Long-chain omega-3 polyunsaturated fatty acids decrease mammary tumor growth, multiorgan metastasis and enhance survival

Abstract

Epidemiological studies show a reduced risk of breast cancer (BC) in women consuming high levels of long-chain (LC) omega-3 (ω-3) fatty acids (FAs) compared with women who consumed low levels. However, the regulatory and mechanistic roles of dietary ω-6 and LC-ω-3 FAs on tumor progression, metastasis and survival are poorly understood. Female BALB/c mice (10-week old) were pair-fed with a diet containing ω-3 or an isocaloric, isolipidic ω-6 diet for 16 weeks prior to the orthotopic implantation of 4T1 mammary tumor cells. Major outcomes studied included: mammary tumor growth, survival analysis, and metastases analyses in multiple organs including pulmonary, hepatic, bone, cardiac, renal, ovarian, and contralateral MG (CMG). The dietary regulation of the tumor microenvironment was evaluated in mice autopsied on day-35 post tumor injection. In mice fed the ω-3 containing diet, there was a significant delay in tumor initiation and prolonged survival relative to the ω-6 diet-fed group. The tumor size on day 35 post tumor injection in the ω-3 group was 50% smaller and the frequencies of pulmonary and bone metastases were significantly lower relative to the ω-6 group. Similarly, the incidence/frequencies and/or size of cardiac, renal, ovarian metastases were significantly lower in mice fed the ω-3 diet. The analyses of the tumor microenvironment showed that tumors in the ω-3 group had significantly lower numbers of proliferating tumor cells (Ki67+)/high power field (HPF), and higher numbers of apoptotic tumor cells (TUNEL+)/HPF, lower neo-vascularization (CD31+ vessels/HPF), infiltration by neutrophil elastase+ cells, and macrophages (F4/80+) relative to the tumors from the ω-6 group. Further, in tumors from the ω-3 diet-fed mice, T-cell infiltration was 102% higher resulting in a neutrophil to T-lymphocyte ratio (NLR) that was 76% lower (p < 0.05). Direct correlations were observed between NLR with tumor size and T-cell infiltration with the number of apoptotic tumor cells. qRT-PCR analysis revealed that tumor IL10 mRNA levels were significantly higher (six-fold) in the tumors from mice fed the ω-3 diet and inversely correlated with the tumor size. Our data suggest that dietary LC-ω-3FAs modulates the mammary tumor microenvironment slowing tumor growth, and reducing metastases to both common and less preferential organs resulting in prolonged survival. The surrogate analyses undertaken support a mechanism of action by dietary LC-ω-3FAs that includes, but is not limited to decreased infiltration by myeloid cells (neutrophils and macrophages), an increase in CD3+ lymphocyte infiltration and IL10 associated anti-inflammatory activity.

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

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7

Abbreviations

AA:

Arachidonic acid

BC:

Breast cancer

CBC:

Contralateral breast cancer

CMG:

Contralateral mammary gland

DHA:

Docosahexaenoic acid

EPA:

Eicosapentaenoic acid

FA:

Fatty acid

HO:

Histologically observed

LC:

Long-chain

MFP:

Mammary fat pad

MG:

Mammary gland

NTB:

Non-tumor bearing

NLR:

Neutrophil to lymphocyte ratio

PUFA:

Polyunsaturated fatty acid

qRT-PCR:

Quantitative real-time polymerase chain reaction

TB:

Tumor bearing

References

  1. 1.

    DeSantis CE et al (2017) Breast cancer statistics, 2017, racial disparity in mortality by state. CA Cancer J Clin 67(6):439–448

    PubMed  Google Scholar 

  2. 2.

    McCracken M et al (2007) Cancer incidence, mortality, and associated risk factors among Asian Americans of Chinese, Filipino, Vietnamese, Korean, and Japanese ethnicities. CA Cancer J Clin 57(4):190–205

    PubMed  Google Scholar 

  3. 3.

    Ziegler RG et al (1993) Migration patterns and breast cancer risk in Asian-American women. J Natl Cancer Inst 85(22):1819–1827

    CAS  PubMed  Google Scholar 

  4. 4.

