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Division of Molecular Biology, School of Life and Health Sciences, University of Delaware, Newark, Delaware 19716-2590
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ABSTRACT |
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Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References
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Cancer is
consistently associated with anorexia. The Lobund-Wistar rat model of
prostate cancer exhibits clinical manifestations (including anorexia)
that resemble many aspects of the human disease. Cytokines are proposed
to be involved in cancer-associated anorexia. Here we investigated mRNA
profiles of feeding-modulatory cytokines and neuropeptides in specific
brain regions of anorectic Lobund-Wistar rats bearing prostate
adenocarcinoma tumor cells. Interleukin (IL)-1
system components
(ligand, signaling receptor, receptor accessory proteins, receptor
antagonist), tumor necrosis factor-
, transforming growth
factor-1, glycoprotein 130 (IL-6 receptor signal transducer),
proopiomelanocortin (POMC, opioid peptide precursor), and neuropeptide
Y (NPY) mRNAs were analyzed with sensitive and specific RNase
protection assays. The same brain region sample was assayed for all
components. The data show that early anorexia in tumor-bearing rats was
associated with an upregulation of IL-1 mRNA in the brain regions
examined (cerebellum, cortex, and hypothalamus). IL-1 receptor
antagonist (IL-1Ra) mRNA and IL-1 receptor type I mRNA levels were also
significantly increased in the cortex and hypothalamus. All other
cytokine components, POMC, or NPY mRNA levels were not significantly
different between tumor-bearing and pair-fed (control) rats. IL-1
mRNA and IL-1Ra mRNA were also significantly upregulated in the spleen
of tumor-bearing rats. These data suggest that
1) IL-1 mRNA upregulation in the brain may be relevant to the anorexia exhibited by the tumor-bearing Lobund-Wistar rat and 2) in vivo
characterization of cytokine components in discrete brain regions
during cancer is necessary to understand underlying molecular
mechanisms responsible for cancer-associated neurological
manifestations.
interleukin; tumor necrosis factor; growth factor; nervous system; neuroimmunology; hypothalamus; cortex; cerebellum; cancer; food intake; feeding; anorexia
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INTRODUCTION |
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Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References
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PROSTATE ADENOCARCINOMA is the most common cancer in men (10). The Lobund-Wistar rat model of autochthonous prostate cancer exhibits clinical manifestations (including anorexia) that resemble many aspects of the human disease (24, 25). Lobund-Wistar rats can be inoculated with prostate adenocarcinoma tumor cells derived from prostate adenocarcinomas that develop spontaneously in aged pathogen-free Lobund-Wistar rats (25). The transplanted prostate adenocarcinoma cells produce a local subcutaneous tumor. These tumor cells are transplantable only to the Lobund-Wistar strain (26). Thus the Lobund-Wistar tumor-bearing rat model allows investigation of tumor-associated processes from initiation to promotion to progression stages.
Cancer progression is multifactorial and involves complex chemical cascades and cell-to-cell interactions. These can be mediated by chemical factors produced by the tumor and/or the host, including cytokines, which are proposed to play a role in various aspects of tumor biology. Constitutive production of cytokines and growth factors has been reported in prostate gland cancer (9, 10). Studies in humans and animals support the involvement of cytokines in the induction of clinical manifestations (including anorexia) during cancer (18). Several studies have reported increased circulating levels of cytokines in a number of patients with various types of cancer, including prostate adenocarcinoma, but not all types (14, 18, 32). Thus no conclusive evidence has been obtained on a requirement of increased cytokine concentrations in the circulation to demonstrate cytokine involvement in the induction of cancer-associated neurological manifestations (15, 18). Cytokines have a short half-life and act not only in an endocrine fashion but also via paracrine, autocrine, and intracrine manners, activities that cannot be detected in the circulation. In fact, paracrine interactions represent a predominant mode of cytokine action. This suggests that cytokines may be involved in cancer-related clinical manifestations due to local synthesis of cytokines in an organ, e.g., the brain. In the present study we tested this possibility.
