Skip to main content

Advertisement

SpringerLink
Log in

The inhibition of lung colonization of B16-F10 melanoma cells in EFA-deficient animals is related to enhanced apoptosis and reduced angiogenesis

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

Abstract

Previous studies conducted in our laboratory showed that the reproduction of spontaneous and experimental metastases was reduced in host animals deprived of essential fatty acids (EFA). In the present study, we have explored the possibility whether apoptosis, proliferation, and angiogenesis might be involved in the antimetastatic effect of EFA deficiency. To this aim, in pulmonary colonies developed from B16-F10 cells in EFA-deficient animals or in animals fed a 5% corn oil diet, we performed an immunohistochemical analysis of bcl-2/bax proteins, PCNA, and VEGF and von Willebrand Factor (vWF), typical markers of apoptosis, proliferation, and angiogenesis, respectively. Apoptosis was also evaluated by detecting DNA fragments in metastatic cells. We found that the reduction of pulmonary colonies grown in EFA-deficient animals was associated with a high expression of apoptotic activity as revealed by the presence of apoptotic nuclei and a high immunoreactivity for bax. Cell proliferation seemed not to be influenced by EFA deficiency in view of the observation that PCNA was highly expressed in pulmonary colonies of control as well as EFA-deficient animals. Pulmonary colonies developed in EFA- deficient animals showed a lower expression of VEGF and a decreased microvessel density, indicating that a reduced angiogenesis contributes to the antimetastatic effects of EFA deficiency. Our analysis of the results invokes the possibility that a relationship between angiogenesis and apoptosis may account for the diminution of the development of experimental metastases in the lungs of EFA-deficient animals.

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

Access this article

Log in via an institution

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

EFA:

essential fatty acids

PUFA:

polyunsaturated fatty acids

VWF:

von Willebrand Factor

References

  1. Reddy BS (1994) Chemoprevention of colon cancer by dietary fatty acids. Cancer Metastasis Rev 13:285–302

    Article  PubMed  CAS  Google Scholar 

  2. Rose DP (1997) Dietary fatty acids and cancer. Am J Clin Nutr 66:998S–1003S

    PubMed  CAS  Google Scholar 

  3. Willett WC (2001) Diet and breast cancer. J Intern Med 249:395–411

    Article  PubMed  CAS  Google Scholar 

  4. Carroll KK (1992) Dietary fat and breast cancer. Lipids 27:793–797

    PubMed  CAS  Google Scholar 

  5. Ip C (1987) Fat and essential fatty acid in mammary carcinogenesis. Am J Clin Nutr 45:218–224

    PubMed  CAS  Google Scholar 

  6. Kollmorgen GM, King MM, Kosanke SD, Do C (1983) Influence of dietary fat and indomethacin on the growth of transplantable mammary tumors in rats. Cancer Res 43:4714–4719

    PubMed  CAS  Google Scholar 

  7. Reddy BS, Sugie S (1988) Effect of different levels of omega-3 and omega-6 fatty acids on azoxymethan induced colon carcinogenesis in F344 rats. Cancer Res 48:6642–6647

    PubMed  CAS  Google Scholar 

  8. Roebuck BD, Longnecker DS, Baumgartner KJ et al (1985) Carcinogen-induced lesions in the rat pancreas: effects of varying levels of essential fatty acid. Cancer Res 45:5252–5256

    PubMed  CAS  Google Scholar 

  9. Hubbard NE, Erikson KL (1987) Enhancement of metastasis from a transplantable mouse mammary tumor by dietary linoleic acid. Cancer Res 47:6171–6175

    PubMed  CAS  Google Scholar 

  10. Katz EB, Boylan ES (1987) Stimulatory effect of high polyunsaturated fat diet on lung metastasis from the 13762 mammary adenocarcinoma in female retired breeder rats. J␣Natl Cancer Inst 79:351–358

    PubMed  CAS  Google Scholar 

  11. Katz EB, Boylan ES (1989) Effect of the quality of dietary fat on tumor growth and metastasis from a rat mammary adenocarcinoma. Nutr Cancer 12:343–350

    Article  PubMed  CAS  Google Scholar 

  12. Rose DP, Hatala MA, Connolly JM et al (1993) Effect of diets containing different levels of linoleic acid on human breast cancer growth and lung metastasis in nude mice. Cancer Res 53:4686–4690

