Abstract. Cachexia is a devastating process especially in
pancreatic cancer patients and contributes to their poor
survival. We attempted to clarify the pathological and
molecular changes that occur in the liver during the develop-
ment of cachexia. Using immunohistochemistry we
investigated the infiltration of inflammatory mononuclear
cells in liver biopsies of pancreatic cancer patients with or
without cachexia, and the potential relevance of the cells for
the nutritional and inflammatory status. Additionally, these
findings were compared with the patients' clinical parameters.
We found a significantly higher amount of CD68 immuno-
reactive macrophages in liver cross sections of patients with
pancreatic cancer and cachexia. The number of CD68-positive
macrophages was significantly inversely correlated with the
nutritional status. Additionally, in these CD68-positive areas a
significant increase in IL-6 and IL-1 immunoreactive cells was
localized. Moreover, we found significantly increased areas
of CD68-positive macrophages in liver biopsies of patients
with a more dedifferentiated (aggressive) grading of the tumor.
In conclusion, these results suggest that a crucial interaction
between the tumor, PBMCs, and the liver may play a central
role in the development and regulation of cachexia. Further-
more, pancreatic cancer may be able to alter systemic organ
function even without obvious metastatic disease.
With a 5-year survival rate of <5% and a death-to-incidence
ratio of 0.99, pancreatic ductal adenocarcinoma (PDAC) is
currently one of the most aggressive gastrointestinal carci-
nomas (1-3). A variety of molecular alterations contributing
to pancreatic cancer have been identified (4,5). In spite of
this, the reason for the aggressiveness of this disease remains
unclear and the causes are multifactorial.
Furthermore, >80% of PDAC patients exhibit cachexia, a
complex metabolic and nutritional syndrome that is
characterized by anorexia and a massive loss of adipose
tissue and skeletal mass (6). Morbidity and mortality in
pancreatic cancer are strongly influenced by the presence of
cachexia, mainly due to severe respiratory muscle impair-
ment and compromised immunity as a result of the massive
loss of proteins (7). Therefore, cachectic PDAC patients have
shorter survival and lower quality of life than patients with
stable weight (8). Furthermore, cachexia already has an
impact on the survival of patients with pancreatic cancer who
are scheduled for tumor resection (9).
There is currently no generally accepted definition of
cachexia. However, an unintentional loss of >10% of total
body weight within 6 months is generally accepted as a
strong indicator for cachexia (10). Several theories have been
suggested for the development of cachexia. One points to
leptin, a hormone secreted by adipocytes. Leptin can reduce
appetite and increase energy expenditure by interacting with
several distinct hypothalamic neuropeptides, such as
orexigenic NPY (neuropeptide Y) or anorexigenic CRF
(corticotropin-releasing factor), melanocortin or neurotensin
(11,12). Thus, any abnormal process which induces or
mimics the hypothalamic effect of leptin might produce
anorexia and weight loss (13).
Other theories postulate the presence of tumor-derived
compounds, such as PIF (proteolysis-inducing factor) and
LMF (lipid-mobilizing factor), which may be responsible
for the massive loss of muscular and adipose tissues,
respectively (14,15). Despite their differences, all these
theories agree on two main concepts: on the one hand, that
cachexia is characterized by a prolonged acute phase
response in which liver protein synthesis changes from
production of normal export proteins such as albumin to
production of compounds such as C-reactive protein (CRP),
·1-antitrypsin and fibrinogen; and on the other hand, that the
de-novo production of cytokines such as TNF·, IL-1ß, IL-6
ONCOLOGY REPORTS 21: 363-369, 2009
Liver macrophages contribute to pancreatic
MARC E. MARTIGNONI1*, CORNELIU DIMITRIU1*, JEANINNE BACHMANN1, HOLGER KRAKOWSKI-ROSEN2,
KNUT KETTERER1, RALF KINSCHERF3and HELMUT FRIESS1
1Department of Surgery, Klinikum rechts der Isar, Technische Universität München, Munich;
2German Cancer Research Center, Heidelberg; 3Department of Anatomy and Developmental
Biology, Medical Faculty Mannheim, University of Heidelberg, Germany
Received July 6, 2008; Accepted August 25, 2008
Correspondence to: Dr Marc E. Martignoni, Department of
Surgery, Klinikum rechts der Isar, Technical University Munich,
Ismaninger Str. 22, 81675 Munich, Germany
Key words: pancreatic cancer, cachexia, liver, macrophages, grading
and IL-8 are linked to the ongoing stimulus in the develop-
ment of cachexia (14,16).