Lobund-Wistar rats bearing prostate adenocarcinoma tumor cells were
continuously monitored for the initiation and progression of anorexia.
After a definitive establishment of early anorexia, the control (pair
fed) and tumor-bearing rats were killed, and their brains and
peripheral organs were dissected. Various cytokine and neuropeptide
component mRNAs were determined in the brain (cerebellum, cerebral
cortex, and hypothalamus) and periphery (spleen, liver, and tumor)
using sensitive and specific RNase protection assays. We focused on the
interleukin (IL)-1 system and tumor necrosis factor- (TNF-)
because of their relevance as anorexigenic cytokines (18) and their
proposed involvement in malignant processes (e.g., Refs. 4, 13, 18, and
31). The IL-1 system includes IL-1 [predominant released
form of IL-1 (3)], IL-1 receptor type I [IL-1RI;
responsible for IL-1 signaling (27), modulation of the in vivo acute
phase response (16), and induction of neurological manifestations (12,
28)], IL-1 receptor accessory protein [IL-1R AcP; a protein
that increases binding affinity of IL-1 for IL-1RI when the 2 proteins are coexpressed (5, 33); IL-1R AcP expression also correlates
with IL-1 responsiveness (33)], and IL-1 receptor antagonist
[IL-1Ra; an endogenous inhibitor that antagonizes, by competitive
inhibition, IL-1-induced central nervous system actions (3, 17) and
binds to IL-1RI with nearly the same affinity as that for
IL-1]. The simultaneous investigation of various components of
a cytokine system (i.e., the ligand, signaling receptor, receptor
accessory protein, and endogenous inhibitor) can provide information on
the feedback regulation and contribution of each cytokine system
component.
We also examined transforming growth factor-1 (TGF-1), which is
proposed to stimulate tumor progression (6) and inhibit IL-1 and
TNF- activity (21). Messenger RNA levels of the following components
were also assayed: glycoprotein 130 (gp130), a common signal transducer
among receptors for members of the anorexigenic IL-6 subfamily (19)
that is homologous to the leptin receptor (1); proopiomelanocortin
(POMC), the precursor of -endorphin and melanocyte-stimulating
hormone that can modulate feeding; and neuropeptide Y (NPY), a potent
feeding-inducing peptide (30). Thus the concomitant analysis of
cytokine and neuropeptide systems can provide information on potential
endogenous chemical interactions (22).
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MATERIALS AND METHODS |
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Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References
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Subjects and maintenance. Male Lobund-Wistar rats (control and tumor bearing) were purchased from Dr. Morris Pollard (Lobund Laboratory, University of Notre Dame, Notre Dame, IN). The prostate gland adenocarcinoma tumor cells were inoculated subcutaneously into the outer side of the right leg of ~12-wk-old rats in Dr. Pollard's laboratory; control Lobund-Wistar rats received the subcutaneous administration of vehicle solution. Shortly afterward, the rats were received at the University of Delaware, placed individually, and maintained ad libitum on powdered rat food (Labdiet, PMI Feeds, St. Louis, MO) and tap water as previously described (23). The behavior of the rats and development of the tumor were monitored daily. Artificial light illumination was from 0600 to 1800, and room temperature was kept at 21 ± 2°C.
Powdered food consumption. The measurement of powdered food intake was the same as in previous studies (23). In all cases, food intake was measured to within 0.1 g. Rats were fed ad libitum daily, except between 1730 and 1800 when food was removed to be measured and replaced. Premeasured food was presented at 1800. Food intake was measured at 1730 (total daily consumption from 1800 to 1730).
Dissection of brain regions.
