LETTER TO THE EDITOR Markers of Angiogenesis in Synchronous and in Metachronous Colorectal Hepatic Metastases To the Editor: he study by van der Wal and colleagues1 explores the important subject of the cancer biology of colorectal hepatic metastases and, in particular, the potential systemic effects of an in situ primary colon tumor on the angiogenic potential of the liver parenchyma. To better understand these findings, it is necessary to understand whether the changes in markers of angiogenesis were present only in the non–tumor-bearing liver parenchyma adjacent to the metastasis or whether the changes were present in the liver parenchyma remote to the metastasis. If the authors’ statement that these changes are a systemic effect of the primary colon cancer is to be confirmed, it would be hypothesized that liver parenchyma remote from the metastasis and liver adjacent to the metastasis would have similar profiles in expression of angiogenesis markers. On the basis of the data provided, it is possible that some of the effects seen are due to changes in liver blood flow adjacent to the metastasis and, thus, may be more marked in patients with tumors with a higher proliferation index, such as the synchronous group in the authors’ study. Three further points that would augment the interpretation of their data are, first, whether in those patients with synchronous disease, the colorectal primary tumor was resected before the hepatic metastasectomy. If these patients had prior colorectal resection before metastasectomy but during the same operation (unlike patients in the other 2 groups), then alterations in hepatic blood flow as a consequence of colonic surgery may influence differential expression of angiogenesis markers. Second, what was the status of the patients with respect to chemotherapy? And finally, the use of a surrogate of tumor growth derived from the ratio of Ki67 positive cells to caspase 3a positive cells may not reflect the worse prognostic behavior of patients with synchronous disease as a high rate of tumor cell turnover and resulting
cell death in this category may produce higher levels of caspase expression. Santhalingam Jegatheeswaran, MRCS Ajith K Siriwardena, MD, FRCS Hepatobiliary Surgery Unit Manchester Royal Infirmary Manchester, UK [email protected]
T
Disclosure: Both authors are not currently receiving any honoraria. Neither is currently receiving grants from any organizations or currently on the speaker’s bureau. They declare no conflicts of interest. C 2013 by Lippincott Williams & Wilkins Copyright ISSN: 0003-4932/13/26101-e0020 DOI: 10.1097/SLA.0000000000000434
e20 | www.annalsofsurgery.com
REFERENCE 1. van der Wal GE, Gouw AS, Kamps JA, et al. Angiogenesis in synchronous and metachronous colorectal liver metastases: the liver as a permissive soil. Ann Surg. 2012;255:86–94.
Reply: n their letter, Drs Jegatheeswaran and Siriwardena ask for additional information regarding our study concerning the potential systemic effects of the primary colon tumor on the angiogenic profile of the adjacent liver parenchyma of liver metastases. They question whether changes in angiogenic markers seen in metastasis-adjacent liver parenchyma are also visible in liver parenchyma remote to the metastases. They furthermore inquire about the sequence of resection of the primary tumor in relation to the hepatic metastasectomy in patients who underwent a simultaneous resection, and they raise the issues of prior chemotherapy and Ki67/caspase 3a ratio. We welcome the opportunity to clarify these matters. We agree that the issue of remote versus adjacent liver parenchyma is relevant. We analyzed remote liver parenchyma versus adjacent liver parenchyma and found no differences in the expression of genes of the VEGF family and the angiopoietin system in the simultaneous synchronous group. It should be realized that it is more complex, and it is known, for instance, that resection of liver metastases can have growthpromoting effects on dormant metastatic deposits elsewhere.1 Whether this is caused by the metastasis having similar effects on remote organs and tissues as the primary tumor is open for discussion. Other possible explanations can be the systemic response associated with liver regeneration after partial liver resection or the inflammatory or angiogenic response associated with surgery per se.2,3 Finally, we tempt to agree with Drs Jegatheeswaran and Siriwardena that metastases will also have a local effect on liver parenchyma not only by paracrine mechanisms of growth factors but also by the as-