    PubMed  CAS  Google Scholar 

  13. Rose DP, Connolly JM, Liu X-H (1994) Effects of linoleic acid on the growth and metastasis of two human breast cancer cell lines in nude mice and the invasive capacity of these cell lines in vitro. Cancer Res 54:6557–6562

    PubMed  CAS  Google Scholar 

  14. Hubbard NE, Chapkin RS, Erickson KL (1988) Inhibition of growth and linoleate-enhanced metastasis of a transplantable mouse mammary tumor by indomethacin. Cancer Lett 43:111–120

    Article  PubMed  CAS  Google Scholar 

  15. Fulton AM (1988) The role of eicosanoids in tumor metastasis. Prostaglandins Leukot Essent Fatty Acids 34:229–237

    PubMed  CAS  Google Scholar 

  16. Eynard AR, Quiroga P, Silva R (1989) Dietary fatty acid composition modulates the metastatic behavior of a murine mammary gland adenocarcinoma. Cell Biol Int Rep 13:813–814

    Article  PubMed  CAS  Google Scholar 

  17. Lala PK, Parhar RS, Singh P (1986) Indomethacin therapy abrogates the prostaglandin-mediated suppression of natural killer activity in tumor-bearing mice and prevents tumor metastasis. Cell Immunol 99:108–118

    Article  PubMed  CAS  Google Scholar 

  18. Calorini L, Ruggieri S (1992) Reduction of the metastatic potential of a RSV-transformed fibroblastic line (B77-AA6 cells) upon transplantation in essential fatty acid-deficient mice. Invasion Metastasis 12:233–240

    PubMed  CAS  Google Scholar 

  19. Mannini A, Calorini L, Mugnai G et al (1998) Diminution of the development of experimental metastases produced by murine metastatic lines in essential fatty acid-deficient host mice. Clin Exp Metastasis 16:407–414

    Article  PubMed  CAS  Google Scholar 

  20. Townson JL, Naumov GN, Chambers AF (2003) The role of apoptosis in tumor progression and metastasis. Curr Mol Med 3:631–642

    Article  PubMed  CAS  Google Scholar 

  21. Granville DJ, Carthy CM, Hunt DW, McManus BM (1998) Apoptosis: molecular aspects of cell death and disease. Lab Invest 78:893–913

    PubMed  CAS  Google Scholar 

  22. Coomber BL, Yu JL, Fathers KE et al (2003) Angiogenesis and the role of epigenetics in metastasis. Clin Exp Metastasis 20:215–227

    Article  PubMed  CAS  Google Scholar 

  23. Zetter BR (1998) Angiogenesis and tumor metastasis. Annu Rev Med 49:407–424

    Article  PubMed  CAS  Google Scholar 

  24. Folkman J (2002) Role of angiogenesis in tumor growth and metastasis. Semin Oncol 29:15–18

    PubMed  CAS  Google Scholar 

  25. Dunham EW, Balasingam M, Privett OS, Nickell EC (1978) Effects of essential fatty acid deficiency on prostaglandin synthesis and fatty acid composition in rat renal medulla. Lipids 13:892–897

    PubMed  CAS  Google Scholar 

  26. Mathias MM, Dupont J (1979) The relationship of dietary fats to prostaglandin biosynthesis. Lipids 14:247–252

    PubMed  CAS  Google Scholar 

  27. Croft KD, Beilin LJ, Vandongen R, Mathews E (1984) Dietary modification of fatty acid and prostaglandin synthesis in the rat. Effect of variations in the level of dietary fat. Biochim Biophys Acta 795:196–207

    PubMed  CAS  Google Scholar 

  28. Parnham MJ, Vincent JE, Zijlstra FJ, Bonta IL (1979) The use of essential fatty acid deficient rats to study pathophysiological roles of prostaglandins. Comparison of prostaglandin production with some parameters of deficiency. Lipids 14:407–412

    PubMed  CAS  Google Scholar 

  29. Tang DG, Chen YQ, Honn KV (1996) Arachidonate lipoxygenases as essential regulators of cell survival and apoptosis. Proc Natl Acad Sci USA 93:5241–5246

    Article  PubMed  CAS  Google Scholar 

  30. Larsson SC, Kumlin M, Ingelman-Sundberg M, Wolk A (2004) Dietary long-chain n−3 fatty acids for the prevention of cancer: a review of potential mechanisms. Am J Clin Nutr 79:935–945

    PubMed  CAS  Google Scholar 

  31. Ghosh J, Myers CE (1998) Inhibition of arachidonate 5-lipoxygenase triggers massive apoptosis in human prostate cancer cells. Proc Natl Acad Sci U S A 95:13182–13187