After the monitoring period, rats were decapitated and their brains
were quickly removed (in <30 s from time of decapitation) and
immediately placed in oxygenated PBS solution at 2-4°C. The brain was rinsed several times, and the cerebellum (vermis),
parietofrontal cortex, and the complete hypothalamus were dissected
with a tissue-slicer blade. Samples from peripheral organs (spleen and
liver) and the tumor were also taken. In all cases, the same
investigator performed the procedure. Each tissue sample was
immediately homogenized with guanidine thiocyanate-phenol solution (see
RNA isolation and analysis of IL-1,
IL-1Ra, IL-1RI, IL-1R AcP I and II, TNF-, TGF-1,
gp130, POMC, NPY, -actin, and GAPDH
mRNAs) and frozen at 
85°C. The tissue
samples were number coded for further processing and analyses. The
complete dissection and homogenization took <6 min.
RNA isolation and analysis of IL-1, IL-1Ra, IL-1RI,
IL-1R AcP I and II, TNF-, TGF-1, gp130,
POMC, NPY, -actin, and GAPDH mRNAs.
Total cell RNA was isolated from the tissue samples after
homogenization of the samples in guanidine thiocyanate-phenol solution (Tri Reagent, Molecular Research Center, Cincinnati, OH) using a
microtissue grinder. Each sample was homogenized and processed individually. RNA concentration was determined by spectrophotometry at
an absorbance of 260 nm. RNA integrity was assessed by agarose gel
electrophoresis with ethidium bromide staining. The levels of rat
-actin and rat glyceraldehyde-3-phosphate dehydrogenase (GAPDH) mRNA
were determined by RNase protection to confirm that an assay was
consistent and that an equal amount of total cell RNA was used for each
assay.
, IL-1RI, IL-1R AcPs, IL-1Ra, TNF-,
TGF-1, gp130, POMC, NPY, -actin, and GAPDH mRNAs.
Hybridization reactions containing 20.0 µg of total cell RNA and 2.5 × 104 counts/min each of
IL-1, IL-1RI, IL-1R AcP, IL-1Ra, TGF-1, and 1.5 × 104 counts/min of TNF-
antisense probe; 6.0 µg of total cell RNA and 2.5 × 104 counts/min each of gp130,
POMC, and NPY antisense probes, or 3.0 µg of total cell RNA and 2.0 × 105 counts/min each of
-actin and GAPDH antisense probes in 30 µl of hybridization buffer
[80% formamide, 0.4 M NaCl, 1 mM EDTA, and 40 mM PIPES (pH
6.4)] were heated to 85°C for 5 min and then incubated at
48°C for 12-18 h. After hybridization, 280 µl of RNase
digestion buffer [50 mM sodium acetate (pH 4.5) and 2 mM EDTA] was added with 30 U of T1 RNase (Sigma, St. Louis, MO) for all assays followed by incubation at 30°C for 60 min. RNase
digestion was terminated by the addition of 10 µl of 20% SDS and 50 µg of proteinase K and incubation for 30 min at 37°C. RNA was
extracted with phenol-chloroform and precipitated with 70 µg of yeast
transfer RNA by the addition of ethanol. RNA was dissolved in loading
buffer [80% formamide, 2 mM EDTA (pH 7.4) containing 0.05%
bromphenol blue and 0.05% xylene cyanol], denatured at 85°C
for 5 min, and resolved on 5% acrylamide-8 M urea gels using TBE
buffer (89 mM Tris pH 8.0, 89 mM boric acid, and 2.7 mM EDTA). Gels
were autoradiographed, and results were quantified with an image
analyzer (Image Quant; Molecular Dynamics, Sunnyvale, CA).
Densitometric values for each mRNA analyzed were converted to
percentage values of the total values for a particular mRNA.
In control experiments on hybridization specificity, an appropriate
amount of yeast transfer RNA was hybridized and processed as described
above. No signal corresponding to IL-1, IL-1RI, IL-1R AcP, IL-1Ra,
TNF-, TGF-1, gp130, POMC, or NPY was detected.
Riboprobe templates.
