Annals of Surgical Oncology

, Volume 15, Issue 11, pp 3308–3315 | Cite as

Metastatic Dormancy Imposed by the Primary Tumor: Does it Exist in Humans?

  • Charlotte F. J. M. PeetersEmail author
  • Robert M. W. de Waal
  • Theo Wobbes
  • Theo J. M. Ruers
Laboratory Research



In cancer patients, occult micrometastases may become apparent shortly after removal of the primary tumor. Animal experiments have shown that metastatic dormancy is maintained by apoptosis, and that primary tumor removal induces a flare-up of angiogenesis, leading to metastatic outgrowth. This phenomenon has led to the hypothesis that the primary tumor generates certain factors that inhibit angiogenesis at distant sites. It is still unknown whether such a phenomenon is operative in human cancer as well. Should it occur, it might have important therapeutic consequences.

Materials and Methods

Evidence for such a mechanism may be obtained from studies that analyze a series of tissue samples of metastases, taken before or after surgical removal of the primary lesion.


Data from our laboratory on colorectal cancer have shown that, in the absence of the primary tumor, vascular density in the metastases is increased as well as their metabolic activity, as measured by 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET). Mitotic activity is increased mildly, while levels of apoptosis are collapsed.


These data indicate that a mechanism of primary-tumor-induced inhibition of angiogenesis exists, maintaining metastatic dormancy. We now suggest that this mechanism may be exploited to avoid the use of exogenous, potentially harmful angiogenesis inhibitors such as bevacizumab in a neoadjuvant setting. Treatment of patients with the primary tumor still in situ could thus be restricted to chemotherapy, since the synergistic effect of an angiogenesis inhibitor would be generated by the primary tumor itself. In the present paper the clinical relevance and possible consequences of our findings and suggestions are discussed.