    Evans DG et al (2018) Breast cancer risk in a screening cohort of Asian and white British/Irish women from Manchester UK. BMC Public Health 18(1):178

    PubMed  PubMed Central  Google Scholar 

  5. 5.

    Zheng J-S et al (2013) Intake of fish and marine n-3 polyunsaturated fatty acids and risk of breast cancer: meta-analysis of data from 21 independent prospective cohort studies. BMJ 346:f3706

    PubMed  Google Scholar 

  6. 6.

    Simopoulos AP (2006) Evolutionary aspects of diet, the omega-6/omega-3 ratio and genetic variation: nutritional implications for chronic diseases. Biomed Pharmacother 60(9):502–507

    CAS  PubMed  Google Scholar 

  7. 7.

    Weylandt KH et al (2012) Omega-3 fatty acids and their lipid mediators: towards an understanding of resolvin and protectin formation. Prostaglandins Other Lipid Mediat 97(3–4):73–82

    CAS  PubMed  Google Scholar 

  8. 8.

    Simopoulos AP (2008) The importance of the omega-6/omega-3 fatty acid ratio in cardiovascular disease and other chronic diseases. Exp Biol Med (Maywood) 233(6):674–688

    CAS  Google Scholar 

  9. 9.

    Khadge S et al (2017) Lipid inflammatory mediators in cancer progression and therapy. Adv Exp Med Biol 1036:145–156

    CAS  PubMed  Google Scholar 

  10. 10.

    D’Eliseo D, Velotti F (2016) Omega-3 fatty acids and cancer cell cytotoxicity: implications for multi-targeted cancer therapy. J Clin Med 5:15

    PubMed Central  Google Scholar 

  11. 11.

    Olivo SE, Hilakivi-Clarke L (2005) Opposing effects of prepubertal low- and high-fat n-3 polyunsaturated fatty acid diets on rat mammary tumorigenesis. Carcinogenesis 26(9):1563–1572

    CAS  PubMed  Google Scholar 

  12. 12.

    MacLennan MB et al (2013) Mammary tumor development is directly inhibited by lifelong n-3 polyunsaturated fatty acids. J Nutr Biochem 24(1):388–395

    CAS  PubMed  Google Scholar 

  13. 13.

    Khadge S et al (2018) Long-chain Omega-3 polyunsaturated fatty acids modulate mammary gland composition and inflammation. J Mammary Gland Biol Neoplasia 23(1):43–58

    PubMed  Google Scholar 

  14. 14.

    McCormack VA, Silva IdosS (2006) Breast density and parenchymal patterns as markers of breast cancer risk: a meta-analysis. Cancer Epidemiol Biomark Prev 15(6):1159–1169

    Google Scholar 

  15. 15.

    Vaysse C et al (2017) Inflammation of mammary adipose tissue occurs in overweight and obese patients exhibiting early-stage breast cancer. NPJ Breast Cancer 3(1):19

    PubMed  PubMed Central  Google Scholar 

  16. 16.

    Talmadge JE, Fidler IJ, AACR Centennial Series (2010) The biology of cancer metastasis: historical perspective. Cancer Res 70(14):5649–5669

    CAS  PubMed  PubMed Central  Google Scholar 

  17. 17.

    Fidler IJ (1970) Metastasis: quantitative analysis of distribution and fate of tumor emboli labeled with 125 I-5-iodo-2′-deoxyuridine. J Natl Cancer Inst 45(4):773–782

    CAS  PubMed  PubMed Central  Google Scholar 

  18. 18.

    Paget S (1989) The distribution of secondary growths in cancer of the breast. 1889. Cancer Metastasis Rev 8(2):98–101

    CAS  PubMed  Google Scholar 

  19. 19.

    Langley RR, Fidler IJ (2011) The seed and soil hypothesis revisited—the role of tumor-stroma interactions in metastasis to different organs. Int J Cancer J Int du Cancer 128(11):2527–2535

    CAS  Google Scholar 

  20. 20.