Rat IL-1 expression plasmid containing the entire mature peptide
coding sequence of rat IL-1 with one extra methionine codon at the
5'-end cloned into plasmid pET-21d (Novagen, Madison, WI) between
EcoR I and Nco I sites was
used. Plasmid rat riboprobe IL-1 (rRIL-1) was generated by
cloning IL-1 containing an Xba I-EcoR I fragment of the rat IL-1 expression plasmid into
pGEM-2 between the Xba I and
EcoR I sites. Plasmid rRIL-1 was linearized with
Hind III and transcribed with SP6 RNA polymerase to generate an ~570 nt-long antisense probe that protects 492 nt in the rat IL-1 mRNA.
cDNA (nt 1-708 of accession no. S40199) was used. Linearization of this plasmid by EcoR I and transcription
with SP6 RNA polymerase produced an ~790-nt-long antisense probe that protects 708 nt in the rat TNF- mRNA.
Rat TGF-1 cDNA (accession no. X52498) cloned into pBluescript II KS
vector (Stratagene) was used. Linearization of this plasmid by
BamH I and transcription with T3 RNA polymerase
produced an ~320-nt-long antisense probe that protects 244 nt in the
rat TGF-1 mRNA.
Rat gp130 cDNA (accession no. M92340) cloned into EcoR I
site of pBS vector was used. This cDNA was linearized with
Bsa I and transcribed with T3 RNA
polymerase to produce an ~590-nt-long antisense probe that protects
530 nt in the rat gp130 mRNA.
Rat POMC cDNA cloned between BamH I and EcoR
I sites of pBluescript KS(+) vector was used. The plasmid was
linearized with Xmn I, and T3 RNA
polymerase transcription resulted in an ~320-nt-long antisense probe
that protects 264 nt in the rat POMC mRNA (predominant form).
Plasmid pBLNPY-1 containing a 511-bp insert (accession no. M20373)
composing most of the cDNA of rat preproNPY ligated into the
EcoR I site of vector Bluescribe M13(-) was used.
Linearization of the plasmid with Bbs
I and transcription with T3 RNA polymerase produced an ~242-nt-long
antisense probe that protects 180 nt in the rat NPY mRNA.
Rat antisense template pTRI-GAPDH (Ambion, which contains a 316-bp
fragment of the rat GAPDH gene) was
used to generate the GAPDH antisense probe. Antisense template
pTRI--actin-125-Rat (Ambion, which contains a 126-bp cDNA fragment
of the rat -actin gene) was used to generate the -actin antisense
probe.
Data analyses. All results are expressed as means ± SE. Data were analyzed using ANOVA and, where appropriate (i.e., after a significant main effect), were followed by post hoc tests for pairwise comparisons (Student-Newman-Keuls method). A Kruskal-Wallis test was applied (followed by post hoc tests) when data did not pass the normality (Kolmogorov-Smirnov) and equal variance (Levene median) tests. Data were also analyzed using t-test or Mann-Whitney test (when data did not pass normality and equal variance tests). Differences were considered significant only for P < 0.05.
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RESULTS |
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Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References
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Food intake. The data are summarized in Fig. 1. Total daily food intake decreased gradually in the Lobund-Wistar rats bearing prostate adenocarcinoma tumor cells. The average total daily food intake was 19.2 g for days 11-19, 17.8 g for days 20-24, 16.0 g for days 25-32, and 13.3 g for the last 4 days (days 33-36). Each period was significantly different from each other period (Fig. 1). Data from days 1-10 are not available because of the rats' transit and quarantine procedures. However, during the initial 5 days of measurement (days 11-15), food intake was similar in both groups [mean of 19.8, 19.1, 20, 19.7, and 19.4 g for days 11-15, respectively, in tumor-bearing rats (n = 7) and 18.9, 18.6, 19.5, 19.5, and 18.9 g, respectively, in controls (n = 7)]. Thereafter, as required, the amount of food given to the control group was adjusted according to the amount of food eaten by the tumor-bearing rats during the previous day. Pair feeding continued until death. At the end of the behavioral monitoring period (36 days after tumor cell inoculation or vehicle administration), the body weights were 327 ± 11 g (n = 7) in the tumor-bearing Lobund-Wistar rats and 323 ± 4 g (n = 7) in the pair-fed controls. These data show that body weights were not significantly different. It should also be noted that animals were killed during the period of early moderate anorexia induced by the tumor; that is, rats were still eating >10 g of food. The subcutaneous tumors were noticeable but small. Thus food intake and body weight data indicate that none of the rats used in this study exhibited significant deterioration that is associated with severe long-term anorexia and the anorexia-cachexia syndrome.