Angiogenesis Colorectal cancer Liver metastases 


  1. 1.
    Sugarbaker E, Thornthwaite J, Ketcham A. Inhibitory effect of a primary tumor on metastasis. In: Day SB, Myers WPL, Stansly P, Garattini S, Lewis MG (eds) Progress in Cancer Research and Therapy. New York: Raven 1977; 227–40.Google Scholar
  2. 2.
    Simpson-Herren L, Sanford AH, Holmquist JP. Effects of surgery on the cell kinetics of residual tumor. Cancer Treat Rep 1976; 60:1749–60.PubMedGoogle Scholar
  3. 3.
    Fisher B, Gunduz N, Saffer EA. Influence of the interval between primary tumor removal and chemotherapy on kinetics and growth of metastases. Cancer Res 1983; 43:1488–92.PubMedGoogle Scholar
  4. 4.
    Carmeliet P, Jain RK. Angiogenesis in cancer and other diseases. Nature 2000; 407:249–57.PubMedCrossRefGoogle Scholar
  5. 5.
    Ronan SG, Eng AM, Briele HA et al. Thin malignant melanomas with regression and metastases. Arch Dermatol 1987; 123:1326–30.PubMedCrossRefGoogle Scholar
  6. 6.
    Schirrmacher V. Cancer metastasis: experimental approaches, theoretical concepts, and impacts for treatment strategies. Adv Cancer Res 1985; 43:1–73.PubMedCrossRefGoogle Scholar
  7. 7.
    Saldbury AJ, McKinna JA, Griffiths JD et al. Circulating cancer cells during excision of carcinomas of the rectum and colon with high ligation of the inferior mesenteric vein. Surg Gynecol Obstet 1965; 120:1266–70.Google Scholar
  8. 8.
    Golinger RC, Gregorio RM, Fisher ER. Tumor cells in venous blood draining mammary carcinomas. Arch Surg 1977; 112:707–8.PubMedGoogle Scholar
  9. 9.
    Turnbull RB Jr. Current concepts in cancer. Cancer of the GI tract: colon, rectum, anus. The no-touch isolation technique of resection. JAMA 1975; 231:1181–2.PubMedCrossRefGoogle Scholar
  10. 10.
    Fisher B, Saffer EA, Fisher ER. Comparison of concomitant and sinecomitant tumor immunity. Proc Soc Exp Biol Med 1970; 135:68–71.PubMedGoogle Scholar
  11. 11.
    Bonfil RD, Ruggiero RA, Bustuoabad OD et al. Role of concomitant resistance in the development of murine lung metastases. Int J Cancer 1988; 41:415–22.PubMedCrossRefGoogle Scholar
  12. 12.
    Fidler IJ. Critical factors in the biology of human cancer metastasis: twenty-eighth G.H.A. Clowes memorial award lecture. Cancer Res 1990; 50:6130–8.PubMedGoogle Scholar
  13. 13.
    O’Reilly MS, Holmgren L, Shing Y et al. Angiostatin: a novel angiogenesis inhibitor that mediates the suppression of metastases by a Lewis lung carcinoma. Cell 1994; 79:315–28.PubMedCrossRefGoogle Scholar
  14. 14.
    O’Reilly MS, Holmgren L, Chen C et al. Angiostatin induces and sustains dormancy of human primary tumors in mice. Nat Med 1996; 2:689–92.PubMedCrossRefGoogle Scholar
  15. 15.
    Folkman J. The role of angiogenesis in tumor growth. Semin Cancer Biol 1992; 3:65–71.PubMedGoogle Scholar
  16. 16.
    Fidler IJ, Ellis LM. The implications of angiogenesis for the biology and therapy of cancer metastasis. Cell 1994; 79:185–8.PubMedCrossRefGoogle Scholar
  17. 17.
    Ellis LM, Fidler IJ. Angiogenesis, metastasis. Eur J Cancer 1996; 32A:2451–60.PubMedCrossRefGoogle Scholar
  18. 18.
    Hanahan D, Folkman J. Patterns and emerging mechanisms of the angiogenic switch during tumorigenesis. Cell 1996; 86:353–64.PubMedCrossRefGoogle Scholar
  19. 19.
    Liotta LA, Steeg PS, Stetler-Stevenson WG. Cancer metastasis and angiogenesis: an imbalance of positive and negative regulation. Cell 1991; 64:327–36.PubMedCrossRefGoogle Scholar
  20. 20.
    O’Reilly MS, Boehm T, Shing Y et al. Endostatin: an endogenous inhibitor of angiogenesis and tumor growth. Cell 1997; 88:277–85.PubMedCrossRefGoogle Scholar
  21. 21.
    Camphausen K, Moses MA, Beecken WD et al. Radiation therapy to a primary tumor accelerates metastatic growth in mice. Cancer Res 2001; 61:2207–11.PubMedGoogle Scholar
  22. 22.
    Sckell A, Safabakhsh N, Dellian M et al. Primary tumor size-dependent inhibition of angiogenesis at a secondary site: an intravital microscopic study in mice. Cancer Res 1998; 58:5866–9.PubMedGoogle Scholar