Previous investigations identified some important new
factors in the development of cachexia in pancreatic cancer.
It was shown that tumor cells and peripheral blood mono-
nuclear cells (PBMCs) produce high quantities of pro-
inflammatory interleukins in pancreatic cancer cachexia
(17,18). Additionally, in vitro PBMCs of pancreatic cancer
patients have been shown to be sensitized and stimulated by
IL-6-positive pancreatic cancer cells to produce IL-6 in large
amounts (17). Furthermore, in vitro PBMCs of cancer
patients induce an acute phase response in primary liver cell
lines via an IL-6-dependent mechanism (18).
In light of these findings, the aim of this study was to
further assess possible interactions between PBMCs/
histiocytes and the liver in pancreatic cancer patients with
and without cachexia and to further investigate the possible
central role of the liver in cachexia induction and regulation.
Patients and methods
Tissue collection from patients. Normal liver tissue samples
were obtained by open liver biopsy from 30 patients, 15 with
and 15 without cachexia, who underwent surgery for PDAC.
Since there is no generally accepted definition, cachexia in
pancreatic cancer patients was defined as unintended loss of
>10% of body weight in the 6 months before diagnosis.
Additionally, liver samples were obtained from 10 patients
with chronic pancreatitis who underwent pancreatic head
resection and from 5 patients with resection of colon cancer.
For use as controls, liver biopsies were obtained through an
organ donor program from 5 previously healthy individuals
who were free of any pancreatic or neoplastic disease.
Two of the 15 patients with PDAC and cachexia were
excluded after the final histological diagnoses proved to be
chronic pancreatitis and mucinous pancreatic carcinoma,
respectively. One patient in the group with PDAC without
cachexia was determined to have a papillary carcinoma and
was also excluded.
The study was approved by the local ethics committee of
the University of Heidelberg, Germany. All patients gave
preoperative written informed consent for the use of their
Immunohistochemistry. To immunohistochemically identify
leukocytes or macrophages we used antibodies directed
against CD68, a transmembrane protein expressed in
monocytes and macrophages, and against CD45, a
glycoprotein found in virtually all hematopoietic cells. All
MARTIGNONI et al: LIVER AND CACHEXIA IN PANCREATIC CANCER
Table I. Demographic characteristics of PDAC patients with or without cachexia.
Female 5 (38.5%)
Age (a) 68 (58/77)
IV 1 (7.7%)
No 8 (61.5%)
Yes 5 (38.5%)
Weight loss (kg)11.0 (8.0/15.0)
Weight loss (%) 14.6 (10.0/19.9)
BMI 23.12 (22.02/25.67)
No cachexia (n=14)P-value
Figure 1. Box plots of percentage of CD45-immunoreactive cross sections
of liver biopsies from patients with pancreatic adenocarcinoma with (n=13)
and without (n=14) cachexia. Patients with chronic pancreatitis (CP) (n=10),
patients with colon cancer (n=5) and normal donors (n=5) served as
freshly removed liver biopsies were immediately fixed in 5%
paraformaldehyde solution for 24 h, then embedded in
paraffin, after which 3-μm cross sections were processed for
immunohistochemistry. Briefly, sections were deparaffinized
in successive dilutions of ethanol. Heat-induced epitope
retrieval was performed in a microwave oven using 10 mM
citrate buffer at pH 6.0 for 20 min. Endogenous peroxidase
activity was blocked with 3% hydrogen peroxide. To block
unspecific activity, tissues were treated with preimmune goat
serum. Tissues were incubated with ready-to-use antibodies
directed against CD68 or CD45. The sections were then
incubated at 4˚C overnight with mouse monoclonal primary
antibody against CD68 or CD45 (both from Dako, Hamburg,
Germany), IL-1 or IL-6 (both from Abcam Inc., Cambridge,
MA, USA). After washing, an antimouse secondary antibody
was applied for 45 min. Dako Envision+ detection system
was applied for signal visualization. Nuclei were counter-
stained with hematoxylin. In each experiment, incubation of
cross sections without using the primary antibody was
performed as a negative control.
Quantification of the stained cells. To allow quantification of
the whole slide, the complete area of the slide was counted
using the KS300 v. 3.0 software from Carl Zeiss Vision
GMBH, Jena, Germany. Stained cells were counted as
follows: all sections were scanned at x200 magnification and
the total area and the stained area of each section were
measured. Then the total stained area of the slide was
measured by semi-automatic counting. The area of immuno-
reactive cells was expressed as the percentage of stained
area out of the total area of the section.