    Peters ITA et al (2017) Prevalence and risk factors of ovarian metastases in breast cancer patients < 41 years of age in the Netherlands: A Nationwide Retrospective Cohort Study. PLoS ONE 12(1):e0168277

    PubMed  PubMed Central  Google Scholar 

  21. 21.

    Bussani R et al (2007) Cardiac metastases. J Clin Pathol 60(1):27–34

    CAS  PubMed  PubMed Central  Google Scholar 

  22. 22.

    Nasu H et al (2015) Breast cancer metastatic to the kidney with renal vein involvement. Jpn J Radiol 33(2):107–111

    PubMed  Google Scholar 

  23. 23.

    Tao K et al (2008) Imagable 4T1 model for the study of late stage breast cancer. BMC Cancer 8:228

    PubMed  PubMed Central  Google Scholar 

  24. 24.

    Hiraga T et al (2004) Zoledronic acid inhibits visceral metastases in the 4T1/luc mouse breast cancer model. Clin Cancer Res 10(13):4559–4567

    CAS  PubMed  Google Scholar 

  25. 25.

    Zhang Y et al (2015) Surgically-induced multi-organ metastasis in an orthotopic syngeneic imageable model of 4T1 murine breast cancer. Anticancer Res 35(9):4641–4646

    PubMed  Google Scholar 

  26. 26.

    Yoneda T et al (2000) Actions of bisphosphonate on bone metastasis in animal models of breast carcinoma. Cancer 88(12 Suppl):2979–2988

    CAS  PubMed  Google Scholar 

  27. 27.

    Khadge S et al (2018) Dietary omega-3 and omega-6 polyunsaturated fatty acids modulate hepatic pathology. J Nutr Biochem 52:92–102

    CAS  PubMed  Google Scholar 

  28. 28.

    Watkins BA et al (2000) Dietary ratio of (n-6)/(n-3) polyunsaturated fatty acids alters the fatty acid composition of bone compartments and biomarkers of bone formation in rats. J Nutr 130(9):2274–2284

    CAS  PubMed  Google Scholar 

  29. 29.

    Yuan J et al (2010) The effects of polyunsaturated fatty acids and their metabolites on osteoclastogenesis in vitro. Prostaglandins Other Lipid Mediat 92(1–4):85–90

    CAS  PubMed  Google Scholar 

  30. 30.

    Wonnacott KE et al (2010) Dietary omega-3 and -6 polyunsaturated fatty acids affect the composition and development of sheep granulosa cells, oocytes and embryos. Reproduction 139(1):57–69

    CAS  PubMed  Google Scholar 

  31. 31.

    Khan RS et al (2013) Fish oil selectively improves heart function in a mouse model of lipid-induced cardiomyopathy. J Cardiovasc Pharmacol 61(4):345–354

    CAS  PubMed  PubMed Central  Google Scholar 

  32. 32.

    Zeng Z et al (2017) Omega-3 polyunsaturated fatty acids attenuate fibroblast activation and kidney fibrosis involving MTORC2 signaling suppression. Sci Rep 7:46146

    CAS  PubMed  PubMed Central  Google Scholar 

  33. 33.

    Aslakson CJ, Miller FR (1992) Selective events in the metastatic process defined by analysis of the sequential dissemination of subpopulations of a mouse mammary tumor. Cancer Res 52(6):1399–1405

    CAS  PubMed  Google Scholar 

  34. 34.

    Talmadge JE (2010) Models of metastasis in drug discovery. Methods Mol Biol 602:215–233

    CAS  PubMed  Google Scholar 

  35. 35.

    Younos IH et al (2012) Tumor regulation of myeloid-derived suppressor cell proliferation and trafficking. Int Immunopharmacol 13(3):245–256

    CAS  PubMed  Google Scholar 

  36. 36.

    Lelekakis M et al (1999) A novel orthotopic model of breast cancer metastasis to bone. Clin Exp Metastasis 17(2):163–170

    CAS  PubMed  Google Scholar 

  37. 37.

    Heppner H, Miller GFR, Malathy PV, Shekhar (2000) Nontransgenic models of breast cancer. Breast Cancer Res 2(5):331–334

    CAS  PubMed  Google Scholar 

  38. 38.