  23. 23.
    Li TS, Kaneda Y, Ueda K et al. The influence of tumour resection on angiostatin levels and tumour growth–an experimental study in tumour-bearing mice. Eur J Cancer 2001; 37:2283–8.PubMedCrossRefGoogle Scholar
  24. 24.
    Guba M, Cernaianu G, Koehl G et al. A primary tumor promotes dormancy of solitary tumor cells before inhibiting angiogenesis. Cancer Res 2001; 61:5575–9.PubMedGoogle Scholar
  25. 25.
    Lange PH, Hekmat K, Bosl G et al. Acclerated growth of testicular cancer after cytoreductive surgery. Cancer 1980; 45:1498–506.PubMedCrossRefGoogle Scholar
  26. 26.
    Elhilali MM, Gleave M, Fradet Y et al. Placebo-associated remissions in a multicentre, randomized, double-blind trial of interferon gamma-1b for the treatment of metastatic renal cell carcinoma. The Canadian Urologic Oncology Group. BJU Int 2000; 86:613–8.PubMedCrossRefGoogle Scholar
  27. 27.
    Yuhas JM, Pazmino NH. Inhibition of subcutaneously growing line 1 carcinomas due to metastatic spread. Cancer Res 1974; 34:2005–10.PubMedGoogle Scholar
  28. 28.
    Igarashi H, Esumi M, Ishida H et al. Vascular endothelial growth factor overexpression is correlated with von Hippel–Lindau tumor suppressor gene inactivation in patients with sporadic renal cell carcinoma. Cancer 2002; 95:47–53.PubMedCrossRefGoogle Scholar
  29. 29.
    Holash J, Maisonpierre PC, Compton D et al. Vessel cooption, regression, and growth in tumors mediated by angiopoietins and VEGF. Science 1999; 284:1994–8.PubMedCrossRefGoogle Scholar
  30. 30.
    Leenders WP, Kusters B, de Waal RM. Vessel co-option: how tumors obtain blood supply in the absence of sprouting angiogenesis. Endothelium 2002; 9:83–7.PubMedCrossRefGoogle Scholar
  31. 31.
    Feldman AL, Alexander HR Jr, Bartlett DL et al. A prospective analysis of plasma endostatin levels in colorectal cancer patients with liver metastases. Ann Surg Oncol 2001; 8:741–5.PubMedCrossRefGoogle Scholar
  32. 32.
    Peeters CF, Westphal JR, de Waal RM et al. Vascular density in colorectal liver metastases increases after removal of the primary tumor in human cancer patients. Int J Cancer 2004; 112:554–9.PubMedCrossRefGoogle Scholar
  33. 33.
    Peeters CF, de Waal RM, Wobbes T, et al. Outgrowth of human liver metastases after resection of the primary colorectal tumor: a shift in the balance between apoptosis and proliferation. Int J Cancer 2006; 15:1249–53CrossRefGoogle Scholar
  34. 34.
    Peeters CF, de Waal RM, Wobbes T et al. Outgrowth of human liver metastases after resection of the primary colorectal tumor: a shift in the balance between apoptosis and proliferation. Int J Cancer 2006; 119:1249–53.PubMedCrossRefGoogle Scholar
  35. 35.
    Peeters CF, de Geus LF, Westphal JR et al. 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; 137:246–9.PubMedCrossRefGoogle Scholar
  36. 36.
    Stetler-Stevenson WG. The tumor microenvironment: regulation by MMP-independent effects of tissue inhibitor of metalloproteinases-2. Cancer Metastasis Rev 2008; 27:57–66.PubMedCrossRefGoogle Scholar
  37. 37.
    Glimelius B, Dahl O, Cedermark B et al. Adjuvant chemotherapy in colorectal cancer: a joint analysis of randomised trials by the Nordic Gastrointestinal Tumour Adjuvant Therapy Group. Acta Oncol 2005; 44:904–12.PubMedCrossRefGoogle Scholar
  38. 38.
    Chau I, Norman AR, Cunningham D et al. A randomised comparison between 6 months of bolus fluorouracil/leucovorin and 12 weeks of protracted venous infusion fluorouracil as adjuvant treatment in colorectal cancer. Ann Oncol 2005; 16:549–57.PubMedCrossRefGoogle Scholar
  39. 39.
    Folkman J. Role of angiogenesis in tumor growth and metastasis. Semin Oncol 2002; 29:15–8.PubMedGoogle Scholar
  40. 40.
    Maeshima Y, Sudhakar A, Lively JC et al. An endothelial cell-specific inhibitor of protein synthesis. Science 2002; 295:140–3.PubMedCrossRefGoogle Scholar
  41. 41.
