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Department of Obstetrics and Gynecology [T. R., C. H., D. R., B. G., K. F.], Institute of Immunology [D. Ko., H-J. T.], University of Rostock, 18055 Rostock, and Department of Immunology, Paul-Ehrlich-Institute, 63225 Langen [D. Ka.], Germany
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ABSTRACT |
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Introduction |
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TopABSTRACTIntroductionMaterials and MethodsResultsDiscussionREFERENCES |
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Recently, it has been shown that an additional mechanism might play an important role in the immune escape of tumors. A variety of apoptosis-inducing ligands like the tumor necrosis factor, FasL, and the tumor necrosis factor-related apoptosis-inducing ligand have been found to induce apoptosis in target cells that express the corresponding receptors. Fas, the receptor of FasL, trimerizes upon activation by FasL and binds to an intracellular death domain containing protein called Fas-associated death domain protein, thereby activating a cascade of caspases perpetuating the apoptotic process of cell killing (7) . Expression of Fas has been detected in numerous different solid tissues (8) and in the hematopoietic system.
Elevated FasL expressions have been found in tumor cells of colon (9) , esophageal (10) , stomach (11 , 12) , lung (13) , and ovarian cancer (14) . In esophageal cancer, areas of the tumor that expressed high FasL levels showed a reduction in the number of TILs and an increased apoptosis of TILs (10) . FasL expressed by tumor cells seemed to induce apoptosis in Fas-sensitive TILs. In another study, FasL-positive hepatoma cells displayed reduced Fas expression, in accordance with loss of sensitivity to Fas-mediated apoptosis (15) .
To assess FasL and Fas expressions in malignant human tissues in comparison with normal human tissues, FasL and Fas levels as well as FasL:Fas ratios were determined in mRNA pools derived from 25 normal human tissues and correlated with results obtained from the analysis of 257 human breast specimens. Absolute copy numbers of FasL and Fas mRNAs were determined by quantitative RT-PCR, and their distribution within the tumor was visualized by immunohistochemical analysis. Expression and distribution of FasL and Fas were analyzed in breast carcinoma (n = 215), fibroadenoma (n = 37), and normal breast tissue (n = 5) at the mRNA and partly at the protein level. The present study was designed to address the role of the apoptosis-inducing ligand FasL and its receptor Fas in breast carcinoma as a possible mechanism for the immune escape of the tumor.
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Materials and Methods |
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TopABSTRACTIntroductionMaterials and MethodsResultsDiscussionREFERENCES |
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In brief, RNA of heart came from 2 female Caucasians, ages 16 and 36; pancreas RNA from 18 male/female Caucasians, ages 17–69; liver RNA from 2 male/female Caucasians, ages 15 and 35; and RNA from cerebellum from a 64-year old male Caucasian (death by acute heart failure). Small intestine RNA was pooled from 11 male/female Caucasians, ages 15–60; stomach RNA from 15 male/female Caucasians, ages 23–61; spleen RNA from 5 male Caucasians, ages 22–48; RNA of bone marrow from 3 male/female Caucasians, ages 24–59; and fetal brain RNA from 8 male/female spontaneously aborted Caucasian fetuses, ages 20–34 weeks. Fetal liver RNA came from spontaneously aborted Caucasian fetuses, ages 15–24 weeks; adrenal gland RNA from 6 male Caucasians, ages 32–50; kidney RNA from 8 male/female Caucasians, ages 24–55; brain RNA from 2 female Caucasians, ages 16 and 36, and salivary gland RNA from 43 male/female Caucasians, ages 13–78. Lung RNA was pooled from 5 male/female Caucasians, ages 14–40; thyroid RNA from 4 male/female Caucasians, ages 10–46; trachea RNA from 84 male/female Caucasians, ages 17–70; mammary gland RNA from 8 female Caucasians, ages 23–47; colon RNA from 2 male Caucasians, ages 35 and 50; prostate RNA from 23 male Caucasians, ages 26–64; and spinal cord RNA from 31 male/female Caucasians, ages 17–72. Skeletal muscle RNA came from 10 male/female Caucasians, ages 23–56; thymus RNA from 13 male/female Caucasians, ages 17–37; testis RNA from 25 male Caucasians, ages 28–64; and placenta RNA from normal afterbirth of 15 female Caucasians, ages 22–41.
