Skip to main content

Advertisement

Log in

The role of vitamin D in hepatic metastases from colorectal cancer

  • Review Article
  • Published:
Clinical and Translational Oncology Aims and scope Submit manuscript

Abstract

Colorectal cancer (CRC) represents a significant health burden worldwide, comprising approximately 10% of annual cancer cases globally. Hepatic metastases are the most common site of CRC metastasis, and are the leading cause of death in CRC patients. There is strong epidemiologic evidence for an inverse association between vitamin D status and risk of CRC; however, the role of vitamin D in the natural history of liver metastases has not yet been investigated. Several researchers have proposed hallmarks of metastases; crucially, metastases can be blocked by interrupting just one rate-limiting step. Vitamin D status has been implicated in each proposed hallmark of metastasis. The aim of this review is to examine the potential role for vitamin D in reducing the development of hepatic metastases from CRC and outline the candidate mechanisms by which vitamin D may mediate these effects. The results of ongoing randomised intervention trials are eagerly awaited to determine whether addressing vitamin D insufficiency in CRC patients could reduce the occurrence of liver metastases, and the consequent morbidity and mortality.

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

Access this article

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

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Adapted with permission from Fidler, 2003 [23]

Fig. 3
Fig. 4

Similar content being viewed by others

Abbreviations

CRC:

Colorectal cancer

UVB:

Ultraviolet B

25(OH)D3 :

Pro-vitamin D (calcidiol, 25-hydroxyvitamin D)

25-OHase:

Vitamin D 25-hydroxylase

CYP27A1:

Cytochrome p450 oxidase

CYP3A4:

Cytochrome p450 3A4

CYP27B1:

Cytochrome p450 27B1

VDR:

Vitamin D receptor

RXR:

Retinoic acid receptor

VDRE:

Vitamin D response element

FGF23:

Fibroblast growth factor 23

CYP24A1:

Cytochrome P450 enzyme (24-hydroxylase, 24-OHase)

NHS:

Nurses’ Health Study

HPFS:

Health Professionals Follow-up Study

EPIC:

European Prospective Investigation into Cancer and Nutrition

HR:

Hazard ratio

NHANES III:

Third National Health and Nutrition Examination Survey

ECM:

Extracellular matrix

CDK:

Cyclin-dependent kinase

5-FU:

5-Fluorouracil

TYMS:

Thymidylate synthase

CDH1:

Cadherin 1 (epithelial cadherin, E-cadherin)

EMT:

Epithelial to mesenchymal transition

TCF:

T-cell transcription factors

LEF:

Lymphoid enhancer factor

JMJD3:

Jumonji domain-containing protein-3

SNAI1:

Snail family Zinc Finger 1

MMP:

Matrix metalloproteinase

PLAU:

Plasminogen activator, urokinase

TIMP:

Tissue inhibitor of metalloproteinase

VEGF:

Vascular endothelial growth factor

HIF:

Hypoxia inducible factor

EPAS1:

Endothelial PAS domain protein 1 (formerly HIF2A)

NK:

Natural killer

NKT:

Natural killer T

VDUP1:

Vitamin D up-regulated protein 1

BCL2:

B-cell lymphoma 2

CEACAM5:

Carcinoembryonic antigen-related cell adhesion molecule 5

IL:

Interleukin

TNF:

Tumour necrosis factor

CXCL12:

C-X-C motif chemokine 12

CXCR4:

C-X-C chemokine receptor type 4

References

  1. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2015. CA Cancer J Clin. 2015;65(1):5–29. doi:10.3322/caac.21254.

    Article  PubMed  Google Scholar 

  2. Canadian Cancer Society’s Advisory Committee on Cancer Statistics. Canadian Cancer Statistics 2015. Toronto: Canadian Cancer Society; 2015.

    Google Scholar 

  3. Pawlik TM, Schulick RD, Choti MA. Expanding criteria for resectability of colorectal liver metastases. Oncologist. 2008;13(1):51–64. doi:10.1634/theoncologist.2007-0142.

    Article  PubMed  Google Scholar 

  4. Stangl R, Altendorf-Hofmann A, Charnley RM, Scheele J. Factors influencing the natural history of colorectal liver metastases. Lancet. 1994;343(8910):1405–10.

    Article  CAS  PubMed  Google Scholar 

  5. McMillan DC, McArdle CS. Epidemiology of colorectal liver metastases. Surg Oncol. 2007;16(1):3–5. doi:10.1016/j.suronc.2007.04.008.

    Article  PubMed  Google Scholar 

  6. Staib L, Link KH, Blatz A, Beger HG. Surgery of colorectal cancer: surgical morbidity and five- and ten-year results in 2400 patients—monoinstitutional experience. World J Surg. 2002;26(1):59–66. doi:10.1007/s00268-001-0182-5.

    Article  PubMed  Google Scholar 

  7. Kievit J. Follow-up of patients with colorectal cancer: numbers needed to test and treat. Eur J Cancer. 2002;38(7):986–99.

    Article  CAS  PubMed  Google Scholar 

  8. Millikan KW, Staren ED, Doolas A. Invasive therapy of metastatic colorectal cancer to the liver. Surg Clin North Am. 1997;77(1):27–48.

    Article  CAS  PubMed  Google Scholar 

  9. Manfredi S, Bouvier AM, Lepage C, Hatem C, Dancourt V, Faivre J. Incidence and patterns of recurrence after resection for cure of colonic cancer in a well defined population. Br J Surg. 2006;93(9):1115–22.

    Article  CAS  PubMed  Google Scholar 

  10. Sobrero A, Aprile G. Resectability of initially unresectable liver metastases from colorectal cancer should not be the primary end point of clinical trials. Gastrointest Cancer Res. 2009;3(1):41–2.

    PubMed  PubMed Central  Google Scholar 

  11. Tomlinson JS, Jarnagin WR, DeMatteo RP, Fong Y, Kornprat P, Gonen M, Kemeny N, Brennan MF, Blumgart LH, D’Angelica M. Actual 10-year survival after resection of colorectal liver metastases defines cure. J Clin Oncol. 2007;25(29):4575–80. doi:10.1200/jco.2007.11.0833.

    Article  PubMed  Google Scholar 

  12. Wei AC, Greig PD, Grant D, Taylor B, Langer B, Gallinger S. Survival after hepatic resection for colorectal metastases: a 10-year experience. Ann Surg Oncol. 2006;13(5):668–76. doi:10.1245/aso.2006.05.039.

    Article  PubMed  Google Scholar 

  13. Ulrich CM, Holmes RS. Shedding light on colorectal cancer prognosis: vitamin d and beyond. J Clin Oncol. 2008;26(18):2937–9. doi:10.1200/jco.2008.16.1380.

    Article  PubMed  Google Scholar 

  14. Dou R, Ng K, Giovannucci EL, Manson JE, Qian ZR, Ogino S. Vitamin D and colorectal cancer: molecular, epidemiological and clinical evidence. Br J Nutr. 2016;115(9):1643–60. doi:10.1017/s0007114516000696.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Giovannucci E. Epidemiology of vitamin D and colorectal cancer. Anticancer Agents Med Chem. 2013;13(1):11–9.

    Article  CAS  PubMed  Google Scholar 

  16. Shui I, Giovannucci E. Vitamin D status and cancer incidence and mortality. Adv Exp Med Biol. 2014;810:33–51.

    PubMed  Google Scholar 

  17. Rohan T. Epidemiological studies of vitamin D and breast cancer. Nutr Rev. 2007;65(8 Pt 2):S80–3.

    Article  PubMed  Google Scholar 

  18. Garland CF, Comstock GW, Garland FC, Helsing KJ, Shaw EK, Gorham ED. Serum 25-hydroxyvitamin D and colon cancer: eight-year prospective study. Lancet. 1989;2(8673):1176–8.

    Article  CAS  PubMed  Google Scholar 

  19. Tangrea J, Helzlsouer K, Pietinen P, Taylor P, Hollis B, Virtamo J, Albanes D. Serum levels of vitamin D metabolites and the subsequent risk of colon and rectal cancer in Finnish men. Cancer Causes Control. 1997;8(4):615–25.

    Article  CAS  PubMed  Google Scholar 

  20. Wactawski-Wende J, Kotchen JM, Anderson GL, Assaf AR, Brunner RL, O’Sullivan MJ, Margolis KL, Ockene JK, Phillips L, Pottern L, Prentice RL, Robbins J, Rohan TE, Sarto GE, Sharma S, Stefanick ML, Van Horn L, Wallace RB, Whitlock E, Bassford T, Beresford SA, Black HR, Bonds DE, Brzyski RG, Caan B, Chlebowski RT, Cochrane B, Garland C, Gass M, Hays J, Heiss G, Hendrix SL, Howard BV, Hsia J, Hubbell FA, Jackson RD, Johnson KC, Judd H, Kooperberg CL, Kuller LH, LaCroix AZ, Lane DS, Langer RD, Lasser NL, Lewis CE, Limacher MC, Manson JE. Calcium plus vitamin D supplementation and the risk of colorectal cancer. N Engl J Med. 2006;354(7):684–96. doi:10.1056/NEJMoa055222.

    Article  CAS  PubMed  Google Scholar 

  21. Ng K. Vitamin D for prevention and treatment of colorectal cancer: what is the evidence? Curr Colorectal Cancer Rep. 2014;10(3):339–45. doi:10.1007/s11888-014-0238-1.

    Article  PubMed  PubMed Central  Google Scholar 

  22. Braun MM, Helzlsouer KJ, Hollis BW, Comstock GW. Colon cancer and serum vitamin D metabolite levels 10–17 years prior to diagnosis. Am J Epidemiol. 1995;142(6):608–11.

    Article  CAS  PubMed  Google Scholar 

  23. Fidler IJ. The pathogenesis of cancer metastasis: the ‘seed and soil’ hypothesis revisited. Nat Rev Cancer. 2003;3(6):453–8. doi:10.1038/nrc1098.

    Article  CAS  PubMed  Google Scholar 

  24. Jones G, Strugnell SA, DeLuca HF. Current understanding of the molecular actions of vitamin D. Physiol Rev. 1998;78(4):1193–231.

    Article  CAS  PubMed  Google Scholar 

  25. Prosser DE, Jones G. Enzymes involved in the activation and inactivation of vitamin D. Trends Biochem Sci. 2004;29(12):664–73. doi:10.1016/j.tibs.2004.10.005.

    Article  CAS  PubMed  Google Scholar 

  26. Gupta RP, Hollis BW, Patel SB, Patrick KS, Bell NH. CYP3A4 is a human microsomal vitamin D 25-hydroxylase. J Bone Miner Res. 2004;19(4):680–8. doi:10.1359/jbmr.0301257.