    Siemeister G, Schirner M, Reusch P et al. An antagonistic vascular endothelial growth factor (VEGF) variant inhibits VEGF-stimulated receptor autophosphorylation and proliferation of human endothelial cells. Proc Natl Acad Sci USA 1998; 95:4625–9.PubMedCrossRefGoogle Scholar
  42. 42.
    Yoon SS, Eto H, Lin CM et al. Mouse endostatin inhibits the formation of lung and liver metastases. Cancer Res 1999; 59:6251–6.PubMedGoogle Scholar
  43. 43.
    Willett CG, Boucher Y, Di Tomaso E et al. Direct evidence that the VEGF-specific antibody bevacizumab has antivascular effects in human rectal cancer. Nat Med 2004; 10:145–7.PubMedCrossRefGoogle Scholar
  44. 44.
    Cunningham D, Humblet Y, Siena S et al. Cetuximab monotherapy and cetuximab plus irinotecan in irinotecan-refractory metastatic colorectal cancer. N Engl J Med 2004; 351:337–45.PubMedCrossRefGoogle Scholar
  45. 45.
    Willett CG, Boucher Y, Duda DG et al. Surrogate markers for antiangiogenic therapy and dose-limiting toxicities for bevacizumab with radiation and chemotherapy: continued experience of a phase I trial in rectal cancer patients. J Clin Oncol 2005; 23:8136–9.PubMedCrossRefGoogle Scholar
  46. 46.
    Hurwitz H, Fehrenbacher L, Novotny W et al. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med 2004; 350:2335–42.PubMedCrossRefGoogle Scholar
  47. 47.
    Hurwitz H, Kabbinavar F. Bevacizumab combined with standard fluoropyrimidine-based chemotherapy regimens to treat colorectal cancer. Oncology 2005; 69:17–24.PubMedCrossRefGoogle Scholar
  48. 48.
    te Velde EA, Voest EE, van Gorp JM et al. Adverse effects of the antiangiogenic agent angiostatin on the healing of experimental colonic anastomoses. Ann Surg Oncol 2002; 9:303–9.PubMedCrossRefGoogle Scholar
  49. 49.
    te Velde EA, Kusters B, Maass C et al. Histological analysis of defective colonic healing as a result of angiostatin treatment. Exp Mol Pathol 2003; 75:119–23.PubMedCrossRefGoogle Scholar
  50. 50.
    Gruenberger T. Tumor response to pre-operative chemotherapy (CT) with FOLFOX-4 for resectable colorectal cancer liver metastases (LM). Interim results of EORTC Intergroup randomized phase III study 40983. J Clin Oncol (abstr 3500) 24[18S]. 2006. Ref Type: AbstractGoogle Scholar
  51. 51.
    Nordlinger B. Final results of the EORTC Intergroup randomized phase III study 40983 [EPOC] evaluating the benefit of peri-operative FOLFOX4 chemotherapy for patients with potentially resectable colorectal cancer liver metastases. J Clin Oncol (abstr LBA5) 25[18S]. 2007. Ref Type: AbstractGoogle Scholar
  52. 52.
    Gruenberger. Effectiveness of neoadjuvant chemotherapy including bevacizumab in patients with resectable colorectal cancer liver metastases. J Clin Oncol (abstr 4060B) 25[ 18S]. 2007. Ref Type: AbstractGoogle Scholar
  53. 53.
    Malavasi N. Phase II trial to evaluate combination of folfox6 + bevacizumab in initially unresectable liver metastases from colorectal cancer (crc). J Clin Oncol (abstr 14603) 25[18S]. 2007. Ref Type: AbstractGoogle Scholar
  54. 54.
    Lowery MA. Hypertensison is a significant adverse effect of bevacizumab treatment. J Clin Oncol (abstr 14134) 25[18S]. 2007. Ref Type: AbstractGoogle Scholar
  55. 55.
    Julie C. Pathological analysis of hepatic injury after oxaliplatin-based neoadjuvant chemotherapy of colorectal cancer liver metastases: results of the EORTC Intergroup phase III study 40983. Gastrointestinal Cancer Symposium, Orlando, Florida (abstr 241). 2007. Ref Type: AbstractGoogle Scholar
  56. 56.
    Ellis LM, Curley SA, Grothey A. Surgical resection after downsizing of colorectal liver metastasis in the era of bevacizumab. J Clin Oncol 2005; 23:4853–5.PubMedCrossRefGoogle Scholar
  57. 57.
    Song SH, Jung KH, Paik JY et al. Distribution and pharmacokinetic analysis of angiostatin radioiodine labeled with high stability. Nucl Med Biol 2005; 32:845–50.PubMedCrossRefGoogle Scholar
  58. 58.
    Hanahan D, Bergers G, Bergsland E. Less is more, regularly: metronomic dosing of cytotoxic drugs can target tumor angiogenesis in mice. J Clin Invest 2000; 105:1045–7.PubMedCrossRefGoogle Scholar
  59. 59.