Patients and Tissue Collection.
Tissue samples of 215 unselected primary breast carcinomas, 37
fibroadenomas, and 5 normal breast tissues were collected during
surgery at the Department of Obstetrics and Gynecology of the
University of Rostock between 1994 and 1998. None of the patients had
received chemo-, radio-, or immunotherapy prior to surgery. The mean
age for breast cancer patients was 58 years (range, 29–90 years); for
patients with a fibroadenoma, 39.7 years (range, 15–67 years); and for
patients with normal breast tissue, 30.2 years (range, 20–42).
Sixty-three (29.3%) patients with breast cancer were premenopausal,
and 152 (70.7%) were postmenopausal. The majority of breast tumors
(n = 199; 92.5%) were invasive ductal
carcinomas; the others were invasive lobular carcinomas
(n = 7, 3.3%), mixed mucinous carcinomas
(n = 1, 0.5%), and medullary
(n = 5, 2.3%) and tubular carcinomas
(n = 3, 1.4%). All carcinoma patients of
this study underwent either total or partial axillary lymph node
dissection (mean number of nodes examined, 18). The main classifying
prognostic factors are shown in Table 1
. One hundred and five women (48.8%) were treated with simple
mastectomy and lymph node dissection, and 110 (51.2%) with lumpectomy
plus axillary clearance. Breast-conserving surgery was followed by
postoperative radiotherapy (n = 98). Two
hundred patients (93%) received adjuvant therapy, consisting of
chemotherapy (n = 52), hormone therapy
(n = 96), or both (n = 52).
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Of these patients, paraffin-embedded sections of 40 unselected breast carcinomas, 7 fibroadenomas, and 5 normal breast tissues were analyzed immunohistochemically. Upon submission of the investigation to the ethic committee of the Rostock Medical Association, it was ruled that no ethical approval was necessary.
Real-Time RT-PCR.
Total RNA of breast tissue was prepared using the acid guanidinium
thiocyanate-phenol-chloroform protocol (17)
. All specimens
were tested by analysis of housekeeping gene expression using
conventional RT-PCR. First-trimester placenta (FasL) from women
undergoing legal abortions and liver mRNA (Fas) served as positive
control.
The primer pairs and probes were designed using the Primer Express 1.0 program (PE Applied Biosystems, Foster City, CA). Oligonucleotide hybridization probes (18) and primer pairs with the following sequences were synthesized as follows: FasL: TaqMan probe 5'-TCC AAC TCA AGG TCC ATG CCT CTG G, forward primer 5'-AAA GTG GCC CAT TTA ACA GGC, and reverse primer 5'-AAA GCA GGA CAA TTC CAT AGG TG. The corresponding sequences for Fas are: TaqMan probe 5'-AAT CAT CAA GGA ATG CAC ACT CAC CAG CA, forward primer 5'-ACT GTG ACC CTT GCA CCA AAT, and reverse primer 5'-GCC ACC CCA AGT TAG ATC TGG. Primers and probes were obtained from Applied Biosystems GmbH (Weiterstadt, Germany). The primers yielded RT-PCR products of 82 (FasL) and 105 (Fas) nucleotides. Direct sequencing of the PCR product was performed with the automatic DNA sequencer ABI PRISM 310 Genetic Analyzer (PE Applied Biosystems) using ABI dye-terminator chemistry according to the manufacturer’s protocol. The sequencing reactions were repeated at least twice in both directions from independent template preparations to avoid the possibility of PCR artifacts.
Preparation of RNA Standard.