I
Disclosure: Supported by Junior Scientific Masterclass MD/PhD-project to Gesiena E. van der Wal. The authors declare no conflicts of interest. 10.1097/SLA.0000000000000563
sociated infiltration of inflammatory cells.4–6 Nevertheless, in our article, we found that in all 3 groups presenting with liver metastases, only the livers from patients in whom the primary tumor was still present exhibited a prosperous angiogenic environment. In patients who are scheduled for a simultaneous resection of the primary tumor and liver metastases, it is our policy to perform the “clean” procedure (the partial liver resection) first and afterward the “contaminated” procedure (the bowel resection). We firmly agree that chemotherapy shortly before liver resection could have an impact on the expression of various angiogenic markers both in the liver parenchyma and in the metastases. None of the patients in our study received chemotherapy in a period of 6 months before liver surgery. Some patients in the metachronous group had adjuvant chemotherapy after resection of the primary tumor, but all were off chemotherapy for at least 6 months before the liver resection. Regarding the final question, we used the ratio Ki67-positive cells/caspase 3a– positive cells as a surrogate marker for tumor growth. It is known that tumors can produce proteins such as angiostatin and endostatin,7–9 which inhibit tumor growth via suppression of angiogenesis at metastatic sites. In mice, it was demonstrated that dormant metastases did not reveal tumor growth because of a high apoptotic rate; removal of the primary tumor resulted in substantial growth of the dormant metastases by inhibition of this high apoptotic rate. Remarkably, dormant and growing metastases did not reveal a difference in tumor cell proliferation rate.10 On the basis of these findings, we analyzed both proliferation and apoptosis in the 3 groups of patients. We, by no means, intended to correlate these data with the prognosis of patients. Gesiena E. van der Wal, MD Department of Pathology and Medical Biology Medical Biology Section University Medical Center Groningen University of Groningen Annette S. H. Gouw, MD, PhD Pathology Section University Medical Center Groningen University of Groningen Groningen, The Netherlands Jan A.A.M. Kamps, PhD Henk E. Moorlag, Ing Department of Pathology and Medical Biology Medical Biology Section University Medical Center Groningen University of Groningen Groningen, The Netherlands
Annals of Surgery r Volume 261, Number 1, January 2015
Copyright © 2013 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Annals of Surgery r Volume 261, Number 1, January 2015
Marian L. C. Bulthuis, Ing Pathology Section University Medical Center Groningen University of Groningen Groningen, The Netherlands Grietje Molema, PhD Department of Pathology and Medical Biology, Medical Biology Section University Medical Center Groningen University of Groningen Groningen, The Netherlands Koert P. de Jong, Md, PhD Department of Surgery, Division of Hepatopancreatobiliary Surgery and Liver Transplantation University Medical Center Groningen University of Groningen Groningen, The Netherlands [email protected]
C 2013 Lippincott Williams & Wilkins
REFERENCES 1. De Jong KP, Sloof MJ, de Vries EG, et al. Effect of partial liver resection on tumor growth. J Hepatol. 1996;25:109–121. 2. De Jong KP, Hoedemakers RM, Fidler V, et al. Portal and systemic serum growth factor and acute-phase response after laparotomy or partial hepatectomy in patients with colorectal liver metastases: a prognostic role for C-reactive protein and hepatocytic growth factor. Scand J Gatroenterol. 2004;39:1141–1148. 3. Van der Bij GJ, Oosterling SJ, Beelen RH, et al. The perioperative period is an underutilized window of therapeutic opportunity in patients with colorectal cancer. Ann Surg. 2009;249:727–734. 4. Balkwill F, Charles KA, Mantovani A. Smoldering and polarized inflammation in the initiation and promotion of malignant disease. Cancer Cell. 2005;7:211–217. 5. Mantovani A, Sozzani S, Locati M, et al. Macrophage polarization: tumor-associated macrophages as a paradigm for polarized M2 mononuclear phagocytes. Trends Immunol. 2002;23:549– 555.
