) ArticleTitleFibulin-1 suppression of fibronectin-regulated cell adhesion and motility Clinical & Experimental Metastasis 114 IssueID24 4587–98

    Google Scholar 

  40. PA Puolakkainen RA Brekken S Muneer et al. (2004) ArticleTitleEnhanced growth of pancreatic tumors in SPARC-Null mice is associated With decreased deposition of extracellular matrix and reduced tumor cell apoptosis Clinical & Experimental Metastasis 2 IssueID4 215–24

    Google Scholar 

  41. GK Yiu WY Chan SW Ng et al. (2001) ArticleTitleSPARC (secreted protein acidic and rich in cysteine) induces apoptosis in ovarian cancer cells Clinical & Experimental Metastasis 159 IssueID2 609–22

    Google Scholar 

  42. W Wang JB Wyckoff VC Frohlich et al. (2002) ArticleTitleSingle cell behavior in metastatic primary mammary tumors correlated with gene expression patterns revealed by molecular profiling Clinical & Experimental Metastasis 62 IssueID21 6278–88

    Google Scholar 

  43. L Hu SH Lau CH Tzang et al. (2004) ArticleTitleAssociation of Vimentin overexpression and hepatocellular carcinoma metastasis Clinical & Experimental Metastasis 23 IssueID1 298–302

    Google Scholar 

  44. CL Sommers SW Byers EW Thompson et al. (1994) ArticleTitleDifferentiation state and invasiveness of human breast cancer cell lines Clinical & Experimental Metastasis 31 IssueID2–3 325–35

    Google Scholar 

  45. SJ Grille A Bellacosa J Upson et al. (2003) ArticleTitleThe protein kinase Akt induces epithelial mesenchymal transition and promotes enhanced motility and invasiveness of squamous cell carcinoma lines Clinical & Experimental Metastasis 63 IssueID9 2172–8

    Google Scholar 

  46. ZM Mu XY Yin EV. Prochownik (2002) ArticleTitlePag, a putative tumor suppressor, interacts with the Myc Box II domain of c-Myc and selectively alters its biological function and target gene expression Clinical & Experimental Metastasis 277 IssueID45 43175–84

    Google Scholar 

  47. LH Butterfield A Merino SH Golub et al. (1999) ArticleTitleFrom cytoprotection to tumor suppression: The multifactorial role of peroxiredoxins Clinical & Experimental Metastasis 1 IssueID4 385–402

    Google Scholar 

  48. ST Wen RA. Etten ParticleVan (1997) ArticleTitleThe PAG gene product, a stress-induced protein with antioxidant properties, is an Abl SH3-binding protein and a physiological inhibitor of c-Abl tyrosine kinaseáactivity Clinical & Experimental Metastasis 11 IssueID19 2456–67

    Google Scholar 

  49. K Hunter DR Welch ET. Liu (2003) ArticleTitleGenetic background is an important determinant of metastatic potential Clinical & Experimental Metastasis 34 IssueID1 23–4

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Laboratory of Population Genetics, National Cancer Institute, 41 Library Drive, Bethesda, MD, 20892, USA

    Haiyan Yang, Jessica Rouse, Luanne Lukes, Mindy Lancaster, Yeong-Gwan Park & Kent Hunter

  2. Laboratory of Proteomics and Analytical Technologies, SAIC-Frederick, National Cancer Institute, Frederick, Maryland, USA

    Timothy Veenstra & Ming Zhou

  3. Molecular & Clinical Hematology Branch, National Institute of Diabetes & Digestive & Kidney Disease, National Institutes of Health, Bethesda, Maryland, USA

    Ying Shi

Authors
  1. Haiyan Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jessica Rouse
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Luanne Lukes
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Mindy Lancaster
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Timothy Veenstra
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Ming Zhou
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Ying Shi
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Yeong-Gwan Park
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Kent Hunter
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Kent Hunter.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Yang, H., Rouse, J., Lukes, L. et al. Caffeine suppresses metastasis in a transgenic mouse model: a prototype molecule for prophylaxis of metastasis. Clin Exp Metastasis 21, 719–735 (2005). https://doi.org/10.1007/s10585-004-8251-4

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10585-004-8251-4

Keywords

Search

Navigation