For calibration of the FasL and Fas TaqMan assays, two RNA standards
were generated by using an in vitro T7-polymerase
transcription system (RiboMAX Large Scale RNA Production System;
Promega Corp., Madison, WI). Using the TaqMan 5' and 3' primers, a
preparative standard PCR reaction was performed to produce a FasL- or
Fas-specific DNA fragment. The cloning procedure was carried out by
ligating the fragments into a SmaI linearized pBluescript KS
vector (Stratagene, La Jolla, CA). The correct plasmid clone was
purified by ionic exchange column DNA preparation (Qiagen, Valencia,
CA) and linearized by XhoI cleavage to generate a useful
template for producing a cutoff in vitro transcript. A
starting mixture was made by diluting the specific RNA molecules with a
competitor yeast tRNA (Life Technologies, Grand Island, NY) to a final
concentration of 1010 in vitro
transcripts in 2 µg of yeast tRNA per 10 µl (in water). This
starting mixture was used to prepare stock dilution series over eight
logs from 109 to 102
specific RNA molecules.
RT-PCR Procedure.
The TaqMan EZ RT-PCR kit (PE Applied Biosystems) was used for reverse
transcription and amplification of both targets and standards
(19)
. Production of cDNA and PCR amplification was carried
out in a single-tube, single-enzyme system without the addition of
subsequent enzymes or buffers. All RT-PCR reactions were performed in
duplicates with a final volume of 25 µl. The reaction conditions for
100 ng of total RNA were 2 min at 50°C, 30 min at 60°C, 5 min at
95°C, 35 cycles with 20 s at 94°C, and 1 min at 60°C. The
quantification of FasL and Fas RNA standards was linear over eight
logs, and the assay measured as little as 100 copies of FasL or Fas
mRNA copies per tube. The threshold cycle values decreased linearly
with increasing target quantity. In all experiments, the correlation
coefficient was between 0.985 and 0.995.
Immunohistochemical Detection of FasL and Fas.
Paraffin-embedded sections of breast carcinomas, fibroadenomas, and
normal breast tissues were deparaffinized in xylene and rehydrated
before analysis. Slides, treated with a pepsin solution and endogenous
peroxidase, quenched with 0.5% hydrogen peroxide, were washed in PBS,
blocked with 5% normal goat serum, and incubated overnight at 4°C
with a rabbit polyclonal antihuman Fas-specific IgG (Santa Cruz
Biotechnology, Santa Cruz, CA) at 0.4 µg/ml. A Vectastain ABC
detection kit (Vector Laboratories, Alexis Corp., San Diego, CA)
containing a biotinylated secondary antibody and avidin-conjugated
horseradish peroxidase was used to identify antibody binding.
Diaminobenzidine was used as substrate for the horseradish peroxidase.
Slides were counterstained with hematoxylin. For control staining, the
immunizing peptide (Fas, amino acids 316–335; Santa Cruz
Biotechnology) was coincubated at 4 µg/ml at primary antibody
incubation. In all cases, staining was inhibited by the immunizing
peptide. Fas, peptide controls, and negative control of one tissue
sample were detected at the same time. A mouse monoclonal antihuman
FasL-specific IgG1 (NOK-1; PharMingen, San Diego, CA) at 40 µg/ml was
used for FasL detection following the same protocol as described above.
The stained slides were evaluated by the department’s pathologist.
Immunohistochemical results were analyzed by light microscopy.
Localization and intensity of staining reaction of different cellular
components were compared with negative controls. Immunohistochemical
staining was considered positive when at least 10% of breast cells
were positive.
Statistical Analysis.
Clinical, histological, and biological parameters were compared using
the most appropriate among the Spearman correlation coefficient,
2 test, Mann-Whitney U test, and
Kruskal-Wallis H test. Disease-free and overall survival were analyzed
using Kaplan-Meier method, and comparison of study groups was performed
with the log-rank test. The Cox regression model was applied over both
univariate and multivariate analyses, with the associated likelihood
ratio test used for tests of trend differences. In all tests, the
significance level was set at P < 0.05, and
all were two-tailed tests.