    Article  CAS  PubMed  Google Scholar 

  27. Cheng JB, Levine MA, Bell NH, Mangelsdorf DJ, Russell DW. Genetic evidence that the human CYP2R1 enzyme is a key vitamin D 25-hydroxylase. Proc Natl Acad Sci USA. 2004;101(20):7711–5. doi:10.1073/pnas.0402490101.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Cheng JB, Motola DL, Mangelsdorf DJ, Russell DW. De-orphanization of cytochrome P450 2R1: a microsomal vitamin D 25-hydroxilase. J Biol Chem. 2003;278(39):38084–93. doi:10.1074/jbc.M307028200.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Bareis P, Bises G, Bischof MG, Cross HS, Peterlik M. 25-hydroxy-vitamin d metabolism in human colon cancer cells during tumor progression. Biochem Biophys Res Commun. 2001;285(4):1012–7. doi:10.1006/bbrc.2001.5289.

    Article  CAS  PubMed  Google Scholar 

  30. Bises G, Kallay E, Weiland T, Wrba F, Wenzl E, Bonner E, Kriwanek S, Obrist P, Cross HS. 25-hydroxyvitamin D3-1alpha-hydroxylase expression in normal and malignant human colon. J Histochem Cytochem. 2004;52(7):985–9. doi:10.1369/jhc.4B6271.2004.

    Article  CAS  PubMed  Google Scholar 

  31. Cross HS. Extrarenal vitamin D hydroxylase expression and activity in normal and malignant cells: modification of expression by epigenetic mechanisms and dietary substances. Nutr Rev. 2007;65(8 Pt 2):S108–12.

    Article  PubMed  Google Scholar 

  32. Zehnder D, Bland R, Chana RS, Wheeler DC, Howie AJ, Williams MC, Stewart PM, Hewison M. Synthesis of 1,25-dihydroxyvitamin D(3) by human endothelial cells is regulated by inflammatory cytokines: a novel autocrine determinant of vascular cell adhesion. J Am Soc Nephrol. 2002;13(3):621–9.

    CAS  PubMed  Google Scholar 

  33. Eyles DW, Smith S, Kinobe R, Hewison M, McGrath JJ. Distribution of the vitamin D receptor and 1 alpha-hydroxylase in human brain. J Chem Neuroanat. 2005;29(1):21–30. doi:10.1016/j.jchemneu.2004.08.006.

    Article  CAS  PubMed  Google Scholar 

  34. Bland R, Markovic D, Hills CE, Hughes SV, Chan SL, Squires PE, Hewison M. Expression of 25-hydroxyvitamin D3-1alpha-hydroxylase in pancreatic islets. J Steroid Biochem Mol Biol. 2004;89–90(1–5):121–5. doi:10.1016/j.jsbmb.2004.03.115.

    Article  PubMed  CAS  Google Scholar 

  35. Zehnder D, Bland R, Williams MC, McNinch RW, Howie AJ, Stewart PM, Hewison M. Extrarenal expression of 25-hydroxyvitamin d(3)-1 alpha-hydroxylase. J Clin Endocrinol Metab. 2001;86(2):888–94. doi:10.1210/jcem.86.2.7220.

    CAS  PubMed  Google Scholar 

  36. Townsend K, Evans KN, Campbell MJ, Colston KW, Adams JS, Hewison M. Biological actions of extra-renal 25-hydroxyvitamin d-1alpha-hydroxylase and implications for chemoprevention and treatment. J Steroid Biochem Mol Biol. 2005;97(1–2):103–9. doi:10.1016/j.jsbmb.2005.06.004.

    Article  CAS  PubMed  Google Scholar 

  37. Rohe B, Safford SE, Nemere K, Farach-Carson MC. Identification and characterization of 1,25D(3)-membrane-associated rapid response, steroid (1,25D(3)-MARRS)-binding protein in rat IEC-6 cells. Steroids. 2005;70(5–7):458–63. doi:10.1016/j.steroids.2005.02.016.

    Article  CAS  PubMed  Google Scholar 

  38. Carlberg C. The vitamin D(3) receptor in the context of the nuclear receptor superfamily: the central role of the retinoid X receptor. Endocrine. 1996;4(2):91–105. doi:10.1007/bf02782754.

    Article  CAS  PubMed  Google Scholar 

  39. Peleg S, Nguyen CV. The importance of nuclear import in protection of the vitamin D receptor from polyubiquitination and proteasome-mediated degradation. J Cell Biochem. 2010;110(4):926–34. doi:10.1002/jcb.22606.

    Article  CAS  PubMed  Google Scholar 

  40. Haussler MR, Haussler CA, Bartik L, Whitfield GK, Hsieh JC, Slater S, Jurutka PW. Vitamin D receptor: molecular signaling and actions of nutritional ligands in disease prevention. Nutr Rev. 2008;66(10 Suppl 2):S98–112. doi:10.1111/j.1753-4887.2008.00093.x.

    Article  PubMed  Google Scholar 

  41. Haussler MR, Whitfield GK, Haussler CA, Hsieh JC, Thompson PD, Selznick SH, Dominguez CE, Jurutka PW. The nuclear vitamin D receptor: biological and molecular regulatory properties revealed. J Bone Miner Res. 1998;13(3):325–49. doi:10.1359/jbmr.1998.13.3.325.

    Article  CAS  PubMed  Google Scholar 

  42. Omdahl JL, Bobrovnikova EA, Choe S, Dwivedi PP, May BK. Overview of regulatory cytochrome P450 enzymes of the vitamin D pathway. Steroids. 2001;66(3–5):381–9.

    Article  CAS  PubMed  Google Scholar 

  43. Omdahl JL, Morris HA, May BK. Hydroxylase enzymes of the vitamin D pathway: expression, function, and regulation. Annu Rev Nutr. 2002;22:139–66. doi:10.1146/annurev.nutr.22.120501.150216.

    Article  CAS  PubMed  Google Scholar 

  44. Kosa JP, Horvath P, Wolfling J, Kovacs D, Balla B, Matyus P, Horvath E, Speer G, Takacs I, Nagy Z, Horvath H, Lakatos P. CYP24A1 inhibition facilitates the anti-tumor effect of vitamin D3 on colorectal cancer cells. World J Gastroenterol. 2013;19(17):2621–8. doi:10.3748/wjg.v19.i17.2621.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Cross HS, Bises G, Lechner D, Manhardt T, Kallay E. The vitamin D endocrine system of the gut—its possible role in colorectal cancer prevention. J Steroid Biochem Mol Biol. 2005;97(1–2):121–8. doi:10.1016/j.jsbmb.2005.06.005.

    Article  CAS  PubMed  Google Scholar 

  46. Lechner D, Kallay E, Cross HS. 1alpha,25-dihydroxyvitamin D3 downregulates CYP27B1 and induces CYP24A1 in colon cells. Mol Cell Endocrinol. 2007;263(1–2):55–64. doi:10.1016/j.mce.2006.08.009.

    Article  CAS  PubMed  Google Scholar 

  47. Holick MF. High prevalence of vitamin D inadequacy and implications for health. Mayo Clin Proc. 2006;81(3):353–73. doi:10.4065/81.3.353.

    Article  CAS  PubMed  Google Scholar 

  48. Hollis BW. Circulating 25-hydroxyvitamin D levels indicative of vitamin D sufficiency: implications for establishing a new effective dietary intake recommendation for vitamin D. J Nutr. 2005;135(2):317–22.

    Article  CAS  PubMed  Google Scholar 

  49. Institute of Medicine. Dietary reference intakes for calcium and vitamin D. Washington, DC: The National Academies Press; 2011. doi:10.17226/13050.

    Google Scholar 

  50. Hanahan D, Weinberg RA. The hallmarks of cancer. Cell. 2000;100(1):57–70.

    Article  CAS  PubMed  Google Scholar 

  51. Welch DR. Do we need to redefine a cancer metastasis and staging definitions? Breast Dis. 2006;26:3–12.

    Article  PubMed  PubMed Central  Google Scholar 

  52. Bird NC, Mangnall D, Majeed AW. Biology of colorectal liver metastases: a review. J Surg Oncol. 2006;94(1):68–80. doi:10.1002/jso.20558.

    Article  CAS  PubMed  Google Scholar 

  53. Rudmik LR, Magliocco AM. Molecular mechanisms of hepatic metastasis in colorectal cancer. J Surg Oncol. 2005;92(4):347–59. doi:10.1002/jso.20393.

    Article  CAS  PubMed  Google Scholar 

  54. Colotta F, Allavena P, Sica A, Garlanda C, Mantovani A. Cancer-related inflammation, the seventh hallmark of cancer: links to genetic instability. Carcinogenesis. 2009;30(7):1073–81. doi:10.1093/carcin/bgp127.

    Article  CAS  PubMed  Google Scholar 

  55. Mantovani A. Cancer: inflaming metastasis. Nature. 2009;457(7225):36–7. doi:10.1038/457036b.

    Article  CAS  PubMed  Google Scholar 

  56. Cantorna MT, Zhu Y, Froicu M, Wittke A. Vitamin D status, 1,25-dihydroxyvitamin D3, and the immune system. Am J Clin Nutr. 2004;80(6 Suppl):1717S–20S.

    Article  CAS  PubMed  Google Scholar 

  57. Cohen-Lahav M, Shany S, Tobvin D, Chaimovitz C, Douvdevani A. Vitamin D decreases NFkappaB activity by increasing IkappaBalpha levels. Nephrol Dial Transplant. 2006;21(4):889–97. doi:10.1093/ndt/gfi254.

    Article  CAS  PubMed  Google Scholar 

  58. Evans KN, Nguyen L, Chan J, Innes BA, Bulmer JN, Kilby MD, Hewison M. Effects of 25-hydroxyvitamin D3 and 1,25-dihydroxyvitamin D3 on cytokine production by human decidual cells. Biol Reprod. 2006;75(6):816–22. doi:10.1095/biolreprod.106.054056.

    Article  CAS  PubMed  Google Scholar 

  59. Giulietti A, van Etten E, Overbergh L, Stoffels K, Bouillon R, Mathieu C. Monocytes from type 2 diabetic patients have a pro-inflammatory profile. 1,25-dihydroxyvitamin D(3) works as anti-inflammatory. Diabetes Res Clin Pract. 2007;77(1):47–57. doi:10.1016/j.diabres.2006.10.007.

    Article  CAS  PubMed  Google Scholar 

  60. Facciorusso A, Del Prete V, Muscatiello N, Crucinio N, Barone M. Prognostic role of 25-hydroxyvitamin d in patients with liver metastases from colorectal cancer treated with radiofrequency ablation. J Gastroenterol Hepatol. 2016;. doi:10.1111/jgh.13326.

    Google Scholar 

  61. Obermannova R, Dusek L, Greplova K, Jarkovsky J, Sterba J, Vyzula R, Demlova R, Zdrazilova-Dubska L, Valik D. Time-course pattern of blood 25-hydroxycholecalciferol is a significant predictor of survival outcome in metastatic colorectal cancer: a clinical practice-based study. Neoplasma. 2015;62(6):958–65. doi:10.4149/neo_2015_116.

    Article  CAS  PubMed  Google Scholar 

  62. Ng K, Meyerhardt JA, Wu K, Feskanich D, Hollis BW, Giovannucci EL, Fuchs CS. Circulating 25-hydroxyvitamin d levels and survival in patients with colorectal cancer. J Clin Oncol. 2008;26(18):2984–91. doi:10.1200/jco.2007.15.1027.