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RNase protection assay of IL-1, IL-1Ra, IL-1RI,
IL-1R AcP I and II, TNF-, TGF-1, gp130,
POMC, NPY, -actin, and GAPDH mRNAs.
The levels of IL-1 system, TNF-, TGF-1, gp130, POMC, NPY,
-actin, and GAPDH mRNAs were determined in the cerebellum,
parietofrontal cortex, and hypothalamus from Lobund-Wistar control and
tumor-bearing rats. The same rats (n = 7 per group) were used to monitor the behavior and analyze the IL-1
system, TNF-, TGF-1, gp130, POMC, NPY, -actin, and GAPDH mRNA
levels in brain regions. Figures 2 and
3 present examples of the RNase protection
assays used. As shown, samples from both control and tumor-bearing
groups and the three brain regions were analyzed concomitantly.
Consistency was verified by analyzing all samples individually, from
which all means ± SE were generated. It should also be noted that
each individual sample was obtained from a different rat, that the same
rat provided all three brain regions, and that the same samples were
analyzed with all of the antisense probes as described in MATERIALS AND METHODS. The levels of
rat -actin mRNA (Fig. 2) and GAPDH mRNA (Fig. 3) were relatively
constant between treatments within a brain region; this indicates
consistency of processing and that an equal amount of total cell RNA
was used for each assay. Moreover, the specificity of the probes used
has been demonstrated previously by various procedures (7, 21),
including control experiments on hybridization specificity in which no
signal corresponding to IL-1, IL-1Ra, IL-1RI, IL-1R AcP, TNF-,
TGF-1, gp130, POMC, or NPY mRNA was detected.
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IL-1 mRNA in brain regions from control and
tumor-bearing rats.
The profile of IL-1 mRNA in the cerebellum, cortex, and hypothalamus
is shown in Fig. 4. ANOVA showed that
groups differed significantly in IL-1 mRNA
[F(5, 36) = 23.0, P < 0.0001, power of performed test
(ppt) = 1.0]. All three brain regions examined had robustly
significant differences between the control and tumor-bearing groups:
cerebellum, P = 0.0008, ppt = 0.98;
cortex, P < 0.0001, ppt = 1.0; and
hypothalamus, P < 0.0005, ppt = 0.99.
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IL-1Ra mRNA in brain regions from control and tumor-bearing rats. The data are summarized in Fig. 5. No significant difference in IL-1Ra mRNA levels between groups was observed in the cerebellum (P = 0.5). The cortex, on the other hand, exhibited a significant increase in IL-1Ra mRNA levels in the tumor-bearing group relative to the control group (P < 0.0001, ppt = 1.0). The difference in the hypothalamus was also significant (P < 0.05).
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IL-1RI mRNA in brain regions from control and tumor-bearing rats. The profile of the IL-1 signaling receptor mRNA is summarized in Fig. 6. The difference in IL-1RI mRNA levels in the cerebellum was not significant (P = 0.1). On the other hand, IL-1RI mRNA levels were significantly increased in the cortex (P = 0.001) and hypothalamus (P = 0.0006) obtained from tumor-bearing rats.
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IL-1R AcPs in brain regions from control and tumor-bearing rats. The profiles of IL-1R AcP I or membrane-bound IL-1R AcP and IL-1R AcP II or soluble form of IL-1R AcP mRNA levels did not change significantly in all three brain regions examined (data not shown).
TNF- mRNA in brain regions from control and
tumor-bearing rats.