    Article  PubMed  CAS  Google Scholar 

  32. Rose DP, Connolly JM (2000) Regulation of tumor angiogenesis by dietary fatty acids and eicosanoids. Nutr Cancer 37:119–127

    Article  PubMed  CAS  Google Scholar 

  33. Form DM, Auerbach R (1983) PGE2 and angiogenesis. Proc Soc Exp Biol Med 172:214–218

    PubMed  CAS  Google Scholar 

  34. Nie D, Tang K, Diglio C, Honn KV (2000) Eicosanoid regulation of angiogenesis: role of endothelial arachidonate 12-lipoxygenase. Blood 95:2304–2311

    PubMed  CAS  Google Scholar 

  35. Collins MK, Lopez Rivas A (1993) The control of apoptosis in mammalian cells. Trends Biochem Sci 18:307–309

    Article  PubMed  CAS  Google Scholar 

  36. Rydén L, Linderholm B, Nielsen NH et al (2003) Tumor specific VEGF-A and VEGFR2/KDR protein are co- expressed in breast cancer. Breast Cancer Res Treat 82:147–154

    Article  PubMed  Google Scholar 

  37. Holley RW, Baldwin JH, Kiernan JA (1974) Control of growth of a tumor cell by linoleic acid. Proc Natl Acad Sci U S A 71:3976–3978

    Article  PubMed  CAS  Google Scholar 

  38. Korystov YuN, Shaposhnikova VV, Levitman MKh et al (1998) The effect of inhibitors of arachidonic acid metabolism on proliferation and death of tumor cells. FEBS Lett 431:224–226

    Article  PubMed  CAS  Google Scholar 

  39. Holman RT (1968) Essential fatty acid deficiency. In: Holman RT (eds). Progress in the chemistry on fats and other lipids. Pergamon Press, Oxford, pp 275–348

    Google Scholar 

  40. Fidler IJ (1973) Selection of successive tumour lines for metastasis. Nat New Biol 242:148–149

    PubMed  CAS  Google Scholar 

  41. Chen TR (1977) In situ detection of mycoplasma contamination in cell cultures by fluorescent Hoechst 33258 stain. Exp Cell Res 104(2):255–262

    Article  PubMed  CAS  Google Scholar 

  42. Chan WY, Cheung KK, Schorge JO et al (2000) Bcl-2 and p53 protein expression, apoptosis, and p53 mutation in human epithelial ovarian cancers. Am J Pathol 156(2):409–417

    PubMed  CAS  Google Scholar 

  43. Gavrieli Y, Sherman Y, Ben-Sasson SA (1992) Identification of programmed cell death in situ via specific labeling of nuclear DNA fragmentation. J Cell Biol 119:493–501

    Article  PubMed  CAS  Google Scholar 

  44. Eling TE, Glasgow WC (1990) Transduction of the epidermal growth factor mitogenic signal in BALB/c 3T3 fibroblasts involves linoleic acid metabolism. Adv Prostaglandin Thromboxane Leukot Res 21B:843–846

    CAS  Google Scholar 

  45. Holman RT (1998) The slow discovery of the importance of omega 3 essential fatty acids in human health. J Nutr 128:427S–433S

    PubMed  CAS  Google Scholar 

  46. Heird WC, Lapillonne A (2005) The role of essential fatty acids in development. Annu Rev Nutr 25:549–571

    Article  PubMed  CAS  Google Scholar 

  47. Kasayama S, Koga M, Kouhara H et al (1994) Unsaturated fatty acids are required for continuous proliferation of transformed androgen-dependent cells by fibroblast growth factor family proteins. Cancer Res 54:6441–6445

    PubMed  CAS  Google Scholar 

  48. Kidwell WR, Monaco ME, Wicha MS, Smith GS (1978) Unsaturated fatty acid requirements for growth and survival of a rat mammary tumor cell line. Cancer Res 38:4091–4100

    PubMed  CAS  Google Scholar 

  49. Rose DP, Connolly JM (1989) Stimulation of growth of human breast cancer cell lines in culture by linoleic acid. Biochem Biophys Res Commun 164:277–283

    Article  PubMed  CAS  Google Scholar 

  50. Tombaccini D, Fallani A, Mugnai G, Ruggieri S (1981) Lipid composition of Balb/c3T3, SV3T3, and Concanavalin A-selected revertant cells grown in media containing lipid-depleted serum. J Lipid Res 22:590–597