    Article  CAS  PubMed  Google Scholar 

  63. Ng K, Venook AP, Sato K, Hollis BW, Niedzwiecki D, Ye C, Chang I-W, O’Neil BH, Innocenti F, Lenz H-J, Blanke CD, Mayer RJ, Fuchs CS, Meyerhardt JA. Vitamin D status and survival of metastatic colorectal cancer patients: results from CALGB/SWOG 80405 (Alliance). Paper presented at the 2015 Gastrointestinal Cancers Symposium (ASCO GI); 2015.

  64. Ng K, Wolpin BM, Meyerhardt JA, Wu K, Chan AT, Hollis BW, Giovannucci EL, Stampfer MJ, Willett WC, Fuchs CS. Prospective study of predictors of vitamin D status and survival in patients with colorectal cancer. Br J Cancer. 2009;101(6):916–23. doi:10.1038/sj.bjc.6605262.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Wesa KM, Segal NH, Cronin AM, Sjoberg DD, Jacobs GN, Coleton MI, Fleisher M, Dnistrian AM, Saltz LB, Cassileth BR. Serum 25-hydroxy vitamin D and survival in advanced colorectal cancer: a retrospective analysis. Nutr Cancer. 2015;67(3):424–30. doi:10.1080/01635581.2015.998838.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Zgaga L, Theodoratou E, Farrington SM, Din FV, Ooi LY, Glodzik D, Johnston S, Tenesa A, Campbell H, Dunlop MG. Plasma vitamin D concentration influences survival outcome after a diagnosis of colorectal cancer. J Clin Oncol. 2014;32(23):2430–9. doi:10.1200/jco.2013.54.5947.

    Article  CAS  PubMed  Google Scholar 

  67. Fedirko V, Riboli E, Tjonneland A, Ferrari P, Olsen A, Bueno-de-Mesquita HB, van Duijnhoven FJ, Norat T, Jansen EH, Dahm CC, Overvad K, Boutron-Ruault MC, Clavel-Chapelon F, Racine A, Lukanova A, Teucher B, Boeing H, Aleksandrova K, Trichopoulou A, Benetou V, Trichopoulos D, Grioni S, Vineis P, Panico S, Palli D, Tumino R, Siersema PD, Peeters PH, Skeie G, Brustad M, Chirlaque MD, Barricarte A, Ramon Quiros J, Sanchez MJ, Dorronsoro M, Bonet C, Palmqvist R, Hallmans G, Key TJ, Crowe F, Khaw KT, Wareham N, Romieu I, McKay J, Wark PA, Romaguera D, Jenab M. Prediagnostic 25-hydroxyvitamin D, VDR and CASR polymorphisms, and survival in patients with colorectal cancer in western European ppulations. Cancer Epidemiol Biomark Prev. 2012;21(4):582–93. doi:10.1158/1055-9965.epi-11-1065.

    Article  CAS  Google Scholar 

  68. Mezawa H, Sugiura T, Watanabe M, Norizoe C, Takahashi D, Shimojima A, Tamez S, Tsutsumi Y, Yanaga K, Urashima M. Serum vitamin D levels and survival of patients with colorectal cancer: post hoc analysis of a prospective cohort study. BMC Cancer. 2010;10:347. doi:10.1186/1471-2407-10-347.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  69. Mohr SB, Gorham ED, Kim J, Hofflich H, Cuomo RE, Garland CF. Could vitamin D sufficiency improve the survival of colorectal cancer patients? J Steroid Biochem Mol Biol. 2015;148:239–44. doi:10.1016/j.jsbmb.2014.12.010.

    Article  CAS  PubMed  Google Scholar 

  70. Li M, Chen P, Li J, Chu R, Xie D, Wang H. Review: the impacts of circulating 25-hydroxyvitamin D levels on cancer patient outcomes: a systematic review and meta-analysis. J Clin Endocrinol Metab. 2014;99(7):2327–36. doi:10.1210/jc.2013-4320.

    Article  CAS  PubMed  Google Scholar 

  71. Maalmi H, Ordonez-Mena JM, Schottker B, Brenner H. Serum 25-hydroxyvitamin D levels and survival in colorectal and breast cancer patients: systematic review and meta-analysis of prospective cohort studies. Eur J Cancer. 2014;50(8):1510–21. doi:10.1016/j.ejca.2014.02.006.

    Article  CAS  PubMed  Google Scholar 

  72. Ng K, Sargent DJ, Goldberg RM, Meyerhardt JA, Green EM, Pitot HC, Hollis BW, Pollak MN, Fuchs CS. Vitamin D status in patients with stage IV colorectal cancer: findings from Intergroup trial N9741. J Clin Oncol. 2011;29(12):1599–606. doi:10.1200/jco.2010.31.7255.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Wang B, Jing Z, Li C, Xu S, Wang Y. Blood 25-hydroxyvitamin D levels and overall mortality in patients with colorectal cancer: a dose-response meta-analysis. Eur J Cancer. 2014;50(12):2173–5. doi:10.1016/j.ejca.2014.05.004.

    Article  CAS  PubMed  Google Scholar 

  74. Ou B, Zhao J, Guan S, Lu A. Plasma 25-hydroxyvitamin D levels and survival of colorectal cancer patients: a meta-analysis. Eur J Cancer. 2015;51(6):786–8. doi:10.1016/j.ejca.2015.01.010.

    Article  CAS  PubMed  Google Scholar 

  75. Freedman DM, Looker AC, Chang SC, Graubard BI. Prospective study of serum vitamin D and cancer mortality in the United States. J Natl Cancer Inst. 2007;99(21):1594–602. doi:10.1093/jnci/djm204.

    Article  CAS  PubMed  Google Scholar 

  76. Freedman AN, Sansbury LB, Figg WD, Potosky AL, Weiss Smith SR, Khoury MJ, Nelson SA, Weinshilboum RM, Ratain MJ, McLeod HL, Epstein RS, Ginsburg GS, Schilsky RL, Liu G, Flockhart DA, Ulrich CM, Davis RL, Lesko LJ, Zineh I, Randhawa G, Ambrosone CB, Relling MV, Rothman N, Xie H, Spitz MR, Ballard-Barbash R, Doroshow JH, Minasian LM. Cancer pharmacogenomics and pharmacoepidemiology: setting a research agenda to accelerate translation. J Natl Cancer Inst. 2010;102(22):1698–705. doi:10.1093/jnci/djq390.

    Article  PubMed  PubMed Central  Google Scholar 

  77. Boscoe FP, Schymura MJ. Solar ultraviolet-B exposure and cancer incidence and mortality in the United States, 1993–2002. BMC Cancer. 2006;6:264. doi:10.1186/1471-2407-6-264.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  78. Chen W, Clements M, Rahman B, Zhang S, Qiao Y, Armstrong BK. Relationship between cancer mortality/incidence and ambient ultraviolet B irradiance in China. Cancer Causes Control. 2010;21(10):1701–9. doi:10.1007/s10552-010-9599-1.

    Article  PubMed  Google Scholar 

  79. Mizoue T. Ecological study of solar radiation and cancer mortality in Japan. Health Phys. 2004;87(5):532–8.

    Article  CAS  PubMed  Google Scholar 

  80. Giessen C, Nagel D, Glas M, Spelsberg F, Lau-Werner U, Modest DP, Michl M, Heinemann V, Stieber P, Schulz C. Evaluation of preoperative serum markers for individual patient prognosis in stage I–III rectal cancer. Tumour Biol. 2014;35(10):10237–48. doi:10.1007/s13277-014-2338-6.

    Article  CAS  PubMed  Google Scholar 

  81. Giessen-Jung C, Nagel D, Glas M, Spelsberg F, Lau-Werner U, Modest DP, Schulz C, Heinemann V, Di Gioia D, Stieber P. Preoperative serum markers for individual patient prognosis in stage I–III colon cancer. Tumour Biol. 2015;36(10):7897–906. doi:10.1007/s13277-015-3522-z.

    Article  CAS  PubMed  Google Scholar 

  82. Lewis C, Xun P, He K. Vitamin D supplementation and quality of life following diagnosis in stage II colorectal cancer patients: a 24-month prospective study. Support Care Cancer. 2016;24(4):1655–61. doi:10.1007/s00520-015-2945-9.

    Article  PubMed  Google Scholar 

  83. Yang B, McCullough ML, Gapstur SM, Jacobs EJ, Bostick RM, Fedirko V, Flanders WD, Campbell PT. Calcium, vitamin D, dairy products, and mortality among colorectal cancer survivors: the Cancer Prevention Study-II Nutrition Cohort. J Clin Oncol. 2014;32(22):2335–43. doi:10.1200/jco.2014.55.3024.

    Article  CAS  PubMed  Google Scholar 

  84. Cooney RV, Chai W, Franke AA, Wilkens LR, Kolonel LN, Le Marchand L. C-reactive protein, lipid-soluble micronutrients, and survival in colorectal cancer patients. Cancer Epidemiol Biomark Prev. 2013;22(7):1278–88. doi:10.1158/1055-9965.epi-13-0199.

    Article  CAS  Google Scholar 

  85. Tretli S, Schwartz GG, Torjesen PA, Robsahm TE. Serum levels of 25-hydroxyvitamin D and survival in Norwegian patients with cancer of breast, colon, lung, and lymphoma: a population-based study. Cancer Causes Control. 2012;23(2):363–70. doi:10.1007/s10552-011-9885-6.

    Article  PubMed  Google Scholar 

  86. Jacobs ET, Kohler LN, Kunihiro AG, Jurutka PW. Vitamin D and colorectal, breast, and prostate cancers: a review of the epidemiological evidence. J Cancer. 2016;7(3):232–40. doi:10.7150/jca.13403.

    Article  PubMed  PubMed Central  Google Scholar 

  87. Avenell A, MacLennan GS, Jenkinson DJ, McPherson GC, McDonald AM, Pant PR, Grant AM, Campbell MK, Anderson FH, Cooper C, Francis RM, Gillespie WJ, Robinson CM, Torgerson DJ, Wallace WA. Long-term follow-up for mortality and cancer in a randomized placebo-controlled trial of vitamin D(3) and/or calcium (RECORD trial). J Clin Endocrinol Metab. 2012;97(2):614–22. doi:10.1210/jc.2011-1309.

    Article  CAS  PubMed  Google Scholar 

  88. Neale RE, Armstrong BK, Baxter C, Duarte Romero B, Ebeling P, English DR, Kimlin MG, McLeod DS, RL OC, van der Pols JC, Venn AJ, Webb PM, Whiteman DC, Wockner L. The D-Health Trial: a randomized trial of vitamin D for prevention of mortality and cancer. Contemp Clin Trials. 2016;48:83–90. doi:10.1016/j.cct.2016.04.005.

    Article  CAS  PubMed  Google Scholar 

  89. Sutton VR, Vaux DL, Trapani JA. Bcl-2 prevents apoptosis induced by perforin and granzyme B, but not that mediated by whole cytotoxic lymphocytes. J Immunol. 1997;158(12):5783–90.