The data are summarized in Table 1. TNF-
mRNA levels were not significantly different in the three brain regions
examined.
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TGF-1 mRNA in brain regions from control and
tumor-bearing rats.
The data are also summarized in Table 1. The levels of cerebellar,
cortical, and hypothalamic TGF-1 mRNA did not differ significantly
between control and tumor-bearing rats.
gp130 mRNA, POMC mRNA, and NPY mRNA in brain regions from control and tumor-bearing rats. As shown in Table 2, no significant differences in gp130, POMC, or NPY mRNA levels in the brain regions examined were observed.
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IL-1 mRNA and IL-1Ra mRNA in peripheral organs from
control and tumor-bearing rats.
We also examined IL-1 mRNA and IL-1Ra mRNA levels in two peripheral
organs, the spleen and liver. Peripheral tissue samples were obtained
from the same rats that provided the brain regions. The data obtained
in the spleen are summarized in Fig. 7.
Both IL-1 mRNA and IL-1Ra mRNA levels were significantly increased in the Lobund-Wistar rats bearing prostate adenocarcinoma tumor cells
relative to the controls. The liver also exhibited significantly higher
levels of IL-1Ra mRNA (32.6 ± 1.7 arbitrary units in tumor-bearing rats vs. 18.1 ± 2.2 arbitrary units in controls;
t = 5.26, P = 0.0004, ppt = 1.0).
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IL-1 mRNA in the tumor.
The prostate gland from control Lobund-Wistar rats had undetectable
levels of IL-1 mRNA. On the other hand, the signal for IL-1 mRNA
was robust in all tumor samples taken from the tumor-bearing rats
(n = 7).
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DISCUSSION |
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Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References
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The data show that anorectic tumor-bearing Lobund-Wistar rats exhibit
an upregulation of IL-1 mRNA in discrete brain regions (cerebellum,
cortex, and hypothalamus). IL-1Ra mRNA and IL-1RI mRNA levels are also
significantly increased in the cortex and hypothalamus. All other
cytokine components, POMC, or NPY mRNA levels were not significantly
different between tumor-bearing and control rats.
These data suggest that IL-1 mRNA upregulation in the brain may be
relevant to the early anorexia exhibited by the Lobund-Wistar rat
bearing prostate adenocarcinoma tumor cells. Previous studies proposed
that IL-1 can participate in the induction and progression of cachexia
(4, 18, 31). Using a colon tumor model, Strassmann et al. (31) showed
that intratumoral administration of IL-1Ra significantly reduced the
cachexia associated with the tumor. Gelin et al. (4) also reported that
treatment of rodents bearing methylcholanthrene-induced sarcoma with
monoclonal antibodies against the IL-1R inhibited tumor growth and
improved food intake. Moreover, the growth of Morris hepatoma in
rodents was also associated with increased levels of IL-1 in the spleen
(13).
The present study is the first to report upregulation of IL-1 mRNA
in peripheral organs and discrete brain regions of the same rat
responding to a peripheral tumor. The consistent increase in levels of
IL-1 mRNA in the tumor, spleen, and discrete brain regions suggests
that the tumor induces a series of events that result in local organ
production of IL-1. This is supported by our data because we used
IL-1 mRNA as an index of local production of the cytokine. Thus the
evidence suggests that local production of IL-1 in the brain (e.g.,
hypothalamus, an important feeding-regulatory brain site) could be
involved in the induction of early anorexia or exacerbation of early
anorexia in the Lobund-Wistar model of prostate cancer. This is
consistent with the fact that IL-1 induces anorexia by direct action
in the hypothalamus (18) and the report that intrahypothalamic
administration of IL-1Ra improves feeding in anorectic rats bearing
methylcholanthrene-induced sarcoma cells (11).