    Morecki S et al (1998) Allogeneic cell therapy for a murine mammary carcinoma. Cancer Res 58(17):3891–3895

    CAS  PubMed  Google Scholar 

  39. 39.

    Faria SS et al (2016) The neutrophil-to-lymphocyte ratio: a narrative review. Ecancermedicalscience 10:702

    PubMed  PubMed Central  Google Scholar 

  40. 40.

    Kim EJ et al (2011) Dietary fat increases solid tumor growth and metastasis of 4T1 murine mammary carcinoma cells and mortality in obesity-resistant BALB/c mice. Breast Cancer Res 13(4):R78–R78

    CAS  PubMed  PubMed Central  Google Scholar 

  41. 41.

    Buckley JD, Howe PR (2009) Anti-obesity effects of long-chain omega-3 polyunsaturated fatty acids. Obes Rev 10(6):648–659

    CAS  PubMed  Google Scholar 

  42. 42.

    Amri EZ, Ailhaud G, Grimaldi PA (1994) Fatty acids as signal transducing molecules: involvement in the differentiation of preadipose to adipose cells. J Lipid Res 35(5):930–937

    CAS  PubMed  Google Scholar 

  43. 43.

    Bing C et al (2006) Adipose atrophy in cancer cachexia: morphologic and molecular analysis of adipose tissue in tumour-bearing mice. Br J Cancer 95(8):1028–1037

    CAS  PubMed  PubMed Central  Google Scholar 

  44. 44.

    Porporato PE (2016) Understanding cachexia as a cancer metabolism syndrome. Oncogenesis 5:e200

    CAS  PubMed  PubMed Central  Google Scholar 

  45. 45.

    Ebadi M, Mazurak VC (2014) evidence and mechanisms of fat depletion in Cancer. Nutrients 6(11):5280–5297

    CAS  PubMed  PubMed Central  Google Scholar 

  46. 46.

    Yee LD et al (2005) Dietary (n-3) polyunsaturated fatty acids inhibit HER-2/neu-induced breast cancer in mice independently of the PPARgamma ligand rosiglitazone. J Nutr 135(5):983–988

    CAS  PubMed  Google Scholar 

  47. 47.

    Yee LD et al (2013) The inhibition of early stages of HER-2/neu-mediated mammary carcinogenesis by dietary n-3 PUFAs. Mol Nutr Food Res 57(2):320–327

    CAS  PubMed  Google Scholar 

  48. 48.

    Olivo-Marston SE et al (2008) Gene signaling pathways mediating the opposite effects of prepubertal low-fat and high-fat n-3 polyunsaturated fatty acid diets on mammary cancer risk. Cancer Prev Res (Phila) 1(7):532–545

    CAS  Google Scholar 

  49. 49.

    Paschall AV, Liu K (2016) An orthotopic mouse model of spontaneous breast cancer metastasis. J Visualized Exp: JoVE. https://doi.org/10.3791/54040

    Article  Google Scholar 

  50. 50.

    Ghochikyan A et al (2014) Primary 4T1 tumor resection provides critical “window of opportunity” for immunotherapy. Clin Exp Metastasis 31(2):185–198

    CAS  PubMed  Google Scholar 

  51. 51.

    Chung H et al (2014) Omega-3 fatty acids reduce obesity-induced tumor progression independent of GPR120 in a mouse model of postmenopausal breast cancer. Oncogene 34:3504

    PubMed  PubMed Central  Google Scholar 

  52. 52.

    Xue M et al (2014) Docosahexaenoic acid inhibited the Wnt/beta-catenin pathway and suppressed breast cancer cells in vitro and in vivo. J Nutr Biochem 25(2):104–110

    CAS  PubMed  Google Scholar 

  53. 53.

    Pulaski BA, Ostrand-Rosenberg S (1998) Reduction of established spontaneous mammary carcinoma metastases following immunotherapy with major histocompatibility complex class II and B7.1 cell-based tumor vaccines. Can Res 58(7):1486–1493

    CAS  Google Scholar 

  54. 54.