    CAS  PubMed  Google Scholar 

  90. Davis JE, Sutton VR, Smyth MJ, Trapani JA. Dependence of granzyme B-mediated cell death on a pathway regulated by Bcl-2 or its viral homolog, BHRF1. Cell Death Differ. 2000;7(10):973–83. doi:10.1038/sj.cdd.4400725.

    Article  CAS  PubMed  Google Scholar 

  91. Holt PR, Arber N, Halmos B, Forde K, Kissileff H, McGlynn KA, Moss SF, Kurihara N, Fan K, Yang K, Lipkin M. Colonic epithelial cell proliferation decreases with increasing levels of serum 25-hydroxy vitamin D. Cancer Epidemiol Biomark Prev. 2002;11(1):113–9.

    CAS  Google Scholar 

  92. Hsu JY, Feldman D, McNeal JE, Peehl DM. Reduced 1alpha-hydroxylase activity in human prostate cancer cells correlates with decreased susceptibility to 25-hydroxyvitamin D3-induced growth inhibition. Cancer Res. 2001;61(7):2852–6.

    CAS  PubMed  Google Scholar 

  93. Zhuang SH, Burnstein KL. Antiproliferative effect of 1alpha,25-dihydroxyvitamin D3 in human prostate cancer cell line LNCaP involves reduction of cyclin-dependent kinase 2 activity and persistent G1 accumulation. Endocrinology. 1998;139(3):1197–207. doi:10.1210/endo.139.3.5770.

    Article  CAS  PubMed  Google Scholar 

  94. Evans SR, Soldatenkov V, Shchepotin EB, Bogrash E, Shchepotin IB. Novel 19-nor-hexafluoride vitamin D3 analog (Ro 25-6760) inhibits human colon cancer in vitro via apoptosis. Int J Oncol. 1999;14(5):979–85.

    CAS  PubMed  Google Scholar 

  95. Scaglione-Sewell BA, Bissonnette M, Skarosi S, Abraham C, Brasitus TA. A vitamin D3 analog induces a G1-phase arrest in CaCo-2 cells by inhibiting cdk2 and cdk6: roles of cyclin E, p21Waf1, and p27Kip1. Endocrinology. 2000;141(11):3931–9. doi:10.1210/endo.141.11.7782.

    Article  CAS  PubMed  Google Scholar 

  96. Narvaez CJ, Zinser G, Welsh J. Functions of 1alpha,25-dihydroxyvitamin D(3) in mammary gland: from normal development to breast cancer. Steroids. 2001;66(3–5):301–8.

    Article  CAS  PubMed  Google Scholar 

  97. Diaz GD, Paraskeva C, Thomas MG, Binderup L, Hague A. Apoptosis is induced by the active metabolite of vitamin D3 and its analogue EB1089 in colorectal adenoma and carcinoma cells: possible implications for prevention and therapy. Cancer Res. 2000;60(8):2304–12.

    CAS  PubMed  Google Scholar 

  98. Park JH, McMillan DC, Horgan PG, Roxburgh CS. The impact of anti-inflammatory agents on the outcome of patients with colorectal cancer. Cancer Treat Rev. 2014;40(1):68–77. doi:10.1016/j.ctrv.2013.05.006.

    Article  CAS  PubMed  Google Scholar 

  99. Nakagawa K, Sasaki Y, Kato S, Kubodera N, Okano T. 22-Oxa-1alpha,25-dihydroxyvitamin D3 inhibits metastasis and angiogenesis in lung cancer. Carcinogenesis. 2005;26(6):1044–54. doi:10.1093/carcin/bgi049.

    Article  CAS  PubMed  Google Scholar 

  100. Alvarez-Diaz S, Valle N, Garcia JM, Pena C, Freije JM, Quesada V, Astudillo A, Bonilla F, Lopez-Otin C, Munoz A. Cystatin D is a candidate tumor suppressor gene induced by vitamin D in human colon cancer cells. J Clin Invest. 2009;119(8):2343–58.

    Article  CAS  PubMed  Google Scholar 

  101. Rao A, Coan A, Welsh JE, Barclay WW, Koumenis C, Cramer SD. Vitamin D receptor and p21/WAF1 are targets of genistein and 1,25-dihydroxyvitamin D3 in human prostate cancer cells. Cancer Res. 2004;64(6):2143–7.

    Article  CAS  PubMed  Google Scholar 

  102. Schwartz GG, Eads D, Rao A, Cramer SD, Willingham MC, Chen TC, Jamieson DP, Wang L, Burnstein KL, Holick MF, Koumenis C. Pancreatic cancer cells express 25-hydroxyvitamin D-1 alpha-hydroxylase and their proliferation is inhibited by the prohormone 25-hydroxyvitamin D3. Carcinogenesis. 2004;25(6):1015–26. doi:10.1093/carcin/bgh086.

    Article  CAS  PubMed  Google Scholar 

  103. Kizildag S, Ates H, Kizildag S. Treatment of K562 cells with 1,25-dihydroxyvitamin D3 induces distinct alterations in the expression of apoptosis-related genes BCL2, BAX, BCLXL, and p21. Ann Hematol. 2010;89(1):1–7. doi:10.1007/s00277-009-0766-y.

    Article  CAS  PubMed  Google Scholar 

  104. Chen SW, Zhu J, Zuo S, Ma J, Zhang JL, Chen GW, Wang X, Pan YS, Liu YC, Wang PY. 1,25(OH)2D3 attenuates TGF-beta 1/beta 2-induced increased migration and invasion via inhibiting epithelial-mesenchymal transition in colon cancer cells. Biochem Biophys Res Commun. 2015;468(1–2):130–5. doi:10.1016/j.bbrc.2015.10.146.

    Article  CAS  PubMed  Google Scholar 

  105. Nakagawa K, Kawaura A, Kato S, Takeda E, Okano T. 1 alpha,25-dihydroxyvitamin D(3) is a preventive factor in the metastasis of lung cancer. Carcinogenesis. 2005;26(2):429–40. doi:10.1093/carcin/bgh332.

    Article  CAS  PubMed  Google Scholar 

  106. Palmer HG, Gonzalez-Sancho JM, Espada J, Berciano MT, Puig I, Baulida J, Quintanilla M, Cano A, de Herreros AG, Lafarga M, Munoz A. Vitamin D(3) promotes the differentiation of colon carcinoma cells by the induction of E-cadherin and the inhibition of beta-catenin signaling. J Cell Biol. 2001;154(2):369–87.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Pendas-Franco N, Garcia JM, Pena C, Valle N, Palmer HG, Heinaniemi M, Carlberg C, Jimenez B, Bonilla F, Munoz A, Gonzalez-Sancho JM. DICKKOPF-4 is induced by TCF/beta-catenin and upregulated in human colon cancer, promotes tumour cell invasion and angiogenesis and is repressed by 1alpha,25-dihydroxyvitamin D3. Oncogene. 2008;27(32):4467–77. doi:10.1038/onc.2008.88.

    Article  CAS  PubMed  Google Scholar 

  108. Maher MT, Flozak AS, Stocker AM, Chenn A, Gottardi CJ. Activity of the beta-catenin phosphodestruction complex at cell-cell contacts is enhanced by cadherin-based adhesion. J Cell Biol. 2009;186(2):219–28. doi:10.1083/jcb.200811108.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Shah S, Islam MN, Dakshanamurthy S, Rizvi I, Rao M, Herrell R, Zinser G, Valrance M, Aranda A, Moras D, Norman A, Welsh J, Byers SW. The molecular basis of vitamin D receptor and beta-catenin crossregulation. Mol Cell. 2006;21(6):799–809. doi:10.1016/j.molcel.2006.01.037.

    Article  PubMed  CAS  Google Scholar 

  110. Timms PM, Mannan N, Hitman GA, Noonan K, Mills PG, Syndercombe-Court D, Aganna E, Price CP, Boucher BJ. Circulating MMP9, vitamin D and variation in the TIMP-1 response with VDR genotype: mechanisms for inflammatory damage in chronic disorders? QJM. 2002;95(12):787–96.

    Article  CAS  PubMed  Google Scholar 

  111. Pereira F, Barbachano A, Silva J, Bonilla F, Campbell MJ, Munoz A, Larriba MJ. KDM6B/JMJD3 histone demethylase is induced by vitamin D and modulates its effects in colon cancer cells. Hum Mol Genet. 2011;20(23):4655–65. doi:10.1093/hmg/ddr399.

    Article  CAS  PubMed  Google Scholar 

  112. Tokunaga R, Sakamoto Y, Nakagawa S, Miyake K, Izumi D, Kosumi K, Taki K, Higashi T, Imamura Y, Ishimoto T, Iwatsuki M, Baba Y, Miyamoto Y, Yoshida N, Oki E, Watanabe M, Baba H. The prognostic significance of histone lysine demethylase JMJD3/KDM6B in colorectal cancer. Ann Surg Oncol. 2016;23(2):678–85. doi:10.1245/s10434-015-4879-3.

    Article  PubMed  Google Scholar 

  113. Kahlert C, Klupp F, Brand K, Lasitschka F, Diederichs S, Kirchberg J, Rahbari N, Dutta S, Bork U, Fritzmann J, Reissfelder C, Koch M, Weitz J. Invasion front-specific expression and prognostic significance of microRNA in colorectal liver metastases. Cancer Sci. 2011;102(10):1799–807. doi:10.1111/j.1349-7006.2011.02023.x.

    Article  CAS  PubMed  Google Scholar 

  114. Feng Y, Zhu J, Ou C, Deng Z, Chen M, Huang W, Li L. MicroRNA-145 inhibits tumour growth and metastasis in colorectal cancer by targeting fascin-1. Br J Cancer. 2014;110(9):2300–9. doi:10.1038/bjc.2014.122.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Qin J, Wang FR, Jiang HY, Xu JF, Jiang YS, Wang ZW. MicroRNA-145 suppresses cell migration and invasion by targeting paxillin in human colorectal cancer cells. Int J Clin Exp Pathol. 2015;8(2):1328–40.

    CAS  PubMed  PubMed Central  Google Scholar 

  116. Cardus A, Panizo S, Encinas M, Dolcet X, Gallego C, Aldea M, Fernandez E, Valdivielso JM. 1,25-dihydroxyvitamin D3 regulates VEGF production through a vitamin D response element in the VEGF promoter. Atherosclerosis. 2009;204(1):85–9. doi:10.1016/j.atherosclerosis.2008.08.020.

    Article  CAS  PubMed  Google Scholar 

  117. Mantell DJ, Owens PE, Bundred NJ, Mawer EB, Canfield AE. 1 alpha,25-dihydroxyvitamin D(3) inhibits angiogenesis in vitro and in vivo. Circ Res. 2000;87(3):214–20.