IL-1Ra mRNA and IL-1RI mRNA levels were also upregulated in brain
regions. IL-1Ra mRNA upregulation accompanies IL-1 mRNA upregulation
in various models (8, 21, 22). A balance between IL-1 and IL-1Ra
appears critical for an appropriate modulation of IL-1-associated
cellular responses in the brain (8, 21). However, a significant excess
of IL-1Ra is required to modulate IL-1-induced cellular responses
because the IL-1 system exhibits spare receptor effects, with maximal
biological response observed with occupancy of only 1-10% of IL-1
receptors. We have discussed this modulation in detail (21).
Upregulation of IL-1RI mRNA may also participate in the modulation of
cellular responses to IL-1 (8, 21).
The brain region cytokine profile obtained in Lobund-Wistar rats
bearing adenocarcinoma tumor cells is significantly different from the
brain cytokine profile observed in all other rodent models we have
investigated. In various models, for example, using specific bacterial
products (22), viral glycoproteins (7), or cytokines (8, 21), TNF-
and TGF-1 mRNAs are also significantly modulated. This indicates
that distinct cytokine profiles and cytokine-cytokine interactions
occur in brain regions depending on the underlying pathophysiological
process or challenge.
Our previous studies also showed that cytokine-cytokine (29) and cytokine-neuropeptide (30) interactions are important in cytokine-induced anorexia, depending on the model. The present study examined other components associated with feeding: gp130, POMC, and NPY mRNAs. These did not differ significantly in any brain region between control and tumor-bearing rats. This suggests that early anorexia in the Lobund-Wistar rat model of prostate cancer is not associated with changes in hypothalamic mRNA for gp130 [a transducer among receptors for IL-6 subfamily receptor members that have been shown to induce anorexia (19)], POMC (opioid peptide precursor that generates various feeding-modulatory opioid peptides), or NPY (a feeding-enhancer peptide proposed to participate in the maintenance of normal feeding). A previous study reported that hypothalamic concentration and release of NPY was reduced in anorectic rats bearing methylcholanthrene-induced sarcoma (2). Thus tumor type and clinical stage of the malignant process could be associated with differential neuropeptide profiles.
Perspectives
The data show that in vivo characterization of cytokine components in discrete brain regions during cancer induction and progression is essential to understand the underlying molecular mechanisms [including cytokine-neurotransmitter-neuropeptide interactions (20)] responsible for cancer-associated neurological manifestations. For example, cytokine upregulation in the hypothalamus is relevant to cancer anorexia, whereas in the cerebral cortex it could be involved in the induction of neuropsychiatric manifestations (e.g., depression, anxiety, and delirium) that commonly occur during cancer. Cytokine profile characterization in other organs may also be relevant to the understanding of the mechanisms involved in the host's biochemical and physiological response to tumor progression.| |
ACKNOWLEDGEMENTS |
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We thank Dr. Morris Pollard (Lobund Laboratory, University of Notre
Dame) for providing the Lobund-Wistar rats. We also thank Dr. Ronald P. Hart (Department of Biological Sciences, Rutgers University) for
providing the rat IL-1, IL-1Ra, IL-1RI, and IL-1R AcP cDNAs; Dr.
Karl Decker (Biochemisches Institut der Albert Ludwigs
Universität) for providing the rat TNF- cDNA; Dr. David Danielpour (National Cancer Institute) for providing the rat TGF-1 cDNA; Dr. Gerald M. Fuller (Department of Cell Biology and Anatomy, University of Alabama at Birmingham) for providing the rat gp130 cDNA;
Dr. Andrea Gore (Center for Neurobiology, The Mount Sinai Medical
Center) for providing the rat POMC cDNA; and Dr. Steven L. Sabol
(Laboratory of Biochemical Genetics, National Heart, Lung, and Blood
Institute) for providing the rat NPY cDNA.
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FOOTNOTES |
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Research was supported by funds from the University of Delaware and the National Institutes of Health (C. R. Plata-Salamán).
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. §1734 solely to indicate this fact.
Address reprint requests to C. R. Plata-Salamán.
Received 5 February 1998; accepted in final form 8 May 1998.
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Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References
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P < 0.05 compared with controls.
P < 0.002 compared with
controls.