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Results |
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. For FasL, low copy numbers of <10,000 molecules/µg total RNA were
detected in heart, pancreas, cerebellum, fetal brain, and skeletal
muscle. High copy numbers of >100,000 FasL/µg RNA molecules are
found in spleen, lung, and trachea (Fig. 1A)
. For Fas, low
copy numbers in the range of 30,000 to 60,000 molecules/µg RNA were
found in skeletal muscle, thyroid, salivary gland, fetal liver, and
cerebellum. High copy numbers of >300,000 molecules/µg RNA were
found in liver, spleen, adrenal gland, lung, trachea, prostate, thymus,
and testis (Fig. 1B)
. In mammary glands, mRNA levels of
34,000 FasL molecules and 268,000 Fas molecules/µg total RNA were
found, resulting in a FasL:Fas ratio of 0.14. A FasL:Fas ratio <1 were
determined in all normal tissues tested except a FasL:Fas-ratio >1 for
the spleen with known antigen-induced turnover of lymphocytes (Fig. 1C)
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Taking the absolute number of FasL and Fas molecules, elevated FasL copy numbers of >100,000 molecules/µg total RNA was found in 8 of 107 tumors of G1 (7.5%), in 14 of 81 tumors of G2 (17.3%), and in 8 of 24 tumors of G3 (33.3%). Of 37 fibroadenomas, only 2 had FasL values slightly >100,000 molecules. Normal breast tissue displayed 51,000 molecules as highest value. Compared with nonmalignant breast tissue (n = 42), invasive breast cancers of grade 1 (n = 105; P = 0.461) and of grade 2 (n = 81; P = 0.881) did not show significant differences regarding FasL mRNA expression. However, FasL expression was significantly higher in breast cancers of grade 3 (n = 24; P < 0.0001) compared with nonmalignant breast tissue.
In case of Fas expressions, high copy numbers of >300,000 molecules/µg RNA were found in 1 of 107 tumors of G1 (0.9%), in 1 of 81 tumors of G2 (1.1%), and in 2 of 24 tumors of G3 (8.3%). Two of 37 (5.4%) were detected in the group of fibroadenomas, and of one of five in normal tissues (20%). Comparison of Fas mRNA copy number per 1 µg total RNA revealed a significant difference, being highest in tissues of fibroadenoma, followed by breast carcinoma and normal breast tissue (P = 0.001/Kruskal-Wallis H test).
Within each group, the tumors were ranked according to their
FasL:Fas ratio. Of 107 G1 tumors, 30 had a ratio >1 (28%), of which
11 had ratios of >2 (10.3%). Of 81 G2 tumors, 25 had a ratio of >1
(30.9%), of which 9 displayed higher ratios than 2 (11.3%). Of 24 G3
tumors, 16 had a ratio >1 (66.7%), of which 6 had a ratio >2 (25%).
Of 37 fibroadenomas tested, none had a FasL:Fas ratio >1, all falling
within a range of 0.11–0.97. Normal tissues had ratios within the
range 0.11 to 0.73. Breast cancer tissue expressed the highest ratio of
FasL:Fas mRNA transcripts, followed by fibroadenoma and normal breast
tissue (P < 0.0001). The FasL:Fas ratios of
199 invasive ductal breast carcinomas are specified according their
histological grades in Fig. 2
. The median for the FasL:Fas ratio in breast cancer was 0.74 (95% CI
for mean, 0.92–1.29); in fibroadenoma, 0.31 (95% CI, 0.31–0.48); and
in normal breast tissue, 0.28 (95% CI, 0–0.64). All fibroadenomas and
normal breast tissues showed a FasL:Fas ratio <1, whereas 34% (72 of
211) of breast cancers showed a ratio >1.
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) and showed a tendency toward increased mortality
(P = 0.19; Fig. 3B
).
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Relationship between FasL and Fas mRNA Copy Numbers and Other
Variables in Fibroadenoma.