Statistical analysis. Data were calculated as median, upper
and lower quartile (median; 25th/75th) unless indicated
otherwise. For statistical analysis, the Mann-Whitney test and
the correlation according to Pearson and Spearman were
performed using the statistical software package SPSS
version 15.1 for Windows from SPSS Inc. (Chicago, IL,
USA). A p<0.05 was considered as statistically significant.
The preoperative characteristics of the PDAC patients with
and without cachexia are summarized in Table I. There were
no differences between the two groups regarding gender, age,
ASA classification, or incidence of preoperative diabetes.
Patients with PDAC and cachexia who had substantial
weight loss and low BMI however reported feeling worse.
CD45 and CD68 immunohistochemistry of cross sections of
liver biopsies. Although there was a tendency toward a
higher infiltration rate of CD45-positive leukocytes in cross
sections of liver biopsies of PDAC patients with cachexia,
CD45-positive areas were similar in cross sections of liver
biopsies of PDAC patients with (11.34; 6.30/14.91) and
without cachexia (8.30; 5.45/12.23), patients with chronic
ONCOLOGY REPORTS 21: 363-369, 2009
Figure 2. Immunohistochemistry of CD68-positive areas in cross sections of liver biopsies from a pancreatic cancer patient with cachexia (A) without
cachexia; (B) a colon cancer patient; (C) and a normal donor and (D) with hematoxylin counterstaining. Magnification, x200.
pancreatitis (7.18; 4.86/15.22), colon cancer patients (4.62;
3.97/6.72) and normal donors (4.11; 3.19/7.23) (Fig. 1; Table II).
However, we found a significantly increased area of CD68-
positive macrophages in cross sections of liver biopsies from
cachectic (6.96; 3.67/9.90) compared to non-cachectic (3.68;
2.84/6.48) PDAC patients (Figs. 2 and 3; Table II). However,
the percentage of CD68-positive areas in cross sections of liver
biopsies from patients without cachexia was similar to that in
liver cross sections from patients with chronic pancreatitis
(3.84; 2.61/5.85), patients with colon cancer (4.39; 3.06/
4.935), or healthy donors (2.69; 2.42/ 5.155), all of whom
served as control groups (Fig. 3).
IL-6 and IL-1ß immunohistochemistry in liver sections. In
liver sections of cachectic PDAC patients, the percentage of
IL-6-immunoreactive area was significantly (p=0.048)
increased (13.16; 8.57/27.77) in comparison with non-
cachectic PDAC patients (6.51; 5.25/12.88) or patients with
chronic pancreatitis (1.52; 0.64/9.52), colon cancer (0.46;
0.0/1.715) or donors (0.04; 0.005/0.135) (Table II). However,
MARTIGNONI et al: LIVER AND CACHEXIA IN PANCREATIC CANCER
Table III. Tumor load and features of patients with PDAC with or without cachexia.
Tumor size (n)
Stage 3 6 (85.7%)
Stage 4 1 (14.3%)
Lymph node (n)
No 6 (46.2%)
Yes 7 (53.8%)
CA 19-9 (U/ml) 1271.0 (40.7/3253.0)
No cachexia (n=14)P-value
Table II. Serum albumin, CRP, Hb and bilirubin levels as well as percentage of CD45, CD68 or IL-6 immunoreactive area in
cross sections of liver biopsies of PDAC patients with and without cachexia.
CD45 11.34 (6.3/14.91)
Albumin (g/l) 41.05 (39.03/42.28)
CrP (mg/l) 6.6 (2.6/22.2)
Hb (mg/dl) 12.6 (10.6/13.3)
Bilirubin (mg/dl) 1.0 (0.35/2.58)
No cachexia (n=14)P-value
Figure 3. Box plots of percentage of CD68-immunoreactive cross sections
of liver biopsies. The area of CD68-positive cells in normal liver tissue was
significantly greater in patients with pancreatic cancer and cachexia than in
patients without cachexia. Patients with chronic pancreatitis and colon
cancer and normal donors served as controls.
IL-1ß immunostaining of liver sections was very faint in all
groups, and thus could not be quantitatively evaluated.