    Article  CAS  PubMed  Google Scholar 

  118. Ben-Shoshan M, Amir S, Dang DT, Dang LH, Weisman Y, Mabjeesh NJ. 1alpha,25-dihydroxyvitamin D3 (Calcitriol) inhibits hypoxia-inducible factor-1/vascular endothelial growth factor pathway in human cancer cells. Mol Cancer Ther. 2007;6(4):1433–9. doi:10.1158/1535-7163.mct-06-0677.

    Article  CAS  PubMed  Google Scholar 

  119. Albert DM, Scheef EA, Wang S, Mehraein F, Darjatmoko SR, Sorenson CM, Sheibani N. Calcitriol is a potent inhibitor of retinal neovascularization. Invest Ophthalmol Vis Sci. 2007;48(5):2327–34. doi:10.1167/iovs.06-1210.

    Article  PubMed  Google Scholar 

  120. Gruber HE, Hoelscher G, Ingram JA, Chow Y, Loeffler B, Hanley EN Jr. 1,25(OH)2-vitamin D3 inhibits proliferation and decreases production of monocyte chemoattractant protein-1, thrombopoietin, VEGF, and angiogenin by human annulus cells in vitro. Spine (Phila Pa 1976). 2008;33(7):755–65. doi:10.1097/BRS.0b013e3181695d59.

    Article  Google Scholar 

  121. Quesada JM, Serrano I, Borrego F, Martin A, Pena J, Solana R. Calcitriol effect on natural killer cells from hemodialyzed and normal subjects. Calcif Tissue Int. 1995;56(2):113–7.

    Article  CAS  PubMed  Google Scholar 

  122. Balogh G, de Boland AR, Boland R, Barja P. Effect of 1,25(OH)(2)-vitamin D(3) on the activation of natural killer cells: role of protein kinase C and extracellular calcium. Exp Mol Pathol. 1999;67(2):63–74. doi:10.1006/exmp.1999.2264.

    Article  CAS  PubMed  Google Scholar 

  123. Lee KN, Kang HS, Jeon JH, Kim EM, Yoon SR, Song H, Lyu CY, Piao ZH, Kim SU, Han YH, Song SS, Lee YH, Song KS, Kim YM, Yu DY, Choi I. VDUP1 is required for the development of natural killer cells. Immunity. 2005;22(2):195–208. doi:10.1016/j.immuni.2004.12.012.

    Article  CAS  PubMed  Google Scholar 

  124. James SY, Mackay AG, Colston KW. Effects of 1,25 dihydroxyvitamin D3 and its analogues on induction of apoptosis in breast cancer cells. J Steroid Biochem Mol Biol. 1996;58(4):395–401.

    Article  CAS  PubMed  Google Scholar 

  125. Guzey M, Kitada S, Reed JC. Apoptosis induction by 1alpha,25-dihydroxyvitamin D3 in prostate cancer. Mol Cancer Ther. 2002;1(9):667–77.

    CAS  PubMed  Google Scholar 

  126. Funyu J, Mochida S, Inao M, Matsui A, Fujiwara K. VEGF can act as vascular permeability factor in the hepatic sinusoids through upregulation of porosity of endothelial cells. Biochem Biophys Res Commun. 2001;280(2):481–5. doi:10.1006/bbrc.2000.4148.

    Article  CAS  PubMed  Google Scholar 

  127. Chen A, Davis BH, Bissonnette M, Scaglione-Sewell B, Brasitus TA. 1,25-Dihydroxyvitamin D(3) stimulates activator protein-1-dependent Caco-2 cell differentiation. J Biol Chem. 1999;274(50):35505–13.

    Article  CAS  PubMed  Google Scholar 

  128. Bettoun DJ, Buck DW 2nd, Lu J, Khalifa B, Chin WW, Nagpal S. A vitamin D receptor-Ser/Thr phosphatase-p70 S6 kinase complex and modulation of its enzymatic activities by the ligand. J Biol Chem. 2002;277(28):24847–50. doi:10.1074/jbc.C200187200.

    Article  CAS  PubMed  Google Scholar 

  129. Palmer HG, Sanchez-Carbayo M, Ordonez-Moran P, Larriba MJ, Cordon-Cardo C, Munoz A. Genetic signatures of differentiation induced by 1alpha,25-dihydroxyvitamin D3 in human colon cancer cells. Cancer Res. 2003;63(22):7799–806.

    CAS  PubMed  Google Scholar 

  130. Freedman LP. Transcriptional targets of the vitamin D3 receptor-mediating cell cycle arrest and differentiation. J Nutr. 1999;129(2S Suppl):581S–6S.

    Article  CAS  PubMed  Google Scholar 

  131. Jakobisiak M, Lasek W, Golab J. Natural mechanisms protecting against cancer. Immunol Lett. 2003;90(2–3):103–22.

    Article  CAS  PubMed  Google Scholar 

  132. Morris VL, MacDonald IC, Koop S, Schmidt EE, Chambers AF, Groom AC. Early interactions of cancer cells with the microvasculature in mouse liver and muscle during hematogenous metastasis: videomicroscopic analysis. Clin Exp Metastasis. 1993;11(5):377–90.

    Article  CAS  PubMed  Google Scholar 

  133. Wyckoff JB, Jones JG, Condeelis JS, Segall JE. A critical step in metastasis: in vivo analysis of intravasation at the primary tumor. Cancer Res. 2000;60(9):2504–11.

    CAS  PubMed  Google Scholar 

  134. Luzzi KJ, MacDonald IC, Schmidt EE, Kerkvliet N, Morris VL, Chambers AF, Groom AC. Multistep nature of metastatic inefficiency: dormancy of solitary cells after successful extravasation and limited survival of early micrometastases. Am J Pathol. 1998;153(3):865–73. doi:10.1016/s0002-9440(10)65628-3.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  135. Wong CW, Lee A, Shientag L, Yu J, Dong Y, Kao G, Al-Mehdi AB, Bernhard EJ, Muschel RJ. Apoptosis: an early event in metastatic inefficiency. Cancer Res. 2001;61(1):333–8.

    CAS  PubMed  Google Scholar 

  136. Mehlen P, Puisieux A. Metastasis: a question of life or death. Nat Rev Cancer. 2006;6(6):449–58. doi:10.1038/nrc1886.

    Article  CAS  PubMed  Google Scholar 

  137. O’Kelly J, Uskokovic M, Lemp N, Vadgama J, Koeffler HP. Novel Gemini-vitamin D3 analog inhibits tumor cell growth and modulates the Akt/mTOR signaling pathway. J Steroid Biochem Mol Biol. 2006;100(4–5):107–16. doi:10.1016/j.jsbmb.2006.04.003.

    Article  PubMed  CAS  Google Scholar 

  138. Moreno J, Krishnan AV, Feldman D. Molecular mechanisms mediating the anti-proliferative effects of vitamin D in prostate cancer. J Steroid Biochem Mol Biol. 2005;97(1–2):31–6. doi:10.1016/j.jsbmb.2005.06.012.

    Article  CAS  PubMed  Google Scholar 

  139. Fingas CD, Altinbas A, Schlattjan M, Beilfuss A, Sowa JP, Sydor S, Bechmann LP, Ertle J, Akkiz H, Herzer K, Paul A, Gerken G, Baba HA, Canbay A. Expression of apoptosis- and vitamin D pathway-related genes in hepatocellular carcinoma. Digestion. 2013;87(3):176–81. doi:10.1159/000348441.

    Article  CAS  PubMed  Google Scholar 

  140. Samuel S, Sitrin MD. Vitamin D’s role in cell proliferation and differentiation. Nutr Rev. 2008;66(10 Suppl 2):S116–24. doi:10.1111/j.1753-4887.2008.00094.x.

    Article  PubMed  Google Scholar 

  141. Jensen SS, Madsen MW, Lukas J, Binderup L, Bartek J. Inhibitory effects of 1alpha,25-dihydroxyvitamin D(3) on the G(1)-S phase-controlling machinery. Mol Endocrinol. 2001;15(8):1370–80. doi:10.1210/mend.15.8.0673.

    CAS  PubMed  Google Scholar 

  142. Maier S, Daroqui MC, Scherer S, Roepcke S, Velcich A, Shenoy SM, Singer RH, Augenlicht LH. Butyrate and vitamin D3 induce transcriptional attenuation at the cyclin D1 locus in colonic carcinoma cells. J Cell Physiol. 2009;218(3):638–42. doi:10.1002/jcp.21642.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  143. van den Bemd GJ, Chang GT. Vitamin D and vitamin D analogs in cancer treatment. Curr Drug Targets. 2002;3(1):85–94.

    PubMed  Google Scholar 

  144. Shtutman M, Zhurinsky J, Simcha I, Albanese C, D’Amico M, Pestell R, Ben-Ze’ev A. The cyclin D1 gene is a target of the beta-catenin/LEF-1 pathway. Proc Natl Acad Sci USA. 1999;96(10):5522–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  145. Tetsu O, McCormick F. Beta-catenin regulates expression of cyclin D1 in colon carcinoma cells. Nature. 1999;398(6726):422–6. doi:10.1038/18884.

    Article  CAS  PubMed  Google Scholar 

  146. Gan L, Liu P, Lu H, Chen S, Yang J, McCarthy JB, Knudsen KE, Huang H. Cyclin D1 promotes anchorage-independent cell survival by inhibiting FOXO-mediated anoikis. Cell Death Differ. 2009;16(10):1408–17. doi:10.1038/cdd.2009.86.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  147. Park WH, Seol JG, Kim ES, Jung CW, Lee CC, Binderup L, Koeffler HP, Kim BK, Lee YY. Cell cycle arrest induced by the vitamin D(3) analog EB1089 in NCI-H929 myeloma cells is associated with induction of the cyclin-dependent kinase inhibitor p27. Exp Cell Res. 2000;254(2):279–86. doi:10.1006/excr.1999.4735.

    Article  CAS  PubMed  Google Scholar 

  148. Liu M, Lee MH, Cohen M, Bommakanti M, Freedman LP. Transcriptional activation of the Cdk inhibitor p21 by vitamin D3 leads to the induced differentiation of the myelomonocytic cell line U937. Genes Dev. 1996;10(2):142–53.

    Article  CAS  PubMed  Google Scholar 

  149. Wolpin BM, Mayer RJ. Systemic treatment of colorectal cancer. Gastroenterology. 2008;134(5):1296–310. doi:10.1053/j.gastro.2008.02.098.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  150. Sobrero A, Guglielmi A, Grossi F, Puglisi F, Aschele C. Mechanism of action of fluoropyrimidines: relevance to the new developments in colorectal cancer chemotherapy. Semin Oncol. 2000;27(5 Suppl 10):72–7.

    CAS  PubMed  Google Scholar 

  151. Refaat B, El-Shemi AG, Kensara OA, Mohamed AM, Idris S, Ahmad J, Khojah A. Vitamin D3 enhances the tumouricidal effects of 5-Fluorouracil through multipathway mechanisms in azoxymethane rat model of colon cancer. J Exp Clin Cancer Res. 2015. doi:10.1186/s13046-015-0187-9

  152. Milczarek M, Filip-Psurska B, Swietnicki W, Kutner A, Wietrzyk J. Vitamin D analogs combined with 5-fluorouracil in human HT-29 colon cancer treatment. Oncol Rep. 2014;32(2):491–504. doi:10.3892/or.2014.3247.