    Saxena M, Christofori G (2013) Rebuilding cancer metastasis in the mouse. Mol Oncol 7(2):283–296

    CAS  PubMed  PubMed Central  Google Scholar 

  55. 55.

    Wright LE et al (2016) Murine models of breast cancer bone metastasis. BoneKEy Rep 5:804

    CAS  PubMed  PubMed Central  Google Scholar 

  56. 56.

    Bolin C et al (2012) Novel mouse mammary cell lines for in vivo bioluminescence imaging (BLI) of bone metastasis. Biol Proced Online 14:6–6

    CAS  PubMed  PubMed Central  Google Scholar 

  57. 57.

    Mandal CC et al (2010) Fish oil prevents breast cancer cell metastasis to bone. Biochem Biophys Res Commun 402(4):602–607

    CAS  PubMed  PubMed Central  Google Scholar 

  58. 58.

    Rahman M et al (2013) DHA is a more potent inhibitor of breast cancer metastasis to bone and related osteolysis than EPA. Breast Cancer Res Treat. https://doi.org/10.1007/s10549-013-2703-y

    Article  PubMed  PubMed Central  Google Scholar 

  59. 59.

    Kruger MC, Schollum LM (2005) Is docosahexaenoic acid more effective than eicosapentaenoic acid for increasing calcium bioavailability? Prostaglandins Leukot Essent Fatty Acids 73(5):327–334

    CAS  PubMed  Google Scholar 

  60. 60.

    Watkins BA, Li Y, Seifert MF (2006) Dietary ratio of n-6/n-3 PUFAs and docosahexaenoic acid: actions on bone mineral and serum biomarkers in ovariectomized rats. J Nutr Biochem 17(4):282–289

    CAS  PubMed  Google Scholar 

  61. 61.

    Huo Z et al (2015) Metastasis of breast cancer to renal cancer: report of a rare case. Int J Clin Exp Pathol 8(11):15417–15421

    PubMed  PubMed Central  Google Scholar 

  62. 62.

    Kline IK (1972) Cardiac lymphatic involvement by metastatic tumor. Cancer 29(3):799–808

    CAS  PubMed  Google Scholar 

  63. 63.

    Lockwood WB, Broghamer WL (1980) The changing prevalence of secondary cardiac neoplasms as related to cancer therapy. Cancer 45(10):2659–2662

    CAS  PubMed  Google Scholar 

  64. 64.

    Reynen K, Köckeritz U, Strasser RH (2004) Metastases to the heart. Ann Oncol 15(3):375–381

    CAS  PubMed  PubMed Central  Google Scholar 

  65. 65.

    PIMENTEL C et al (2016) Ovarian metastases from breast cancer: a series of 28 cases. Anticancer Res 36(8):4195–4200

    CAS  PubMed  Google Scholar 

  66. 66.

    Lee S-J et al (2009) Clinical characteristics of metastatic tumors to the ovaries. J Korean Med Sci 24(1):114–119

    PubMed  PubMed Central  Google Scholar 

  67. 67.

    Eilati E et al (2013) Flaxseed enriched diet-mediated reduction in ovarian cancer severity is correlated to the reduction of prostaglandin E2 in laying hen ovaries. Prostaglandins Leukot Essent Fatty Acids (PLEFA) 89(4):179–187

    CAS  Google Scholar 

  68. 68.

    Wan XH, Fu X, Ababaikeli G (2016) Docosahexaenoic acid induces growth suppression on epithelial ovarian cancer cells more effectively than eicosapentaenoic acid. Nutr Cancer 68(2):320–327

    CAS  PubMed  Google Scholar 

  69. 69.

    Wang Y-C et al (2016) Docosahexaenoic acid modulates invasion and metastasis of human ovarian cancer via multiple molecular pathways. Int J Gynecol Cancer 26(6):994–1003

    PubMed  PubMed Central  Google Scholar 

  70. 70.

    Chen Y et al (1999) Epidemiology of contralateral breast cancer. Cancer Epidemiol Biomark Prevent 8(10):855–861

    CAS  Google Scholar 

  71. 71.

