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Profile of Plasma Angiogenic Factors Before and After Hepatectomy for Colorectal Cancer Liver Metastases

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Abstract

Background

Circulating angiogenic factors in patients with colorectal cancer liver metastases may promote tumor growth and contribute to liver regeneration after partial hepatectomy.

Methods

We analyzed blood samples from 26 patients with colorectal cancer liver metastases before and after liver resection and used samples from 20 healthy controls as a reference. Plasma levels of vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), epidermal growth factor (EGF), and hepatocyte growth factor (HGF) were measured, and levels were correlated with recurrence.

Results

The median preoperative levels of all four factors were significantly higher and more variable in colorectal cancer liver metastasis patients than in controls. HGF and bFGF levels increased significantly 3 days and 1 month after hepatectomy, respectively, and returned to near preoperative levels at 3 months. Postoperative VEGF and EGF levels remained relatively stably increased over 3 months. After a median follow-up of 19 months, 10 patients (42%) experienced recurrence. Higher preoperative VEGF and HGF levels correlated with subsequent recurrence (P = .018 and .021, respectively), and a preoperative adjusted total value of all four factors accurately identified patients at low, moderate, and high risk of recurrence (P = .034). Patients who experienced disease recurrence also had relatively higher bFGF levels 3 months after operation (P = .035).

Conclusions

Plasma angiogenic factors are increased in patients with colorectal cancer liver metastases and remain increased at least 3 months after partial hepatectomy. Measurement of certain factors before and after hepatic resection can predict recurrence. Targeted biological agents may counteract the tumor-promoting effects of these circulating factors on subclinical disease.

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References

  1. Jemal A, Murray T, Ward E, et al. Cancer statistics. 2005 CA Cancer J Clin 55:10–30

    PubMed  Google Scholar 

  2. Weiss L, Grundmann E, Torhorst J, et al. Haematogenous metastatic patterns in colonic carcinoma: an analysis of 1541 necropsies. J Pathol 1986;150:195–203

    Article  CAS  PubMed  Google Scholar 

  3. Ballantyne GH, Quin J. Surgical treatment of liver metastases in patients with colorectal cancer. Cancer 1993;71:4252–66

    CAS  PubMed  Google Scholar 

  4. Folkman J. Tumor angiogenesis: therapeutic implications. N Engl J Med 1971;285:1182–6

    CAS  PubMed  Google Scholar 

  5. Hanahan D, Folkman J. Patterns, emerging mechanisms of the angiogenic switch during tumorigenesis. Cell 1996;86:353–64

    Article  CAS  PubMed  Google Scholar 

  6. Cross MJ, Claesson-Welsh L. FGF, VEGF function in angiogenesis: signalling pathways, biological responses and therapeutic inhibition. Trends Pharmacol Sci 2001;22:201–7

    Article  CAS  PubMed  Google Scholar 

  7. Dvorak HF. Vascular permeability factor/vascular endothelial growth factor: a critical cytokine in tumor angiogenesis, a potential target for diagnosis and therapy. J Clin Oncol 2002;20:4368–80

    Article  CAS  PubMed  Google Scholar 

  8. Shing Y, Folkman J, Sullivan R, Butterfield C, Murray J, Klagsbrun M. Heparin affinity: purification of a tumor-derived capillary endothelial cell growth factor. Science 1984;223:1296–9

    CAS  PubMed  Google Scholar 

  9. Poon RT, Fan ST, Wong J. Clinical implications of circulating angiogenic factors in cancer patients. J Clin Oncol 2001;19:1207–1225

    CAS  PubMed  Google Scholar 

  10. Yoon SS, Tanabe KK. Surgical treatment, other regional treatments for colorectal cancer liver metastases. Oncologist 1999;4:197–208

    CAS  PubMed  Google Scholar 

  11. Choti MA, Sitzmann JV, Tiburi MF, et al. Trends in long-term survival following liver resection for hepatic colorectal metastases. Ann Surg 2002;235:759–66

    Article  PubMed  Google Scholar 

  12. Jarnagin WR, Gonen M, Fong Y, et al. Improvement in perioperative outcome after hepatic resection: analysis of 1,803 consecutive cases over the past decade. Ann Surg 2002;236:397–406