    Article  PubMed  PubMed Central  Google Scholar 

  153. Milczarek M, Psurski M, Kutner A, Wietrzyk J. Vitamin D analogs enhance the anticancer activity of 5-fluorouracil in an in vivo mouse colon cancer model. BMC Cancer. 2013;13:294. doi:10.1186/1471-2407-13-294.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  154. Liu G, Hu X, Chakrabarty S. Vitamin D mediates its action in human colon carcinoma cells in a calcium-sensing receptor-dependent manner: downregulates malignant cell behavior and the expression of thymidylate synthase and survivin and promotes cellular sensitivity to 5-FU. Int J Cancer. 2010;126(3):631–9. doi:10.1002/ijc.24762.

    Article  CAS  PubMed  Google Scholar 

  155. Li C, Xu N, Li YQ, Wang Y, Zhu ZT. Inhibition of SW620 human colon cancer cells by upregulating miRNA-145. World J Gastroenterol. 2016;22(9):2771–8. doi:10.3748/wjg.v22.i9.2771.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  156. Yin Y, Song MX, Gu B, Qi XW, Hu YL, Feng YY, Liu HY, Zhou LY, Bian ZH, Zhang JW, Zuo XB, Huang ZH. Systematic analysis of key miRNAs and related signaling pathways in colorectal tumorigenesis. Gene. 2016;578(2):177–84. doi:10.1016/j.gene.2015.12.015.

    Article  CAS  PubMed  Google Scholar 

  157. Pellatt DF, Stevens JR, Wolff RK, Mullany LE, Herrick JS, Samowitz W, Slattery ML. Expression profiles of miRNA subsets distinguish human colorectal carcinoma and normal colonic mucosa. Clin Transl Gastroenterol. 2016;. doi:10.1038/ctg.2016.11.

    PubMed  PubMed Central  Google Scholar 

  158. Chang SE, Gao L, Yang Y, Tong DD, Guo B, Liu LY, Li ZF, Song TS, Huang C. miR-145 mediates the antiproliferative and gene regulatory effects of vitamin D3 by directly targeting E2F3 in gastric cancer cells. Oncotarget. 2015;6(10):7675–85.

    PubMed  PubMed Central  Google Scholar 

  159. Thiery JP. Epithelial-mesenchymal transitions in tumour progression. Nat Rev Cancer. 2002;2(6):442–54. doi:10.1038/nrc822.

    Article  CAS  PubMed  Google Scholar 

  160. Onder TT, Gupta PB, Mani SA, Yang J, Lander ES, Weinberg RA. Loss of E-cadherin promotes metastasis via multiple downstream transcriptional pathways. Cancer Res. 2008;68(10):3645–54. doi:10.1158/0008-5472.can-07-2938.

    Article  CAS  PubMed  Google Scholar 

  161. Larriba MJ, de Herreros AG, Munoz A. Vitamin D and the epithelial to mesenchymal transition. Stem Cells Int. 2016. doi:10.1155/2016/6213872

  162. Singh M, Spoelstra NS, Jean A, Howe E, Torkko KC, Clark HR, Darling DS, Shroyer KR, Horwitz KB, Broaddus RR, Richer JK. ZEB1 expression in type I vs type II endometrial cancers: a marker of aggressive disease. Mod Pathol. 2008;21(7):912–23. doi:10.1038/modpathol.2008.82.

    Article  CAS  PubMed  Google Scholar 

  163. Wong NA, Pignatelli M. Beta-catenin—a linchpin in colorectal carcinogenesis? Am J Pathol. 2002;160(2):389–401.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  164. Bandapalli OR, Dihlmann S, Helwa R, Macher-Goeppinger S, Weitz J, Schirmacher P, Brand K. Transcriptional activation of the beta-catenin gene at the invasion front of colorectal liver metastases. J Pathol. 2009;218(3):370–9. doi:10.1002/path.2539.

    Article  CAS  PubMed  Google Scholar 

  165. Xu H, McCann M, Zhang Z, Posner GH, Bingham V, El-Tanani M, Campbell FC. Vitamin D receptor modulates the neoplastic phenotype through antagonistic growth regulatory signals. Mol Carcinog. 2009;48(8):758–72. doi:10.1002/mc.20520.

    Article  CAS  PubMed  Google Scholar 

  166. Pereira F, Barbachano A, Singh PK, Campbell MJ, Munoz A, Larriba MJ. Vitamin D has wide regulatory effects on histone demethylase genes. Cell Cycle. 2012;11(6):1081–9. doi:10.4161/cc.11.6.19508.

    Article  CAS  PubMed  Google Scholar 

  167. Yook JI, Li XY, Ota I, Fearon ER, Weiss SJ. Wnt-dependent regulation of the E-cadherin repressor snail. J Biol Chem. 2005;280(12):11740–8. doi:10.1074/jbc.M413878200.

    Article  CAS  PubMed  Google Scholar 

  168. De Craene B, Gilbert B, Stove C, Bruyneel E, van Roy F, Berx G. The transcription factor snail induces tumor cell invasion through modulation of the epithelial cell differentiation program. Cancer Res. 2005;65(14):6237–44. doi:10.1158/0008-5472.can-04-3545.

    Article  PubMed  Google Scholar 

  169. Peinado H, Olmeda D, Cano A. Snail, Zeb and bHLH factors in tumour progression: an alliance against the epithelial phenotype? Nat Rev Cancer. 2007;7(6):415–28. doi:10.1038/nrc2131.

    Article  CAS  PubMed  Google Scholar 

  170. Palmer HG, Larriba MJ, Garcia JM, Ordonez-Moran P, Pena C, Peiro S, Puig I, Rodriguez R, de la Fuente R, Bernad A, Pollan M, Bonilla F, Gamallo C, de Herreros AG, Munoz A. The transcription factor SNAIL represses vitamin D receptor expression and responsiveness in human colon cancer. Nat Med. 2004;10(9):917–9. doi:10.1038/nm1095.

    Article  CAS  PubMed  Google Scholar 

  171. Pena C, Garcia JM, Silva J, Garcia V, Rodriguez R, Alonso I, Millan I, Salas C, de Herreros AG, Munoz A, Bonilla F. E-cadherin and vitamin D receptor regulation by SNAIL and ZEB1 in colon cancer: clinicopathological correlations. Hum Mol Genet. 2005;14(22):3361–70. doi:10.1093/hmg/ddi366.

    Article  CAS  PubMed  Google Scholar 

  172. Larriba MJ, Valle N, Palmer HG, Ordonez-Moran P, Alvarez-Diaz S, Becker KF, Gamallo C, de Herreros AG, Gonzalez-Sancho JM, Munoz A. The inhibition of Wnt/beta-catenin signalling by 1alpha,25-dihydroxyvitamin D3 is abrogated by Snail1 in human colon cancer cells. Endocr Relat Cancer. 2007;14(1):141–51. doi:10.1677/erc-06-0028.

    Article  CAS  PubMed  Google Scholar 

  173. Rosivatz E, Becker KF, Kremmer E, Schott C, Blechschmidt K, Hofler H, Sarbia M. Expression and nuclear localization of Snail, an E-cadherin repressor, in adenocarcinomas of the upper gastrointestinal tract. Virchows Arch. 2006;448(3):277–87. doi:10.1007/s00428-005-0118-9.

    Article  CAS  PubMed  Google Scholar 

  174. Franci C, Gallen M, Alameda F, Baro T, Iglesias M, Virtanen I, Garcia de Herreros A. Snail1 protein in the stroma as a new putative prognosis marker for colon tumours. PLoS One. 2009;4(5):e5595. doi:10.1371/journal.pone.0005595.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  175. Ye Y, Xiao Y, Wang W, Yearsley K, Gao JX, Shetuni B, Barsky SH. ERalpha signaling through slug regulates E-cadherin and EMT. Oncogene. 2010;29(10):1451–62. doi:10.1038/onc.2009.433.

    Article  CAS  PubMed  Google Scholar 

  176. Barrallo-Gimeno A, Nieto MA. The Snail genes as inducers of cell movement and survival: implications in development and cancer. Development. 2005;132(14):3151–61. doi:10.1242/dev.01907.

    Article  CAS  PubMed  Google Scholar 

  177. Zucker S, Vacirca J. Role of matrix metalloproteinases (MMPs) in colorectal cancer. Cancer Metastasis Rev. 2004;23(1–2):101–17.

    Article  CAS  PubMed  Google Scholar 

  178. Schwartz GG, Wang MH, Zang M, Singh RK, Siegal GP. 1 alpha,25-Dihydroxyvitamin D (calcitriol) inhibits the invasiveness of human prostate cancer cells. Cancer Epidemiol Biomark Prev. 1997;6(9):727–32.

    CAS  Google Scholar 

  179. Koli K, Keski-Oja J. 1alpha,25-dihydroxyvitamin D3 and its analogues down-regulate cell invasion-associated proteases in cultured malignant cells. Cell Growth Differ. 2000;11(4):221–9.

    CAS  PubMed  Google Scholar 

  180. Bao BY, Yeh SD, Lee YF. 1alpha,25-dihydroxyvitamin D3 inhibits prostate cancer cell invasion via modulation of selective proteases. Carcinogenesis. 2006;27(1):32–42. doi:10.1093/carcin/bgi170.

    Article  CAS  PubMed  Google Scholar 

  181. Bodenstine TM, Welch DR. Metastasis suppressors and the tumor microenvironment. Cancer Microenviron. 2008;1(1):1–11. doi:10.1007/s12307-008-0001-8.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  182. Hewison M, Zehnder D, Chakraverty R, Adams JS. Vitamin D and barrier function: a novel role for extra-renal 1 alpha-hydroxylase. Mol Cell Endocrinol. 2004;215(1–2):31–8. doi:10.1016/j.mce.2003.11.017.

    Article  CAS  PubMed  Google Scholar 

  183. Claffey KP, Brown LF, del Aguila LF, Tognazzi K, Yeo KT, Manseau EJ, Dvorak HF. Expression of vascular permeability factor/vascular endothelial growth factor by melanoma cells increases tumor growth, angiogenesis, and experimental metastasis. Cancer Res. 1996;56(1):172–81.

    CAS  PubMed  Google Scholar 

  184. Esser S, Lampugnani MG, Corada M, Dejana E, Risau W. Vascular endothelial growth factor induces VE-cadherin tyrosine phosphorylation in endothelial cells. J Cell Sci. 1998;111(Pt 13):1853–65.

    CAS  PubMed  Google Scholar 

  185. Kevil CG, Payne DK, Mire E, Alexander JS. Vascular permeability factor/vascular endothelial cell growth factor-mediated permeability occurs through disorganization of endothelial junctional proteins. J Biol Chem. 1998;273(24):15099–103.