    Alkner S et al (2015) Contralateral breast cancer can represent a metastatic spread of the first primary tumor: determination of clonal relationship between contralateral breast cancers using next-generation whole genome sequencing. Breast Cancer Res 17(1):102

    PubMed  PubMed Central  Google Scholar 

  72. 72.

    Raghavendra A et al (2017) Mammographic breast density is associated with the development of contralateral breast cancer. Cancer 123(11):1935–1940

    CAS  PubMed  PubMed Central  Google Scholar 

  73. 73.

    Khadge S et al (2018) Long-chain omega-3 polyunsaturated fatty acids modulate mammary gland composition and inflammation. J Mammary Gland Biol Neoplasia. https://doi.org/10.1007/s10911-018-9391-5

    Article  PubMed  Google Scholar 

  74. 74.

    Schley PD et al (2005) Mechanisms of omega-3 fatty acid-induced growth inhibition in MDA-MB-231 human breast cancer cells. Breast Cancer Res Treat 92(2):187–195

    CAS  PubMed  Google Scholar 

  75. 75.

    Jiang W et al (2012) Identification of a molecular signature underlying inhibition of mammary carcinoma growth by dietary N-3 fatty acids. Can Res 72(15):3795–3806

    CAS  Google Scholar 

  76. 76.

    El Fadli M et al (2017) Breast cancer metastasis to the spleen: a case report and literature review. Oxford Med Case Rep 2017(12):omx069

    Google Scholar 

  77. 77.

    Roomi MW et al (2014) In vitro and in vivo effects of a nutrient mixture on breast cancer progression. Int J Oncol 44(6):1933–1944

    CAS  PubMed  Google Scholar 

  78. 78.

    DuPre SA, Hunter KW Jr (2007) Murine mammary carcinoma 4T1 induces a leukemoid reaction with splenomegaly: association with tumor-derived growth factors. Exp Mol Pathol 82(1):12–24

    CAS  PubMed  Google Scholar 

  79. 79.

    Talmadge JE, Gabrilovich DI (2013) History of myeloid derived suppressor cells (MDSCs) in the macro- and micro-environment of tumour-bearing hosts. Nat Rev Cancer 13(10):739–752

    CAS  PubMed  PubMed Central  Google Scholar 

  80. 80.

    Younos I et al (2011) Tumor- and organ-dependent infiltration by myeloid-derived suppressor cells. Int Immunopharmacol 11(7):816–826

    CAS  PubMed  Google Scholar 

  81. 81.

    Gonzalez MJ et al (1993) Dietary fish oil inhibits human breast carcinoma growth: a function of increased lipid peroxidation. Lipids 28(9):827–832

    CAS  PubMed  Google Scholar 

  82. 82.

    Hammamieh R et al (2007) Control of the growth of human breast cancer cells in culture by manipulation of arachidonate metabolism. BMC Cancer 7(1):138

    PubMed  PubMed Central  Google Scholar 

  83. 83.

    Albino AP et al (2000) Cell cycle arrest and apoptosis of melanoma cells by docosahexaenoic acid: association with decreased pRb phosphorylation. Can Res 60(15):4139–4145

    CAS  Google Scholar 

  84. 84.

    Istfan NW, Wan J, Chen ZY (1995) Fish oil and cell proliferation kinetics in a mammary carcinoma tumor model. Adv Exp Med Biol 375:149–156

    CAS  PubMed  Google Scholar 

  85. 85.

    Murray M et al (2015) Anti-tumor activities of lipids and lipid analogues and their development as potential anticancer drugs. Pharmacol Ther 150:109–128

    CAS  PubMed  Google Scholar 

  86. 86.

    Merendino N et al (2013) Dietary ω-3 polyunsaturated fatty acid DHA: a potential adjuvant in the treatment of cancer. BioMed Res Int. https://doi.org/10.1155/2013/310186

    Article  PubMed  PubMed Central  Google Scholar 

  87. 87.

    Hardman WE et al (2001) Three percent dietary fish oil concentrate increased efficacy of doxorubicin against MDA-MB 231 breast cancer xenografts. Clin Cancer Res 7(7):2041–2049

    CAS  PubMed  Google Scholar 

  88. 88.