    PubMed  CAS  Google Scholar 

  51. Bailey JM, Dunbar LM (1971) Lipid metabolism in cultured cells: growth of tumor cells deficient in essential fatty acids. Cancer Res 31:91–97

    PubMed  CAS  Google Scholar 

  52. Balakrishnan A, Cramer S, Bandyopadhyay GK et al (1989) Differential proliferative response to linoleate in cultures of epithelial cells from normal human breast and fibroadenomas. Cancer Res 49:857–862

    PubMed  CAS  Google Scholar 

  53. Tang DG, Guan K-L, Li L et al (1997) Suppression of W256 carcinoma cell apoptosis by arachidonic acid and other polynsaturated fatty acids. Int J Cancer 72:1078–1087

    Article  PubMed  CAS  Google Scholar 

  54. Sun Y, Tang XM, Half E et al (2002) Cyclooxygenase-2 overexpression reduces apoptotic susceptibility by inhibiting the cytochrome c-dependent apoptotic pathway in human colon cancer cells. Cancer Res 62:6323–6328

    PubMed  CAS  Google Scholar 

  55. Jantke J, Ladehoff M, Kurzel F et al (2004) Inhibition of the arachidonic acid metabolism blocks endothelial cell migration and induces apoptosis. Acta Neurochir (Wien) 146:483–494

    Article  CAS  Google Scholar 

  56. Mukutmoni M, Hubbard NE, Erickson KL (2001) Prostaglandin E(2) modulation of vascular endothelial growth factor production in murine macrophages. Prostaglandins Leukot Essent Fatty Acids 65:123–131

    Article  PubMed  CAS  Google Scholar 

  57. Dubois RN (2000) Review article: cyclooxygenase–a target for colon cancer prevention. Aliment Pharmacol Ther 14:64–67

    Article  PubMed  CAS  Google Scholar 

  58. Williams CS, Mann M, DuBois RN (1999) The role of cyclooxygenases in inflammation, cancer, and development. Oncogene 18:7908–7916

    Article  PubMed  CAS  Google Scholar 

  59. Liu CH, Chang SH, Narko K et al (2001) Overexpression of cyclooxygenase-2 is sufficient to induce tumorigenesis in transgenic mice. J Biol Chem 276:18563–18569

    Article  PubMed  CAS  Google Scholar 

  60. Duff M, Stapleton PP, Mestre JR, et al (2003) Cyclooxygenase-2 inhibition improves macrophage function in melanoma and increases the antineoplastic activity of interferon gamma. Ann Surg Oncol 10:305–313

    Article  PubMed  Google Scholar 

  61. Lu X, Xie W, Reed D et al (1995) Nonsteroidal antiinflammatory drugs cause apoptosis and induce cyclooxygenases in chicken embryo fibroblasts. Proc Natl Acad Sci USA 92:7961–7965

    Article  PubMed  CAS  Google Scholar 

  62. Dubois RN, Abramson SB, Crofford L et al (1998) Cyclooxygenase in biology and disease. FASEB J 12:1063–1073

    PubMed  CAS  Google Scholar 

  63. Perrone G, Santini D, Verzi A, Vincenzi B, Borzomati D, Vecchio F, Coppola R, Antinori A, Magistrelli P, Tonini G, Rabitti C (2006) COX-2 expression in ampullary carcinoma: correlation with angiogenesis process and clinicopathological variables. J Clin Pathol 59:492–496

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgements

This work was supported by grants from MURST (60%) and ECRF (Italy).

Author information

Authors and Affiliations

  1. Department of Experimental Pathology and Oncology, University of the Studies of Florence, 50 Viale G.B. Morgagni, 50134, Florence, Italy

    Antonella Mannini, Lido Calorini, Gabriele Mugnai & Salvatore Ruggieri

  2. Department of Human Pathology and Oncology, University of the Studies of Florence, 85 Viale G.B. Morgagni, 50134, Florence, Italy

    Anna Calzolari

Authors
  1. Antonella Mannini
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Anna Calzolari
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Lido Calorini
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Gabriele Mugnai
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Salvatore Ruggieri
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Salvatore Ruggieri.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Mannini, A., Calzolari, A., Calorini, L. et al. The inhibition of lung colonization of B16-F10 melanoma cells in EFA-deficient animals is related to enhanced apoptosis and reduced angiogenesis. Clin Exp Metastasis 23, 159–165 (2006). https://doi.org/10.1007/s10585-006-9022-1

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10585-006-9022-1

Keywords

Search

Navigation