    Article  PubMed  Google Scholar 

  13. Koniaris LG, McKillop IH, Schwartz SI, Zimmers TA. Liver regeneration. J Am Coll Surg 2003;197:634–59

    PubMed  Google Scholar 

  14. Weglarz TC, Sandgren EP. Timing of hepatocyte entry into DNA synthesis after partial hepatectomy is cell autonomous. Proc Natl Acad Sci U S A 2000;97:12595–600

    Article  CAS  PubMed  Google Scholar 

  15. Chen MF, Hwang TL, Hung CF. Human liver regeneration after major hepatectomy. A study of liver volume by computed tomography. Ann Surg 1991;213:227–9

    CAS  PubMed  Google Scholar 

  16. Court FG, Wemyss-Holden SA, Dennison AR, Maddern GJ. The mystery of liver regeneration. Br J Surg 2002;89:1089–95

    Article  CAS  PubMed  Google Scholar 

  17. Schmidt C, Bladt F, Goedecke S, et al. Scatter factor/hepatocyte growth factor is essential for liver development. Nature 1995;373:699–702

    Article  CAS  PubMed  Google Scholar 

  18. Jones DE Jr, Tran-Patterson R, Cui DM, Davin D, Estell KP, Miller DM. Epidermal growth factor secreted from the salivary gland is necessary for liver regeneration. Am J Physiol 1995;268:G872–78

    CAS  PubMed  Google Scholar 

  19. Funakoshi H, Nakamura T. Hepatocyte growth factor: from diagnosis to clinical applications. Clin Chim Acta 2003;327:1–23

    Article  CAS  PubMed  Google Scholar 

  20. Morishita R, Aoki M, Hashiya N, et al. Therapeutic angiogenesis using hepatocyte growth factor (HGF). Curr Gene Ther 2004;4:199–206

    CAS  PubMed  Google Scholar 

  21. Bruns CJ, Solorzano CC, Harbison MT, et al. Blockade of the epidermal growth factor receptor signaling by a novel tyrosine kinase inhibitor leads to apoptosis of endothelial cells and therapy of human pancreatic carcinoma. Cancer Res 2000;60:2926–35

    CAS  PubMed  Google Scholar 

  22. Ross MA, Sander CM, Kleeb TB, Watkins SC, Stolz DB. Spatiotemporal expression of angiogenesis growth factor receptors during the revascularization of regenerating rat liver. Hepatology 2001;34:1135–48

    Article  CAS  PubMed  Google Scholar 

  23. Kaplan E, Meier P. Nonparametric estimation from incomplete observations. J Am Stat Assoc 1958;53:457–481

    Google Scholar 

  24. Davies MM, Jonas SK, Kaur S, Allen-Mersh TG. Plasma vascular endothelial but not fibroblast growth factor levels correlate with colorectal liver metastasis vascularity, volume. Br J Cancer 2000;82:1004–8

    CAS  PubMed  Google Scholar 

  25. Dirix LY, Vermeulen PB, Hubens G, et al. Serum basic fibroblast growth factor and vascular endothelial growth factor and tumour growth kinetics in advanced colorectal cancer. Ann Oncol 1996;7:843–848

    CAS  PubMed  Google Scholar 

  26. Fujisaki K, Mitsuyama K, Toyonaga A, Matsuo K, Tanikawa K. Circulating vascular endothelial growth factor in patients with colorectal cancer. Am J Gastroenterol 1998;93:249–52

    Article  CAS  PubMed  Google Scholar 

  27. Hyodo I, Doi T, Endo H, et al. Clinical significance of plasma vascular endothelial growth factor in gastrointestinal cancer. Eur J Cancer 1998;34:2041–2045

    Article  CAS  PubMed  Google Scholar 

  28. Landriscina M, Cassano A, Ratto C, et al. Quantitative analysis of basic fibroblast growth factor and vascular endothelial growth factor in human colorectal cancer. Br J Cancer 1998;78:765–70

    CAS  PubMed  Google Scholar 

  29. Dirix LY, Vermeulen PB, Pawinski A, et al. Elevated levels of the angiogenic cytokines basic fibroblast growth factor and vascular endothelial growth factor in sera of cancer patients. Br J Cancer 1997;76:238–243