Double staining of liver sections revealed localization of
CD68-positive macrophages close to IL-6-immunoreactive
hepatocytes. CD68-positive macrophages and IL-6-immuno-
reactive hepatocytes were mainly localized in the portal-
venous fields of the liver (Fig. 4).
Correlation with clinical parameters. PDAC patients with G3
tumors (7.36; 5.76/9.14) exhibited a significantly increased
percentage of CD68-immunoreactive areas in liver sections
compared to patients with G2 tumors (3.50; 2.73/6.89) (p=0.03;
Fig. 5A). In contrast, patients with high and low tumor grades
showed no difference in the percentage of CD45-immuno-
reactive area. However, there was no correlation between the
percentage of CD68-immunoreactive area in liver sections and
either tumor size, lymph node status or resectability of the
tumor. In addition, no correlation with the presence of liver
metastasis was found [CD68 in M0: (5.37; 1.93/7.70) and in
M1: (3.67; 3.17/6.73) patients], although patients with
cachexia had a higher incidence of metastatic disease
(Table III; Fig. 5B).
ONCOLOGY REPORTS 21: 363-369, 2009
Figure 4. Immunohistochemistry in liver tissue of IL-1ß and IL-6 from patients with pancreatic adenocarcinoma without cachexia (A and D) and with
cachexia (B and D). CD68 cells are stained in brown and IL-1ß and IL-6 are stained green. Magnification, x100.
Figure 5. (A) Percentage of CD68-positive areas in PDAC patients are significantly higher for G3 tumors than for G2 tumors (n=19). (B) The presence of
liver metastasis in patients with PDAC did not change the percentage of CD68-positive areas in liver biopsies of normal liver tissue.
However, a significant positive correlation (p=0.04)
between the percentage of CD68-positive area in liver cross
sections and the serum CrP concentration was found for
PDAC patients, although this significant correlation depends
on one outlier (highest CrP level). Furthermore, the percen-
tage of CD68-immunoreactive area in liver sections was
significantly (p=0.019) inversely correlated with the total
blood protein count and with albumin concentration in
patients with and without cachexia.
In liver sections of PDAC patients, the percentage of IL-6-
immunoreactive area significantly correlated with the
presence of cachexia (p=0.003) and the degree of weight loss
(p=0.017), whereas no correlation was found with regard to
Cachexia is a wasting condition with a significant impact on
mortality and morbidity in pancreatic cancer (7). Despite
intensive efforts to uncover its intricate pathways, the chain
of events leading to cachexia is still not fully understood.
Some of the main factors previously identified in the
development of cachexia in pancreatic cancer are the tumor
itself, PBMCs (peripheral blood mononuclear cells), as well
as muscle and fat tissue (14,17,19). Recent studies suggest
that the liver may play an important role in the development
of cancer cachexia, but the underlying mechanisms and the
degree of involvement of the liver in the pathogenesis are
still unclear (18,20,21). Therefore, we investigated the
histomorphologic changes in liver sections of PDAC patients
with or without cachexia and correlated these findings with
the clinical status of the patients. Up to now all available data
concerning an interaction between the tumor and the liver are
based on in vitro studies (20,22). Therefore, our objective
was to directly investigate the pathology of the normal liver
in cancer patients and to view these results in the context of
apparent changes in the liver tissue. As earlier and recent
studies suggest an interaction of the liver and the tumor
possibly mediated by mononuclear cells, we focused on
infiltration of these cells into the liver in this context (17,18,20).
For this purpose we used the pan-leukocyte marker CD45
and the CD68 antibody to identify macrophages, such as
those localized in the liver (liver macrophages, Kupffer cells)
(23,24). Whereas the leukocyte infiltration (identified by
CD45 immunoreactivity) into the liver seemed not to be
different in the groups tested, the number of CD68-positive
macrophages was significantly higher in liver sections of
cachectic PDAC patients in comparison with all other
Based on these results, it is tempting to speculate that the
number of infiltrating leukocytes and of macrophages is not
different, but that in liver sections of cachectic PDAC
patients the macrophages/Kupffer cells are specifically
activated as indicated by CD68 immunoreactivity. This
hypothesis may be confirmed by our finding of a positive
relationship between the percentage of CD68-immuno-
reactive area in liver sections and the presence of cachexia in
PDAC patients (Fig. 2A).
