Eric Belt

G Heuff

Gerben van der Bij

GJ Bij van der

GP Pidgeon

H Katoh

Hein Stockmann

Marjolein van Egmond

SD Killeen

SJ Oosterling

Steven Oosterling

Oosterling, S.

Stockmann, H.

van der Bij, G.

Belt, E.

van Egmond, M.

NARCIS 

Underlying Mechanisms of Anastomotic Leakage and Systemic Recurrences in Colorectal Cancer

Crossref

Journal of Gastrointestinal Surgery

Bij, G. van der

Egmond, M. van

DSpace at VU

LETTER TO THE EDITOR
Underlying Mechanisms of Anastomotic Leakage
and Systemic Recurrences in Colorectal Cancer
Steven Oosterling & Hein Stockmann &
Gerben van der Bij & Eric Belt & Marjolein van Egmond
Received: 23 January 2011 /Accepted: 20 June 2011 /Published online: 14 July 2011
# 2011 The Society for Surgery of the Alimentary Tract
Dear Sir,
With interest we read the recent article of Katoh et al. in
which the contribution of anastomotic leakage to the risk
for systemic recurrence in a series of 207 stage II colorectal
cancer patients was investigated.1 In their multivariable
analysis, anastomotic leakage proved the most robust
independent prognostic factor for a 5-year disease-free
survival. The authors address in their discussion a main
factor that might contribute to increased risk of recurrences.
The use of perioperative blood transfusions was reported as
a risk factor for anastomotic leakage and has earlier been
established as a prognostic factor for cancer recurrence. As
stated by the authors, blood transfusions are associated with
impaired cell-mediated immune responses which might
facilitate development of (micro) metastases.
Here, we would like to discuss several other biological
mechanisms that might be responsible for increased
recurrences seen following anastomotic leakages. In the
case of anastomotic leakage or otherwise failure of the
barrier function, the gut provides a major source of
endotoxins that ubiquitously circulate while leading to
sepsis. Endotoxins or lipopolysaccharides (LPS), which are
cell-wall constituents of Gram-negative bacteria, have been
shown to enhance tumor cell adhesion and metastasis
outgrowth in experimental models.2,3 Mice that received
endotoxin injections showed increased metastatic burden
compared to those receiving a saline injection. This
increase was reflected in higher tumor cell proliferation
and decreased apoptosis within lung metastases.2 We earlier
showed in several experimental models that the perioper-
ative milieu itself facilitates both local and systemic tumor
metastasis formation.4,5 Electron microscopic investigation
demonstrated that abdominal surgery resulted in endothelial
stress, leading to impaired liver vessel integrity and
subsequent exposure of underlying extracellular matrix,
which served as preferred adhesion sites for tumor cells
leading to enhanced metastasis outgrowth.5 In accordance,
in a recent in vitro study, LPS enhanced tumor cell adhesion
and invasion, both fundamental processes in tumor pro-
gression.3 Moreover, continued and repetitive exposure to
endotoxins, such as during abdominal sepsis, results in
reduced immune responsiveness or even immune paralysis.
This is exemplified by diminished capability of innate
immune cells, such as macrophages, to produce the
cytotoxic tumor necrosis factor α. Since liver macrophages,
the so-called Kupffer cells, have been shown to be pivotal
in arresting and eliminating circulating tumor cells in liver
sinusoids,6 this immunosuppression may impede an effec-
tive antitumor response. Thus, endotoxins such as LPS
seem to play an important role in the observations of Katoh
et al. and might be connected as one of the main
responsible mechanisms for increased recurrence following
anastomotic leakage. As such, the link between endotoxins
and tumor recurrence is a further subject of our current
investigation.
References
1. Katoh H, Yamashita K, Wang G et al. Anastomotic Leakage
Contributes to the Risk for Systemic Recurrence in Stage II
Colorectal Cancer. J Gastrointest Surg 2011 Jan; 15(1):120–9.
2. Pidgeon GP, Harmey JH, Kay E et al. The role of endotoxin/
lipopolysaccharide in surgically induced tumour growth in a murine
model of metastatic disease. Br J Cancer 1999; 81:1311–1317.
S. Oosterling (*) :H. Stockmann :G. van der Bij : E. Belt :
M. van Egmond
Kennemer Gasthuis,
Haarlem, The Netherlands
e-mail: sj.oosterling@gmail.com
J Gastrointest Surg (2011) 15:1904–1905
DOI 10.1007/s11605-011-1602-y
3. Killeen SD, Wang JH, Andrews EJ et al. Bacterial endotoxin
enhances colorectal cancer cell adhesion and invasion through
TLR-4 and NF-kappaB-dependent activation of the urokinase
plasminogen activator system. Br J Cancer 2009; 100:1589–1602.
4. Oosterling SJ, van der Bij GJ, Bogels M et al. Anti-beta1 integrin
antibody reduces surgery-induced adhesion of colon carcinoma cells
to traumatized peritoneal surfaces. Ann Surg 2008; 247:85–94.
5. van der Bij GJ, Oosterling SJ, Bogels M et al. Blocking alpha2
integrins on rat CC531s colon carcinoma cells prevents operation-
induced augmentation of liver metastases outgrowth. Hepatology
2008; 47:532–543.
6. Heuff G, Oldenburg HS, Boutkan H et al. Enhanced tumour growth
in the rat liver after selective elimination of Kupffer cells. Cancer
Immunol Immunother 1993; 37:125–130.
J Gastrointest Surg (2011) 15:1904–1905 1905


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Underlying Mechanisms of Anastomotic Leakage and Systemic Recurrences in Colorectal Cancer

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