    Gasparini G. Metronomic scheduling: the future of chemotherapy? Lancet Oncol 2001; 2:733–40.PubMedCrossRefGoogle Scholar
  60. 60.
    Munoz R, Shaked Y, Bertolini F et al. Anti-angiogenic treatment of breast cancer using metronomic low-dose chemotherapy. Breast 2005; 14:466–79.PubMedCrossRefGoogle Scholar
  61. 61.
    Cunningham D, Allum WH, Stenning SP et al. Perioperative chemotherapy versus surgery alone for resectable gastroesophageal cancer. N Engl J Med 2006; 355:11–20.PubMedCrossRefGoogle Scholar
  62. 62.
    Cunningham D, Allum WH, Stenning SP, et al, for the NCRI Upper GI Cancer Clinical Studies Groups. Perioperative chemotherapy in operable gastric and lower oesophageal cancer: final results of a randomized controlles trial (the MAGIC trial, ISRCTN 93793971). Proc Am Soc Clin Oncol 23[308s]. 2005. Ref Type: AbstractGoogle Scholar
  63. 63.
    Mauri D, Pavlidis N, Ioannidis JP. Neoadjuvant versus adjuvant systemic treatment in breast cancer: a meta-analysis. J Natl Cancer Inst 2005; 97:188–94.PubMedCrossRefGoogle Scholar
  64. 64.
    Bonadonna G, Valagussa P, Brambilla C et al. Primary chemotherapy in operable breast cancer: eight-year experience at the Milan Cancer Institute. J Clin Oncol 1998; 16:93–100.PubMedGoogle Scholar
  65. 65.
    van der Hage JA, Van de Velde CJ, Julien JP et al. Preoperative chemotherapy in primary operable breast cancer: results from the European Organization for Research and Treatment of Cancer trial 10902. J Clin Oncol 2001; 19:4224–37.PubMedGoogle Scholar
  66. 66.
    Sauer R, Becker H, Hohenberger W et al. Preoperative versus postoperative chemoradiotherapy for rectal cancer. N Engl J Med 2004; 351:1731–40.PubMedCrossRefGoogle Scholar
  67. 67.
    Bosset JF, Collette L, Calais G et al. Chemotherapy with preoperative radiotherapy in rectal cancer. N Engl J Med 2006; 355:1114–23.PubMedCrossRefGoogle Scholar
  68. 68.
    Gerard JP, Conroy T, Bonnetain F et al. Preoperative radiotherapy with or without concurrent fluorouracil and leucovorin in T3-4 rectal cancers: results of FFCD 9203. J Clin Oncol 2006; 24:4620–5.PubMedCrossRefGoogle Scholar
  69. 69.
    Bosset JF, Calais G, Mineur L et al. Enhanced tumorocidal effect of chemotherapy with preoperative radiotherapy for rectal cancer: preliminary results–EORTC 22921. J Clin Oncol 2005; 23:5620–7.PubMedCrossRefGoogle Scholar
  70. 70.
    Janjan NA, Khoo VS, Abbruzzese J et al. Tumor downstaging and sphincter preservation with preoperative chemoradiation in locally advanced rectal cancer: the M. D. Anderson Cancer Center experience. Int J Radiat Oncol Biol Phys 1999; 44:1027–38.PubMedGoogle Scholar
  71. 71.
    Chari RS, Tyler DS, Anscher MS et al. Preoperative radiation and chemotherapy in the treatment of adenocarcinoma of the rectum. Ann Surg 1995; 221:778–86.PubMedCrossRefGoogle Scholar
  72. 72.
    Chen ET, Mohiuddin M, Brodovsky H et al. Downstaging of advanced rectal cancer following combined preoperative chemotherapy and high dose radiation. Int J Radiat Oncol Biol Phys 1994; 30:169–75.PubMedGoogle Scholar
  73. 73.
    Isomoto H, Tomita M, Sugimachi K, et al. Pre- and postoperative adjuvant chemotherapy in colorectal cancer. Int J Oncol 2003; 23:1103–8PubMedGoogle Scholar
  74. 74.
    Matsuura T, Fukuda Y, Fujitaka T, et al. Preoperative treatment with tegafur suppositories enhances apoptosis and reduces the intratumoral microvessel density of human colorectal carcinoma. Cancer 2000; 88:1007–15PubMedCrossRefGoogle Scholar

Copyright information

© Society of Surgical Oncology 2008

Authors and Affiliations

  • Charlotte F. J. M. Peeters
    • 1
    • 2
    Email author
  • Robert M. W. de Waal
    • 1
  • Theo Wobbes
    • 2
  • Theo J. M. Ruers
    • 3
  1. 1.Department of PathologyUniversity Medical Centre NijmegenNijmegenThe Netherlands
  2. 2.Department of Surgical OncologyUniversity Medical Centre NijmegenNijmegenThe Netherlands
  3. 3.Department of SurgeryThe Netherlands Cancer InstituteAmsterdamThe Netherlands

Personalised recommendations