    Reddy S, Raffin M, Kaklamani V (2012) Targeting angiogenesis in metastatic breast cancer. Oncologist 17(8):1014–1026

    CAS  PubMed  PubMed Central  Google Scholar 

  89. 89.

    Fidler IJ, Ellis LM (1994) The implications of angiogenesis for the biology and therapy of cancer metastasis. Cell 79(2):185–188

    CAS  PubMed  Google Scholar 

  90. 90.

    Zhang G et al (2013) Epoxy metabolites of docosahexaenoic acid (DHA) inhibit angiogenesis, tumor growth, and metastasis. Proc Natl Acad Sci USA 110(16):6530–6535

    CAS  PubMed  Google Scholar 

  91. 91.

    Albini A et al (2005) Tumor inflammatory angiogenesis and its chemoprevention. Cancer Res 65(23):10637–10641

    CAS  PubMed  Google Scholar 

  92. 92.

    Lewis CE et al (1995) Cytokine regulation of angiogenesis in breast cancer: the role of tumor-associated macrophages. J Leukoc Biol 57(5):747–751

    CAS  PubMed  Google Scholar 

  93. 93.

    Nozawa H, Chiu C, Hanahan D, (2006) Infiltrating neutrophils mediate the initial angiogenic switch in a mouse model of multistage carcinogenesis. Proc Natl Acad Sci USA 103(33):12493–12498

    CAS  PubMed  Google Scholar 

  94. 94.

    Wroblewski M et al (2017) Mast cells decrease efficacy of anti-angiogenic therapy by secreting matrix-degrading granzyme B. Nat Commun 8(1):269

    CAS  PubMed  PubMed Central  Google Scholar 

  95. 95.

    Liang P et al (2016) Effect of dietary omega-3 fatty acids on tumor-associated macrophages and prostate cancer progression. Prostate 76(14):1293–1302

    CAS  PubMed  PubMed Central  Google Scholar 

  96. 96.

    Kzhyshkowska J et al (2014) Role of tumor associated macrophages in tumor angiogenesis and lymphangiogenesis. Front Physiol. https://doi.org/10.3389/fphys.2014.00075

    Article  PubMed  PubMed Central  Google Scholar 

  97. 97.

    Mantovani A, Locati M (2016) Macrophage metabolism shapes angiogenesis in tumors. Cell Metab 24(5):653–654

    CAS  PubMed  Google Scholar 

  98. 98.

    Bingle L et al (2005) Macrophages promote angiogenesis in human breast tumour spheroids in vivo. Br J Cancer 94:101

    Google Scholar 

  99. 99.

    Denkert C et al (2010) Tumor-associated lymphocytes as an independent predictor of response to neoadjuvant chemotherapy in breast cancer. J Clin Oncol 28(1):105–113

    CAS  Google Scholar 

  100. 100.

    Zhang X, Xu W (2017) Neutrophils diminish T-cell immunity to foster gastric cancer progression: the role of GM-CSF/PD-L1/PD-1 signalling pathway. Gut. https://doi.org/10.1136/gutjnl-2017-313923

    Article  PubMed  PubMed Central  Google Scholar 

  101. 101.

    Wei B et al (2016) The neutrophil lymphocyte ratio is associated with breast cancer prognosis: an updated systematic review and meta-analysis. OncoTargets Ther 9:5567–5575

    Google Scholar 

  102. 102.

    Jiao Y et al (2017) Docosahexaenoic acid and disulfiram act in concert to kill cancer cells: a mutual enhancement of their anticancer actions. Oncotarget 8(11):17908–17920

    PubMed  PubMed Central  Google Scholar 

  103. 103.

    Hajjaji N, Bougnoux P (2013) Selective sensitization of tumors to chemotherapy by marine-derived lipids: a review. Cancer Treat Rev 39(5):473–488

    CAS  PubMed  Google Scholar 

  104. 104.

    Slagsvold JE et al (2010) DHA alters expression of target proteins of cancer therapy in chemotherapy resistant SW620 colon cancer cells. Nutr Cancer 62(5):611–621

    CAS  PubMed  Google Scholar 

  105. 105.