    Article  CAS  PubMed  Google Scholar 

  186. Iseki K, Tatsuta M, Uehara H, Iishi H, Yano H, Sakai N, Ishiguro S. Inhibition of angiogenesis as a mechanism for inhibition by 1alpha-hydroxyvitamin D3 and 1,25-dihydroxyvitamin D3 of colon carcinogenesis induced by azoxymethane in Wistar rats. Int J Cancer. 1999;81(5):730–3.

    Article  CAS  PubMed  Google Scholar 

  187. Lee TH, Avraham HK, Jiang S, Avraham S. Vascular endothelial growth factor modulates the transendothelial migration of MDA-MB-231 breast cancer cells through regulation of brain microvascular endothelial cell permeability. J Biol Chem. 2003;278(7):5277–84. doi:10.1074/jbc.M210063200.

    Article  CAS  PubMed  Google Scholar 

  188. Weis SM, Cheresh DA. Pathophysiological consequences of VEGF-induced vascular permeability. Nature. 2005;437(7058):497–504. doi:10.1038/nature03987.

    Article  CAS  PubMed  Google Scholar 

  189. Senger DR, Galli SJ, Dvorak AM, Perruzzi CA, Harvey VS, Dvorak HF. Tumor cells secrete a vascular permeability factor that promotes accumulation of ascites fluid. Science. 1983;219(4587):983–5.

    Article  CAS  PubMed  Google Scholar 

  190. Lam SY, Tipoe GL, Liong EC, Fung ML. Differential expressions and roles of hypoxia-inducible factor-1alpha, -2alpha and -3alpha in the rat carotid body during chronic and intermittent hypoxia. Histol Histopathol. 2008;23(3):271–80.

    CAS  PubMed  Google Scholar 

  191. Fakih MG. Metastatic colorectal cancer: current state and future directions. J Clin Oncol. 2015;33(16):1809–24. doi:10.1200/jco.2014.59.7633.

    Article  CAS  PubMed  Google Scholar 

  192. Sullivan R, Graham CH. Hypoxia-driven selection of the metastatic phenotype. Cancer Metastasis Rev. 2007;26(2):319–31. doi:10.1007/s10555-007-9062-2.

    Article  CAS  PubMed  Google Scholar 

  193. Jung YJ, Isaacs JS, Lee SM, Trepel J, Liu ZG, Neckers L. Hypoxia-inducible factor induction by tumour necrosis factor in normoxic cells requires receptor-interacting protein-dependent nuclear factor kappa B activation. Biochem J. 2003;370:1011–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  194. Ehrlich P. Über den jetzigen stand der karzinomforschung. Ned Tijdschr Geneeskd. 1909;5:273–90.

    Google Scholar 

  195. Smyth MJ, Thia KY, Street SE, Cretney E, Trapani JA, Taniguchi M, Kawano T, Pelikan SB, Crowe NY, Godfrey DI. Differential tumor surveillance by natural killer (NK) and NKT cells. J Exp Med. 2000;191(4):661–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  196. Kim R, Emi M, Tanabe K. Cancer immunoediting from immune surveillance to immune escape. Immunology. 2007;121(1):1–14. doi:10.1111/j.1365-2567.2007.02587.x.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  197. Swann JB, Smyth MJ. Immune surveillance of tumors. J Clin Invest. 2007;117(5):1137–46. doi:10.1172/jci31405.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  198. Waldhauer I, Steinle A. NK cells and cancer immunosurveillance. Oncogene. 2008;27(45):5932–43. doi:10.1038/onc.2008.267.

    Article  CAS  PubMed  Google Scholar 

  199. Cullen SP, Martin SJ. Mechanisms of granule-dependent killing. Cell Death Differ. 2008;15(2):251–62. doi:10.1038/sj.cdd.4402244.

    Article  CAS  PubMed  Google Scholar 

  200. Shi L, Kraut RP, Aebersold R, Greenberg AH. A natural killer cell granule protein that induces DNA fragmentation and apoptosis. J Exp Med. 1992;175(2):553–66.

    Article  CAS  PubMed  Google Scholar 

  201. Mareel M, Oliveira MJ, Madani I. Cancer invasion and metastasis: interacting ecosystems. Virchows Arch. 2009;454(6):599–622. doi:10.1007/s00428-009-0784-0.

    Article  CAS  PubMed  Google Scholar 

  202. Edfeldt K, Liu PT, Chun R, Fabri M, Schenk M, Wheelwright M, Keegan C, Krutzik SR, Adams JS, Hewison M, Modlin RL. T-cell cytokines differentially control human monocyte antimicrobial responses by regulating vitamin D metabolism. Proc Natl Acad Sci USA. 2010;107(52):22593–8. doi:10.1073/pnas.1011624108.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  203. Song M, Nishihara R, Wang M, Chan AT, Qian ZR, Inamura K, Zhang X, Ng K, Kim SA, Mima K, Sukawa Y, Nosho K, Fuchs CS, Giovannucci EL, Wu K, Ogino S. Plasma 25-hydroxyvitamin D and colorectal cancer risk according to tumour immunity status. Gut. 2016;65(2):296–304. doi:10.1136/gutjnl-2014-308852.

    Article  CAS  PubMed  Google Scholar 

  204. Basse PH, Whiteside TL, Chambers W, Herberman RB. Therapeutic activity of NK cells against tumors. Int Rev Immunol. 2001;20(3–4):439–501. doi:10.3109/08830180109054416.

    Article  CAS  PubMed  Google Scholar 

  205. Brodt P, Fallavollita L, Bresalier RS, Meterissian S, Norton CR, Wolitzky BA. Liver endothelial E-selectin mediates carcinoma cell adhesion and promotes liver metastasis. Int J Cancer. 1997;71(4):612–9.

    Article  CAS  PubMed  Google Scholar 

  206. Takada A, Ohmori K, Yoneda T, Tsuyuoka K, Hasegawa A, Kiso M, Kannagi R. Contribution of carbohydrate antigens sialyl Lewis A and sialyl Lewis X to adhesion of human cancer cells to vascular endothelium. Cancer Res. 1993;53(2):354–61.

    CAS  PubMed  Google Scholar 

  207. Tozeren A, Kleinman HK, Grant DS, Morales D, Mercurio AM, Byers SW. E-selectin-mediated dynamic interactions of breast- and colon-cancer cells with endothelial-cell monolayers. Int J Cancer. 1995;60(3):426–31.

    Article  CAS  PubMed  Google Scholar 

  208. Witz IP. The selectin–selectin ligand axis in tumor progression. Cancer Metastasis Rev. 2008;27(1):19–30. doi:10.1007/s10555-007-9101-z.

    Article  CAS  PubMed  Google Scholar 

  209. Kaplanski G, Farnarier C, Benoliel AM, Foa C, Kaplanski S, Bongrand P. A novel role for E- and P-selectins: shape control of endothelial cell monolayers. J Cell Sci. 1994;107(Pt 9):2449–57.

    CAS  PubMed  Google Scholar 

  210. Laferriere J, Houle F, Huot J. Adhesion of HT-29 colon carcinoma cells to endothelial cells requires sequential events involving E-selectin and integrin beta4. Clin Exp Metastasis. 2004;21(3):257–64.

    Article  CAS  PubMed  Google Scholar 

  211. Kobayashi H, Boelte KC, Lin PC. Endothelial cell adhesion molecules and cancer progression. Curr Med Chem. 2007;14(4):377–86.

    Article  CAS  PubMed  Google Scholar 

  212. Borsig L, Wong R, Feramisco J, Nadeau DR, Varki NM, Varki A. Heparin and cancer revisited: mechanistic connections involving platelets, P-selectin, carcinoma mucins, and tumor metastasis. Proc Natl Acad Sci USA. 2001;98(6):3352–7. doi:10.1073/pnas.061615598.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  213. Locker GY, Hamilton S, Harris J, Jessup JM, Kemeny N, Macdonald JS, Somerfield MR, Hayes DF, Bast RC Jr. ASCO 2006 update of recommendations for the use of tumor markers in gastrointestinal cancer. J Clin Oncol. 2006;24(33):5313–27. doi:10.1200/jco.2006.08.2644.

    Article  CAS  PubMed  Google Scholar 

  214. Duffy MJ, van Dalen A, Haglund C, Hansson L, Holinski-Feder E, Klapdor R, Lamerz R, Peltomaki P, Sturgeon C, Topolcan O. Tumour markers in colorectal cancer: European Group on Tumour Markers (EGTM) guidelines for clinical use. Eur J Cancer. 2007;43(9):1348–60. doi:10.1016/j.ejca.2007.03.021.

    Article  CAS  PubMed  Google Scholar 

  215. Thomas SN, Zhu F, Schnaar RL, Alves CS, Konstantopoulos K. Carcinoembryonic antigen and CD44 variant isoforms cooperate to mediate colon carcinoma cell adhesion to E- and L-selectin in shear flow. J Biol Chem. 2008;283(23):15647–55. doi:10.1074/jbc.M800543200.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  216. Paschos KA, Canovas D, Bird NC. The engagement of selectins and their ligands in colorectal cancer liver metastases. J Cell Mol Med. 2010;14(1–2):165–74. doi:10.1111/j.1582-4934.2009.00852.x.

    Article  CAS  PubMed  Google Scholar 

  217. Bajenova O, Chaika N, Tolkunova E, Davydov-Sinitsyn A, Gapon S, Thomas P, O’Brien S. Carcinoembryonic antigen promotes colorectal cancer progression by targeting adherens junction complexes. Exp Cell Res. 2014;324(2):115–23. doi:10.1016/j.yexcr.2014.04.007.

    Article  CAS  PubMed  Google Scholar 

  218. Gangopadhyay A, Bajenova O, Kelly TM, Thomas P. Carcinoembryonic antigen induces cytokine expression in Kuppfer cells: implications for hepatic metastasis from colorectal cancer. Cancer Res. 1996;56(20):4805–10.

    CAS  PubMed  Google Scholar 

  219. Gangopadhyay A, Lazure DA, Thomas P. Carcinoembryonic antigen induces signal transduction in Kupffer cells. Cancer Lett. 1997;118(1):1–6.

    Article  CAS  PubMed  Google Scholar 

  220. Gangopadhyay A, Lazure DA, Thomas P. Adhesion of colorectal carcinoma cells to the endothelium is mediated by cytokines from CEA stimulated Kupffer cells. Clin Exp Metastasis. 1998;16(8):703–12.

    Article  CAS  PubMed  Google Scholar 

  221. Minami S, Furui J, Kanematsu T. Role of carcinoembryonic antigen in the progression of colon cancer cells that express carbohydrate antigen. Cancer Res. 2001;61(6):2732–5.

    CAS  PubMed  Google Scholar 

  222. Aarons CB, Bajenova O, Andrews C, Heydrick S, Bushell KN, Reed KL, Thomas P, Becker JM, Stucchi AF. Carcinoembryonic antigen-stimulated THP-1 macrophages activate endothelial cells and increase cell-cell adhesion of colorectal cancer cells. Clin Exp Metastasis. 2007;24(3):201–9. doi:10.1007/s10585-007-9069-7.