6. Wagner M, Bjerkvig R, Wiig H, et al. Inflamed tumor-associated adipose tissue is a depot for macrophages that stimulate tumor growth and angiogenesis. Angiogenesis. 2012;15:481–495. 7. Beecken WD, Engl T, Jonas D, et al. Expression of angiogenesis inhibitors in human bladder cancer may explain rapid metastatic progression after radical cystectomy. Int J Mol Med. 2009;23:261– 266. 8. Peeters CFJM, 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;137:246–249. 9. Szarvas T, J¨ager T, Laszlo V, et al. Circulating angiostatin, bFGF, and Tie2/TEK levels and their prognostic impact in bladder cancer. Urology. 2012;80:737e.13–737e.18. 10. Holmgren L, O’Reilly MS, Folkman J. Dormancy of micrometastases: balanced proliferation and apoptosis in the presence of angiogenesis suppression. Nat Med. 1995;1:149–153.
www.annalsofsurgery.com | e21
Copyright © 2013 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
cell death in this category may produce higher levels of caspase expression. Santhalingam Jegatheeswaran, MRCS Ajith K Siriwardena, MD, FRCS Hepatobiliary Surgery Unit Manchester Royal Infirmary Manchester, UK [email protected]
T
Disclosure: Both authors are not currently receiving any honoraria. Neither is currently receiving grants from any organizations or currently on the speaker’s bureau. They declare no conflicts of interest. C 2013 by Lippincott Williams & Wilkins Copyright ISSN: 0003-4932/13/26101-e0020 DOI: 10.1097/SLA.0000000000000434
e20 | www.annalsofsurgery.com
REFERENCE 1. van der Wal GE, Gouw AS, Kamps JA, et al. Angiogenesis in synchronous and metachronous colorectal liver metastases: the liver as a permissive soil. Ann Surg. 2012;255:86–94.
Reply: n their letter, Drs Jegatheeswaran and Siriwardena ask for additional information regarding our study concerning the potential systemic effects of the primary colon tumor on the angiogenic profile of the adjacent liver parenchyma of liver metastases. They question whether changes in angiogenic markers seen in metastasis-adjacent liver parenchyma are also visible in liver parenchyma remote to the metastases. They furthermore inquire about the sequence of resection of the primary tumor in relation to the hepatic metastasectomy in patients who underwent a simultaneous resection, and they raise the issues of prior chemotherapy and Ki67/caspase 3a ratio. We welcome the opportunity to clarify these matters. We agree that the issue of remote versus adjacent liver parenchyma is relevant. We analyzed remote liver parenchyma versus adjacent liver parenchyma and found no differences in the expression of genes of the VEGF family and the angiopoietin system in the simultaneous synchronous group. It should be realized that it is more complex, and it is known, for instance, that resection of liver metastases can have growthpromoting effects on dormant metastatic deposits elsewhere.1 Whether this is caused by the metastasis having similar effects on remote organs and tissues as the primary tumor is open for discussion. Other possible explanations can be the systemic response associated with liver regeneration after partial liver resection or the inflammatory or angiogenic response associated with surgery per se.2,3 Finally, we tempt to agree with Drs Jegatheeswaran and Siriwardena that metastases will also have a local effect on liver parenchyma not only by paracrine mechanisms of growth factors but also by the as-
I
Disclosure: Supported by Junior Scientific Masterclass MD/PhD-project to Gesiena E. van der Wal. The authors declare no conflicts of interest. 10.1097/SLA.0000000000000563
sociated infiltration of inflammatory cells.4–6 Nevertheless, in our article, we found that in all 3 groups presenting with liver metastases, only the livers from patients in whom the primary tumor was still present exhibited a prosperous angiogenic environment. In patients who are scheduled for a simultaneous resection of the primary tumor and liver metastases, it is our policy to perform the “clean” procedure (the partial liver resection) first and afterward the “contaminated” procedure (the bowel resection). We firmly agree that chemotherapy shortly before liver resection could have an impact on the expression of various angiogenic markers both in the liver parenchyma and in