Among 37 fibroadenomas, no association was seen between FasL or Fas
mRNA copy numbers and tumor size, age, body mass index, partus,
or day of menstrual cycle.
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Discussion |
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TopABSTRACTIntroductionMaterials and MethodsResultsDiscussionREFERENCES |
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In our study, FasL expression appears to be highly correlated with the
histological grading of breast carcinomas. In particular, the ratio of
invasive ductal breast tumors with a FasL:Fas ratio <1 decreased with
histological grades from 1 to 3 (Fig. 2)
. Thus, it is tempting to
speculate on whether FasL expression is implicated in selecting more
highly aggressive tumor clones. In particular, tumor cells expressing
FasL might essentially escape the attack by immune cells
(counter-attack model). However, in addition, FasL-expressing tumor
cells should definitely facilitate the selection of more aggressive
tumor variants by tumor fratricide, leading to tumor cells that become
resistant to FasL-mediated programmed cell death.
The expression of FasL and Fas on mRNA as well as on the protein level
was determined in breast carcinoma, fibroadenoma, and normal breast
tissue. Although FasL mRNA copy numbers did not differ between breast
cancers and fibroadenomas, the ratio of FasL:Fas transcripts was
significantly higher in breast cancers than in fibroadenomas. In
comparison to the human body screening of FasL and Fas RNA transcripts,
the cutoff value of 1 for the FasL:Fas ratio seems to be a reliable
parameter (Fig. 1)
. With the exception of spleen RNA, our results
indicate that FasL:Fas ratios >1 might be an exclusive feature of
malignant tissues. Eighty-five % of breast carcinomas were found to be
positive for immunohistochemical staining of FasL, whereas only one
fibroadenoma and one normal breast tissue showed a positive reaction.
All of these findings indicate an important difference between
malignant and benign breast tissues.
In our study, FasL mRNA copy numbers were positively correlated to
histological grading. In addition, a positive lymph node status was
related to higher FasL copy numbers. A relationship between our RT-PCR
and immunohistochemical results on FasL and Fas in breast carcinomas
can be demonstrated. In cases of negative immunohistological stainings,
a tendency toward the presence of low RNA copy numbers became evident
(Table 2)
. The rate of positive immunohistochemical findings increases
with the median of mRNA copy numbers. Especially for FasL, weak
staining reaction (only 10–15% of breast cells were positive) was
associated with lower median values of mRNA copy numbers. However, the
comparison of the two techniques used is limited because the TaqMan
RT-PCR analysis quantitates mRNA copy numbers, whereas
immunohistochemical studies deliver qualitative data on protein
expression. Thus, the RT-PCR analysis confers higher sensitivity and
accuracy compared with immunohistochemical staining. Furthermore, the
sensitivity of the immunohistochemical data might vary depending on the
binding affinities of antibodies being used. Fibroadenomas expressed
the highest copy numbers of Fas mRNA, which was consistent with the
immunohistochemical finding of strong, homogeneous expression of Fas in
these benign tumors. Surprisingly, we also found a high amount of copy
numbers for Fas mRNA in mammary carcinomas. Eighty-eight % of the
immunohistochemically analyzed carcinoma specimens stained positive for
Fas. It appears that the malignant potential of tumors is correlated to
the absolute amount of FasL and partially to the copy numbers of Fas.
Finally, the ratio of FasL:Fas mRNA transcripts has been found to be
the most reliable parameter to determine the prognostic status of the
disease. A subgroup of one-third of breast cancer patients with a
FasL:Fas ratio >1 showed a significant shorter disease-free survival
(Fig. 3A)
. From 31 patients having breast tumor of grade 1
and a FasL:Fas ratio >1, one patient died and three had a relapse;
from 24 patients having tumors of grade 2, four died and one relapsed;
and from 16 patients having tumors of grade 3, three died and three
relapsed (Fig. 2)
. The importance of the FasL:Fas ratio as a prognostic
factor needs to be assessed over a longer period with extended numbers
of patients. However, ratios >1 identify a group of highly malignant
breast cancers and therefore might be considered as criteria for the
determination of therapeutic regimens.