Recently it was shown that during hepatic immuno-
response to various insults, Kupffer cells are key initiators
of inflammation (25). Therefore, according to our data, the
presence of an increased number of CD68-positive
macrophages in the liver suggests that this organ may play a
much more important role in the development of cachexia in
PDAC patients than has been suspected up to now. These
findings are supported by in vitro experiments of Watchorn
et al, showing that tumor-derived factors such as the muscle
proteolytic proteoglycan PIF are able to trigger the release of
TNF-·, IL-6 and IL-8 from isolated Kupffer cells.
Subsequently, transcription factors such as nuclear factor-
kappa B (NF-κB) and STAT3 are activated, which can
further trigger neighboring hepatocytes to produce additional
pro inflammatory cytokines and acute phase proteins (20).
The amount of IL-6 staining in hepatocytes surrounding the
CD68-positive liver macrophages was significantly greater
in cachectic PDAC patients than in patients without
cachexia, whereas IL-1ß staining in the liver was very faint
in all groups, with a tendency to be more intense in cachectic
patients. This suggests that in patients developing cachexia,
liver parenchymal cells may be triggered by macrophages to
produce pro-inflammatory cytokines like IL-6, whereas IL-
1ß may play a more important role in muscle and fat tissue
In previous studies clinical parameters for liver function
were assessed (18,26). A strong inverse correlation with
serum levels of albumin and total protein concentration was
found, indicating a profound alteration of protein synthesis in
the liver. With regard to these data, it provides further
evidence that the liver might be one of the key factors in the
development of cancer cachexia. This could be a further
argument for the consideration of serum level of CrP as a co-
marker of cachexia in pancreatic cancer, as has been
proposed in recently published clinical studies (26).
To check for specificity of this CD68 pattern in pancreatic
cancer, normal liver tissue samples from patients with
chronic pancreatitis and colon cancer were subsequently
analyzed. All CD68-positive areas in liver tissues of
pancreatic cancer patients without cachexia and in chronic
pancreatitis and colon cancer patients were comparable with
those found in the livers of normal donors, suggesting that
pancreatic ductal adenocarcinoma and colon cancer do not
entirely share the same pathways of cachexia (Fig. 2).
However, the extent to which this CD68 liver pattern can be
found in other digestive neoplasias is still a matter for further
To assess these liver features in the context of pancreatic
cancer, the anatomical parameters of the tumor were
analyzed. Patients with cachexia had a higher incidence of
liver metastasis than patients without cachexia, and there was
a tendency toward more dedifferentiated tumor grading (66.7
vs. 38.5%), but tumor size, lymph node involvement and
tumor load indicated by CA 19-9 were not significantly
different (Table III). This may suggest that the development
of cachexia is not necessarily related to the growth or size of
the tumor, but is dependent on the aggressiveness of the
tumor, as represented by histopathological grading. This is
underlined by the finding that there was no relationship
between percentage of CD68-positive areas and resection
status, tumor size, lymph node involvement, or preoperative
identification of liver metastases, but cachectic pancreatic
MARTIGNONI et al: LIVER AND CACHEXIA IN PANCREATIC CANCER
cancer patients with G3 tumors exhibited significantly more Download full-text
enhanced CD68-positive areas in liver than patients with G2
tumors. Higher amounts of CD68-positive cells in liver
correlated with the presence of cachexia, a finding that
underlines the importance of histopathological grading of
pancreatic cancer patients (8).
One of the most important prognostic parameters in
pancreatic cancer is histopathological grading of the tumor.
Mayer et al observed a significant correlation between tumor
grading and survival time in a series of 113 patients, with
5-year survival rates of 33% for patients with G1 tumors,
10% for those with G2 tumors and 0% for those with G3
tumors. Furthermore, tumor grading appeared to be an
independent factor in multivariate analysis (27). In view of
these data, we may hypothesize that histopathological
features of the tumor produce structural changes in the liver,
which are subsequently related to cachexia. Since there was
no correlation between these changes and the resection
status, tumor size, lymph node involvement or preoperative
identification of liver metastases, we can further hypothesize
that, once in place, these structural modifications of the liver
might be able to trigger and maintain a cachectic status,
independent of the further presence of the tumor in the
organism. Under these circumstances, we suggest pancreatic
cancer to be a systemic disease, since it is able to produce
structural alterations in organs other than the pancreas itself,
independent of the presence of metastases, tumor size or
lymph node involvement.
We wish to thank Mrs. Silke Vorwald for excellent technical
assistance with immunohistochemistry and Mrs. Magdalena
Geiss for excellent support during the study. This study was
supported by a grant of the National Cancer Center
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