the metastases. None of the patients in our study received chemotherapy in a period of 6 months before liver surgery. Some patients in the metachronous group had adjuvant chemotherapy after resection of the primary tumor, but all were off chemotherapy for at least 6 months before the liver resection. Regarding the final question, we used the ratio Ki67-positive cells/caspase 3a– positive cells as a surrogate marker for tumor growth. It is known that tumors can produce proteins such as angiostatin and endostatin,7–9 which inhibit tumor growth via suppression of angiogenesis at metastatic sites. In mice, it was demonstrated that dormant metastases did not reveal tumor growth because of a high apoptotic rate; removal of the primary tumor resulted in substantial growth of the dormant metastases by inhibition of this high apoptotic rate. Remarkably, dormant and growing metastases did not reveal a difference in tumor cell proliferation rate.10 On the basis of these findings, we analyzed both proliferation and apoptosis in the 3 groups of patients. We, by no means, intended to correlate these data with the prognosis of patients. Gesiena E. van der Wal, MD Department of Pathology and Medical Biology Medical Biology Section University Medical Center Groningen University of Groningen Annette S. H. Gouw, MD, PhD Pathology Section University Medical Center Groningen University of Groningen Groningen, The Netherlands Jan A.A.M. Kamps, PhD Henk E. Moorlag, Ing Department of Pathology and Medical Biology Medical Biology Section University Medical Center Groningen University of Groningen Groningen, The Netherlands
Annals of Surgery r Volume 261, Number 1, January 2015
Copyright © 2013 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Annals of Surgery r Volume 261, Number 1, January 2015
Marian L. C. Bulthuis, Ing Pathology Section University Medical Center Groningen University of Groningen Groningen, The Netherlands Grietje Molema, PhD Department of Pathology and Medical Biology, Medical Biology Section University Medical Center Groningen University of Groningen Groningen, The Netherlands Koert P. de Jong, Md, PhD Department of Surgery, Division of Hepatopancreatobiliary Surgery and Liver Transplantation University Medical Center Groningen University of Groningen Groningen, The Netherlands [email protected]
C 2013 Lippincott Williams & Wilkins
REFERENCES 1. De Jong KP, Sloof MJ, de Vries EG, et al. Effect of partial liver resection on tumor growth. J Hepatol. 1996;25:109–121. 2. De Jong KP, Hoedemakers RM, Fidler V, et al. Portal and systemic serum growth factor and acute-phase response after laparotomy or partial hepatectomy in patients with colorectal liver metastases: a prognostic role for C-reactive protein and hepatocytic growth factor. Scand J Gatroenterol. 2004;39:1141–1148. 3. Van der Bij GJ, Oosterling SJ, Beelen RH, et al. The perioperative period is an underutilized window of therapeutic opportunity in patients with colorectal cancer. Ann Surg. 2009;249:727–734. 4. Balkwill F, Charles KA, Mantovani A. Smoldering and polarized inflammation in the initiation and promotion of malignant disease. Cancer Cell. 2005;7:211–217. 5. Mantovani A, Sozzani S, Locati M, et al. Macrophage polarization: tumor-associated macrophages as a paradigm for polarized M2 mononuclear phagocytes. Trends Immunol. 2002;23:549– 555.
6. Wagner M, Bjerkvig R, Wiig H, et al. Inflamed tumor-associated adipose tissue is a depot for macrophages that stimulate tumor growth and angiogenesis. Angiogenesis. 2012;15:481–495. 7. Beecken WD, Engl T, Jonas D, et al. Expression of angiogenesis inhibitors in human bladder cancer may explain rapid metastatic progression after radical cystectomy. Int J Mol Med. 2009;23:261– 266. 8. Peeters CFJM, 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;137:246–249. 9. Szarvas T, J¨ager T, Laszlo V, et al. Circulating angiostatin, bFGF, and Tie2/TEK levels and their prognostic impact in bladder cancer. Urology. 2012;80:737e.13–737e.18. 10. Holmgren L, O’Reilly MS, Folkman J. Dormancy of micrometastases: balanced proliferation and apoptosis in the presence of angiogenesis suppression. Nat Med. 1995;1:149–153.
www.annalsofsurgery.com | e21
Copyright © 2013 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