Ideally, a new prognostic factor should be evaluated only in the setting of individuals who have not received any systemic therapy. According to the Sixth International Conference on Adjuvant Therapy of Primary Breast Cancer held in St. Gallen, Switzerland (February 1998), all patients with axillary lymph node-positive tumors should have adjuvant systemic treatment, and >95% of node-negative patients are candidates for adjuvant therapies. Ninety-three % of all patients in our study received adjuvant therapy, of which 57% were lymph node negative.
The possibility that there is an interaction between the FasL:Fas ratio and response to various therapies must be taken into account. However, until now there has not been any evidence that apoptotic parameters like FasL or Fas are predictive factors in treatment of breast carcinomas. The reverse distribution of G1 (50.5% G1) versus G2 (38.2%) tumor grades in our study might be explained by the limited sample number of n = 215 and by low intra- and interobserver reliabilities known to occur by semiquantitative grading analysis.
Several mechanisms of escaping Fas-mediated apoptosis have been
described. Down-regulation of Fas has been shown in some carcinomas,
such as hepatoma, intestinal-type stomach carcinoma, or breast cancer
cell lines (12
, 15
, 23)
. However, other carcinomas, such
as esophageal carcinoma (10)
and the breast carcinomas in
this study, still express Fas on the cell surface. Therefore, other
mechanisms for evasion of Fas-mediated apoptosis downstream of the
receptor are required. The Fas-resistant cell line MCF-7 became
sensitive to Fas-mediated apoptosis upon transfection with the
interleukin-1ß-converting enzyme, an important protein acting
downstream of Fas (23)
. Recently, 39 of 40 breast
carcinoma tissues were found to express only weak or no
bax-
mRNA. Transfection of the MCF-7 cell line
with bax- cDNA increased strongly the sensitivity of
these cells to Fas-mediated apoptosis (24)
.
Initial studies (25)
undertaken on a small number of
ductal invasive breast carcinoma (n = 18)
confirm our own observation that the presence of FasL mRNA in the whole
breast tissue is not a product of leukocytic contamination. In their
breast cancer sections, FasL was localized to the cytoplasm and
membrane of tumor cells. In our study, FasL:Fas ratios of >1 strongly
correlate with the grade of invasive ductal carcinomas (Fig. 2)
. The
proportion of invasive ductal carcinomas with FasL:Fas ratios <1 seems
to decrease with grades 1–3. These data are highly suggestive of
selection processes involving tumor fratricide. Up-regulation of FasL
expression probably induces killing of Fas-bearing tumor cells by
promoting the selection of malignant tumor variants, the Fas pathway of
which has become insensitive to FasL binding. Initially, induced Fas
expression might have been expected to favor the elimination of
cellular tumor mutants, but on the contrary, the contemporary
expression of FasL promotes the selection of cells also defective in
the Fas pathway. Furthermore, reducing the tumor size by eliminating
fewer malignant cells enables limited nutrients and oxygen to be used
predominantly for propagating more aggressive tumor variants.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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1 Supported by the general research fund of the
Department of Obstetrics and Gynecology, University of Rostock (to
T. R., C. H., D. R., B. G., and K. F.). 
2 T. Reimer and C. Herrnring contributed equally
to this work.
3 To whom requests for reprints should be
addressed, at Institute of Immunology, Post Office Box 10 08 88,
D-18055 Rostock, Germany.
4 The abbreviations used are: TIL,
tumor-infiltrating lymphocyte; FasL, Fas ligand; Fas, Fas receptor;
RT-PCR, reverse transcription-PCR; CI, confidence interval.
Received 9/14/99. Revised 12/ 1/99. Accepted 1/ 4/00.
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, which is downregulated in breast cancer, restores sensitivity to different apoptotic stimuli and reduces tumor growth in SCID mice. J. Clin. Investig., 97: 2651-2659, 1996.[Medline]
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