    CAS  PubMed  Google Scholar 

  30. Fukuura T, Miki C, Inoue T, Matsumoto K, Suzuki H. Serum hepatocyte growth factor as an index of disease status of patients with colorectal carcinoma. Br J Cancer 1998;78:454–459

    CAS  PubMed  Google Scholar 

  31. Fong Y, Fortner J, Sun RL, Brennan MF, Blumgart LH. Clinical score for predicting recurrence after hepatic resection for metastatic colorectal cancer: analysis of 1001 consecutive cases. Ann Surg 1999;230:309–18

    Article  CAS  PubMed  Google Scholar 

  32. Kaneko A, Hayashi N, Tanaka Y, et al. Changes in serum human hepatocyte growth factor levels after transcatheter arterial embolization and partial hepatectomy. Am J Gastroenterol 1992;87:1014–17

    CAS  PubMed  Google Scholar 

  33. Shiota G, Okano J, Kawasaki H, Kawamoto T, Nakamura T. Serum hepatocyte growth factor levels in liver diseases: clinical implications. Hepatology 1995;21:106–112

    Article  CAS  PubMed  Google Scholar 

  34. Curley SA, Izzo F, Abdalla E, Vauthey JN. Surgical treatment of colorectal cancer metastasis. Cancer Metastasis Rev 2004;23:165–82

    Article  PubMed  Google Scholar 

  35. Ellis LM, Liu W, Ahmad SA, et al. Overview of angiogenesis: biologic implications for antiangiogenic therapy. Semin Oncol 2001;28:94–104

    Article  CAS  PubMed  Google Scholar 

  36. 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

    Article  CAS  PubMed  Google Scholar 

  37. Kabbinavar F, Hurwitz HI, Fehrenbacher L, et al. Phase II, randomized trial comparing bevacizumab plus fluorouracil (FU)/leucovorin (LV) with FU/LV alone in patients with metastatic colorectal cancer. J Clin Oncol 2003;21:60–5

    CAS  PubMed  Google Scholar 

  38. Saltz LB, Meropol NJ, Loehrer PJ Sr, Needle MN, Kopit J, Mayer RJ. Phase II trial of cetuximab in patients with refractory colorectal cancer that expresses the epidermal growth factor receptor. J Clin Oncol 2004;22:1201–8

    Article  CAS  PubMed  Google Scholar 

  39. 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

    Article  CAS  PubMed  Google Scholar 

  40. Saltz LB, Lenz H, Kindler H, et al. Interim report of randomized phase II trial of cetuximab/bevacizumab/irinotecan (CBI) versus cetuximab/bevacizumab (CB) in irinotecan-refractory colorectal cancer (abstract). ASCO Gastrointestinal Cancers Symposium. 2005

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Acknowledgments

Supported by National Institutes of Health grant K12CA87723-02 (S.S.Y.) and CA94503 (R.P.D.). The authors thank Rachel Jacobi, Beata Korytowski, and Brenda Guilfoyle for assistance with blood specimen collection and Sandra Ryeom, PhD for reviewing the manuscript.

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Authors and Affiliations

  1. Department of Surgery, Division of Surgical Oncology, Massachusetts General Hospital, Harvard Medical School, Yawkey 7B-7926, 55 Fruit Street, Boston, Massachusetts, 02114

    Sam S. Yoon MD, Sung H. Kim MD, PhD, Kara Y. Detwiller BS & Kenneth K. Tanabe MD

  2. Department of Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, New York, 10021

    Mithat Gonen PhD

  3. Department of Surgery, Hepatobiliary Service, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, New York, 10021

    Nancy M. Heffernan RN, BSN, William R. Jarnagin MD, Michael D’Angelica MD, Leslie H. Blumgart MD & Ronald P. DeMatteo MD

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  1. Sam S. Yoon MD
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Correspondence to Sam S. Yoon MD.

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Yoon, S.S., Kim, S.H., Gonen, M. et al. Profile of Plasma Angiogenic Factors Before and After Hepatectomy for Colorectal Cancer Liver Metastases. Ann Surg Oncol 13, 353–362 (2006). https://doi.org/10.1245/ASO.2006.03.060

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  • DOI: https://doi.org/10.1245/ASO.2006.03.060

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