    Hamidullah B, Changkija, Konwar R (2012) Role of interleukin-10 in breast cancer. Breast Cancer Res Treat 133(1):11–21

    CAS  PubMed  Google Scholar 

  106. 106.

    Bhattacharjee HK et al (2016) Is Interleukin 10 (IL10) expression in breast cancer a marker of poor prognosis? Indian J Surg Oncol 7(3):320–325

    PubMed  PubMed Central  Google Scholar 

  107. 107.

    Ahmad N et al (2018) IL-6 and IL-10 are associated with good prognosis in early stage invasive breast cancer patients. Cancer Immunol Immunother 67(4):537–549

    CAS  PubMed  Google Scholar 

  108. 108.

    Fujii S et al (2001) Interleukin-10 promotes the maintenance of antitumor CD8(+) T-cell effector function in situ. Blood 98(7):2143–2151

    CAS  PubMed  Google Scholar 

  109. 109.

    Mumm JB et al (2011) IL-10 elicits IFNgamma-dependent tumor immune surveillance. Cancer Cell 20(6):781–796

    CAS  PubMed  Google Scholar 

  110. 110.

    Sun Z et al (2015) IL10 and PD-1 cooperate to limit the activity of tumor-specific CD8+ T Cells. Cancer Res 75(8):1635–1644

    CAS  PubMed  PubMed Central  Google Scholar 

  111. 111.

    Bradley RL, Fisher FM, Eleftheria MF (2008) Dietary fatty acids differentially regulate production of TNF-α and IL-10 by Murine 3T3-L1 Adipocytes. Obesity 16(5):938–944

    CAS  PubMed  Google Scholar 

  112. 112.

    Foitzik T et al (2002) Omega-3 fatty acid supplementation increases anti-inflammatory cytokines and attenuates systemic disease sequelae in experimental pancreatitis. JPEN J Parenter Enteral Nutr 26(6):351–356

    CAS  PubMed  Google Scholar 

  113. 113.

    Donkor MK et al (2009) Mammary tumor heterogeneity in the expansion of myeloid-derived suppressor cells. Int Immunopharmacol 9(7–8):937–948

    CAS  PubMed  Google Scholar 

  114. 114.

    Kowanetz M et al (2010), Granulocyte-colony stimulating factor promotes lung metastasis through mobilization of Ly6G+ Ly6C+ granulocytes. Proc Natl Acad Sci USA 107(50):21248–21255

    CAS  PubMed  Google Scholar 

  115. 115.

    Roche-Nagle G et al (2004) Antimetastatic activity of a cyclooxygenase-2 inhibitor. Br J Cancer 91:359

    CAS  PubMed  PubMed Central  Google Scholar 

  116. 116.

    Brault MS, Kurt RA (2005) Impact of tumor-derived CCL2 on macrophage effector function. J Biomed Biotechnol 2005(1):37–43

    CAS  PubMed  PubMed Central  Google Scholar 

  117. 117.

    Waight JD et al (2011) Tumor-derived G-CSF facilitates neoplastic growth through a granulocytic myeloid-derived suppressor cell-dependent mechanism. PLoS ONE 6(11):e27690

    CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We gratefully acknowledge funding from the Fred & Pamela Buffett Cancer Center’s NIH Cancer Center Support Grant No. (P30CA036727) and the Nebraska Center for Integrated Biomolecular Communications (Grant No. P20GM113126) for this project. Also, funding from the UNMC College of Medicine (LWK) Endowed Chair.

Author information

Affiliations

Authors

Corresponding author

Correspondence to James E. Talmadge.

Ethics declarations

Conflict of interest

The authors declare that there are no conflicts of interest.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (DOCX 2659 KB)

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Khadge, S., Thiele, G.M., Sharp, J.G. et al. Long-chain omega-3 polyunsaturated fatty acids decrease mammary tumor growth, multiorgan metastasis and enhance survival. Clin Exp Metastasis 35, 797–818 (2018). https://doi.org/10.1007/s10585-018-9941-7

Download citation

Keywords

  • PUFA
  • Omega-3
  • Mammary tumor
  • Metastasis
  • Survival