    Article  PubMed  Google Scholar 

  223. Vestweber D, Blanks JE. Mechanisms that regulate the function of the selectins and their ligands. Physiol Rev. 1999;79(1):181–213.

    Article  CAS  PubMed  Google Scholar 

  224. Equils O, Naiki Y, Shapiro AM, Michelsen K, Lu D, Adams J, Jordan S. 1,25-Dihydroxyvitamin D inhibits lipopolysaccharide-induced immune activation in human endothelial cells. Clin Exp Immunol. 2006;143(1):58–64. doi:10.1111/j.1365-2249.2005.02961.x.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  225. Mathiasen IS, Hansen CM, Foghsgaard L, Jaattela M. Sensitization to TNF-induced apoptosis by 1,25-dihydroxy vitamin D(3) involves up-regulation of the TNF receptor 1 and cathepsin B. Int J Cancer. 2001;93(2):224–31. doi:10.1002/ijc.1325.

    Article  CAS  PubMed  Google Scholar 

  226. Wisse E. An electron microscopic study of the fenestrated endothelial lining of rat liver sinusoids. J Ultrastruct Res. 1970;31(1):125–50.

    Article  CAS  PubMed  Google Scholar 

  227. Yokomori H. New insights into the dynamics of sinusoidal endothelial fenestrae in liver sinusoidal endothelial cells. Med Mol Morphol. 2008;41(1):1–4. doi:10.1007/s00795-007-0390-7.

    Article  PubMed  Google Scholar 

  228. Wisse E, Jacobs F, Topal B, Frederik P, De Geest B. The size of endothelial fenestrae in human liver sinusoids: implications for hepatocyte-directed gene transfer. Gene Ther. 2008;15(17):1193–9. doi:10.1038/gt.2008.60.

    Article  CAS  PubMed  Google Scholar 

  229. Smedsrod B, Le Couteur D, Ikejima K, Jaeschke H, Kawada N, Naito M, Knolle P, Nagy L, Senoo H, Vidal-Vanaclocha F, Yamaguchi N. Hepatic sinusoidal cells in health and disease: update from the 14th International Symposium. Liver Int. 2009;29(4):490–501. doi:10.1111/j.1478-3231.2009.01979.x.

    Article  PubMed  CAS  Google Scholar 

  230. Schluter K, Gassmann P, Enns A, Korb T, Hemping-Bovenkerk A, Holzen J, Haier J. Organ-specific metastatic tumor cell adhesion and extravasation of colon carcinoma cells with different metastatic potential. Am J Pathol. 2006;169(3):1064–73. doi:10.2353/ajpath.2006.050566.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  231. Braet F, Wisse E. Structural and functional aspects of liver sinusoidal endothelial cell fenestrae: a review. Comp Hepatol. 2002;1(1):1.

    Article  PubMed  PubMed Central  Google Scholar 

  232. Warren A, Le Couteur DG, Fraser R, Bowen DG, McCaughan GW, Bertolino P. T lymphocytes interact with hepatocytes through fenestrations in murine liver sinusoidal endothelial cells. Hepatology. 2006;44(5):1182–90. doi:10.1002/hep.21378.

    Article  CAS  PubMed  Google Scholar 

  233. Carpenter B, Lin Y, Stoll S, Raffai RL, McCuskey R, Wang R. VEGF is crucial for the hepatic vascular development required for lipoprotein uptake. Development. 2005;132(14):3293–303. doi:10.1242/dev.01902.

    Article  CAS  PubMed  Google Scholar 

  234. Al-Mehdi AB, Tozawa K, Fisher AB, Shientag L, Lee A, Muschel RJ. Intravascular origin of metastasis from the proliferation of endothelium-attached tumor cells: a new model for metastasis. Nat Med. 2000;6(1):100–2. doi:10.1038/71429.

    Article  CAS  PubMed  Google Scholar 

  235. Brand S, Dambacher J, Beigel F, Olszak T, Diebold J, Otte JM, Goke B, Eichhorst ST. CXCR4 and CXCL12 are inversely expressed in colorectal cancer cells and modulate cancer cell migration, invasion and MMP-9 activation. Exp Cell Res. 2005;310(1):117–30. doi:10.1016/j.yexcr.2005.07.006.

    Article  CAS  PubMed  Google Scholar 

  236. Kim J, Mori T, Chen SL, Amersi FF, Martinez SR, Kuo C, Turner RR, Ye X, Bilchik AJ, Morton DL, Hoon DS. Chemokine receptor CXCR4 expression in patients with melanoma and colorectal cancer liver metastases and the association with disease outcome. Ann Surg. 2006;244(1):113–20. doi:10.1097/01.sla.0000217690.65909.9c.

    Article  PubMed  PubMed Central  Google Scholar 

  237. Rubie C, Kollmar O, Frick VO, Wagner M, Brittner B, Graber S, Schilling MK. Differential CXC receptor expression in colorectal carcinomas. Scand J Immunol. 2008;68(6):635–44. doi:10.1111/j.1365-3083.2008.02163.x.

    CAS  PubMed  Google Scholar 

  238. Dwinell MB, Eckmann L, Leopard JD, Varki NM, Kagnoff MF. Chemokine receptor expression by human intestinal epithelial cells. Gastroenterology. 1999;117(2):359–67.

    Article  CAS  PubMed  Google Scholar 

  239. Jordan NJ, Kolios G, Abbot SE, Sinai MA, Thompson DA, Petraki K, Westwick J. Expression of functional CXCR4 chemokine receptors on human colonic epithelial cells. J Clin Invest. 1999;104(8):1061–9. doi:10.1172/jci6685.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  240. Smith JM, Johanesen PA, Wendt MK, Binion DG, Dwinell MB. CXCL12 activation of CXCR4 regulates mucosal host defense through stimulation of epithelial cell migration and promotion of intestinal barrier integrity. Am J Physiol Gastrointest Liver Physiol. 2005;288(2):G316–26. doi:10.1152/ajpgi.00208.2004.

    Article  CAS  PubMed  Google Scholar 

  241. Schimanski CC, Schwald S, Simiantonaki N, Jayasinghe C, Gonner U, Wilsberg V, Junginger T, Berger MR, Galle PR, Moehler M. Effect of chemokine receptors CXCR4 and CCR7 on the metastatic behavior of human colorectal cancer. Clin Cancer Res. 2005;11(5):1743–50. doi:10.1158/1078-0432.ccr-04-1195.

    Article  CAS  PubMed  Google Scholar 

  242. Shibuta K, Mori M, Shimoda K, Inoue H, Mitra P, Barnard GF. Regional expression of CXCL12/CXCR4 in liver and hepatocellular carcinoma and cell-cycle variation during in vitro differentiation. Jpn J Cancer Res. 2002;93(7):789–97.

    Article  CAS  PubMed  Google Scholar 

  243. Wendt MK, Drury LJ, Vongsa RA, Dwinell MB. Constitutive CXCL12 expression induces anoikis in colorectal carcinoma cells. Gastroenterology. 2008;135(2):508–17. doi:10.1053/j.gastro.2008.05.033.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  244. Matsusue R, Kubo H, Hisamori S, Okoshi K, Takagi H, Hida K, Nakano K, Itami A, Kawada K, Nagayama S, Sakai Y. Hepatic stellate cells promote liver metastasis of colon cancer cells by the action of SDF-1/CXCR4 axis. Ann Surg Oncol. 2009;16(9):2645–53. doi:10.1245/s10434-009-0599-x.

    Article  PubMed  Google Scholar 

  245. Hong F, Tuyama A, Lee TF, Loke J, Agarwal R, Cheng X, Garg A, Fiel MI, Schwartz M, Walewski J, Branch A, Schecter AD, Bansal MB. Hepatic stellate cells express functional CXCR4: role in stromal cell-derived factor-1alpha-mediated stellate cell activation. Hepatology. 2009;49(6):2055–67. doi:10.1002/hep.22890.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  246. Zeelenberg IS, Ruuls-Van Stalle L, Roos E. The chemokine receptor CXCR4 is required for outgrowth of colon carcinoma micrometastases. Cancer Res. 2003;63(13):3833–9.

    CAS  PubMed  Google Scholar 

  247. Schioppa T, Uranchimeg B, Saccani A, Biswas SK, Doni A, Rapisarda A, Bernasconi S, Saccani S, Nebuloni M, Vago L, Mantovani A, Melillo G, Sica A. Regulation of the chemokine receptor CXCR4 by hypoxia. J Exp Med. 2003;198(9):1391–402. doi:10.1084/jem.20030267.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  248. Gascon-Barre M, Demers C, Mirshahi A, Neron S, Zalzal S, Nanci A. The normal liver harbors the vitamin D nuclear receptor in nonparenchymal and biliary epithelial cells. Hepatology. 2003;37(5):1034–42. doi:10.1053/jhep.2003.50176.

    Article  CAS  PubMed  Google Scholar 

  249. Peeters CF, de Geus LF, Westphal JR, de Waal RM, Ruiter DJ, Wobbes T, Oyen WJ, Ruers TJ. Decrease in circulating anti-angiogenic factors (angiostatin and endostatin) after surgical removal of primary colorectal carcinoma coincides with increased metabolic activity of liver metastases. Surgery. 2005;137(2):246–9. doi:10.1016/j.surg.2004.06.004.

    Article  PubMed  Google Scholar 

  250. Scheer MG, Stollman TH, Vogel WV, Boerman OC, Oyen WJ, Ruers TJ. Increased metabolic activity of indolent liver metastases after resection of a primary colorectal tumor. J Nucl Med. 2008;49(6):887–91. doi:10.2967/jnumed.107.048371.

    Article  PubMed  Google Scholar 

  251. Peeters CF, de Waal RM, Wobbes T, Ruers TJ. Metastatic dormancy imposed by the primary tumor: does it exist in humans? Ann Surg Oncol. 2008;15(11):3308–15. doi:10.1245/s10434-008-0029-5.

    Article  PubMed  Google Scholar 

  252. van der Bij GJ, Oosterling SJ, Beelen RH, Meijer S, Coffey JC, van Egmond M. The perioperative period is an underutilized window of therapeutic opportunity in patients with colorectal cancer. Ann Surg. 2009;249(5):727–34. doi:10.1097/SLA.0b013e3181a3ddbd.

    Article  PubMed  Google Scholar 

  253. Finlay IG, Meek D, Brunton F, McArdle CS. Growth rate of hepatic metastases in colorectal carcinoma. Br J Surg. 1988;75(7):641–4.

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to N. T. Brockton.

Ethics declarations

Funding

This work was supported by funding from the Alberta Cancer Foundation (#25053).

Conflict of interest

The authors declare that they have no conflict of interest.

Ethics

This article does not contain any studies with human participants or animals performed by any of the authors.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Shaw, E., Massaro, N. & Brockton, N.T. The role of vitamin D in hepatic metastases from colorectal cancer. Clin Transl Oncol 20, 259–273 (2018). https://doi.org/10.1007/s12094-017-1735-x

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12094-017-1735-x

Keywords

Navigation