© 1999 by Oxford University Press
Journal of the National Cancer Institute, Vol. 91, No. 21, 1882-1887,
November 3, 1999
© 1999 Oxford University Press
REPORTS |
Laminin-5 as a Marker of Invasiveness in Cervical Lesions
Affiliations of authors: B. Skyldberg, Division of Cellular and Molecular Tumor Pathology, Department of Oncology and Pathology, Karolinska Institute, and Division of Biomedical Laboratory Technology, Department of Immunology, Microbiology, Pathology and Infectious Diseases, Huddinge Hospital, Karolinska Institute, Stockholm, Sweden; E. Eriksson, U. Aspenblad, G. Auer, Division of Cellular and Molecular Tumor Pathology, Department of Oncology and Pathology, Cancer Center Karolinska, Karolinska Institute and Hospital; S. Salo, Biocenter Oulu and Department of Biochemistry, University of Oulu, Finland; B. Moberger, Division of Obstetrics and Gynecology, Department of Woman and Child Health, Karolinska Institute and Hospital; K. Tryggvason, Biocenter Oulu and Department of Biochemistry, University of Oulu, Finland, and Division of Matrix Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institute.
Correspondence to: Barbro Skyldberg, Ph.D., Cancer Center Karolinska, R8:04, Karolinska Hospital, S-171 76 Stockholm, Sweden (e-mail: Barbro.Skyldberg{at}cck.ki.se).
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ABSTRACT |
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BACKGROUND: Treatment decisions for cervical cancer, a common disease worldwide, depend on demonstrating whether or not tumor invasion of the surrounding tissue has occurred. Invasion can be difficult to assess by standard histopathologic methods, especially when limited amounts of tissue are available. Several studies of a variety of cancers have reported increased expression of laminin-5—an important attachment protein for epithelial cells—in invasive carcinomas. This study was designed to investigate whether the presence of laminin-5 is related to the invasive capacity of cervical lesions. METHODS: We used immunohistochemical methods to stain archival, paraffin-embedded sections of cervical lesions with a polyclonal antibody specifically targeting the
2 chain of human laminin-5 protein. The study sample included 23
lesions of mild and moderate dysplasia (cervical intraepithelial neoplasia [CIN] 1 and
2, respectively), 32 lesions of severe dysplasia or carcinoma in situ (CIN 3), 15 lesions of
microinvasive cancer, and 20 lesions of frankly invasive cancer. Cellular proliferative activity was
also investigated by the use of monoclonal MIB-1 (directed against the antigen Ki-67) and
anticyclin A antibodies. RESULTS: Invasiveness of cervical lesions was positively associated with
immunohistochemical staining of the 2 chain of laminin-5 (two-sided P =
.001). All CIN 1 and CIN 2 lesions—except one CIN 2 lesion later shown to be invasive
cancer—and 21 CIN 3 lesions tested negative for the 2 chain of laminin-5. Eleven
CIN 3 lesions and all invasive cancers tested positive for this protein. One lymph node metastasis
and a pleural metastasis from one of the patients with invasive cancer showed strong
immunohistochemical positivity. Proliferative activity increased with advancement of the lesion
but was not confined to cells positive for the 2 chain of laminin-5. CONCLUSIONS: These
data suggest that antibodies directed against the 2 chain of laminin-5 can identify cervical
lesions with invasive capacity and thus may be useful as a sensitive marker of early invasion.
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INTRODUCTION |
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Cancer of the uterine cervix is one of the most frequent malignancies in women worldwide and the most common cancer in developing countries. Approximately 437 000 new cases of cervical cancer are diagnosed each year, and about 200 000 women die of the disease (1). In Sweden, it currently accounts for 2.4% of female cancers, a considerable reduction from 8.4% over the last 20 years (2). This fact is most likely due to the effectiveness of the cervical screening program in Sweden.
Approximately 90% of all cervical malignancies are squamous cell carcinomas. It is well documented that the sexually transmitted, genital human papillomaviruses (HPVs) (about 30 have been identified, mainly consisting of HPV16 and HPV18) are able to transform immature epithelial cells into precancerous cells (3,4). The precancerous stages develop preferentially from the immature cells in the transformation zone at the junction between the cervical squamous and glandular epithelia (5). The precancerous stages of invasive cervical carcinoma are defined as different grades of dysplasia; mild (cervical intraepithelial neoplasia: CIN 1), moderate (CIN 2), and severe dysplasia or carcinoma in situ (CIN 3) (6). Approximately 30% of all carcinomas in situ, when left untreated, are suggested to develop into invasive cancer after 13 years or longer (7). A later investigation (8) reported the proportion of cases of new carcinoma in situ that progressed to invasive cancer to be 12.2%, with a mean duration of the in situ stage of 13.3 years.
Treatment of cervical lesions is totally dependent on histopathologic judgment of whether or not a lesion is invasive. This distinction can be extremely difficult to assess, especially in small biopsy specimens and curettage material. A sensitive and objective diagnostic procedure determining the invasive potential of cervical neoplastic cells would, therefore, be of substantial value.
Invasion of the cancer into the stromal tissue requires, first, the ability of the cells to penetrate
the underlying basement membranes and, second, migration that involves adhesion to extracellular
matrix constituents, such as laminins, collagens, and fibronectins. Laminins are a family of
extracellular proteins that constitute a major component of basement membranes. The laminin
molecules are heterotrimeric proteins formed by the association of three different gene products,
one heavy 
chain and two light ß and chains [nomenclature according to
Burgeson et al. (9)]. To date, five chains, three ß chains,
and three chains that are known to form at least 10 laminin isoforms have been reported (10-13). Laminin-5, previously termed kalinin, nicein, epiligrin, or ladsin,
consists of 3 (14), ß3 (15), and 2
(16) chains. It is intimately involved in the attachment of epithelial cells
such as keratinocytes to the basement membranes (17-22). Accumulating
data suggest increased laminin-5 2 chain expression in most cases of carcinomas studied so
far, i.e., colorectal, pancreatic, and oral cancers (23-27), but decreases
have also been reported—e.g., in prostate cancer (28). In normal
epithelial cells, the expression of laminin-5 is strongly related to tissue renewal. During healing
skin wounds, strong laminin-5 expression has been observed in migrating keratinocytes (14,23,29). In 1995, Pyke et al. (24) suggested
that laminin 2 chain expression can serve as a marker of invasive cancer in colon
adenocarcinomas and in various types of squamous cell carcinomas. Similar results were reported
by Sordat et al. (27) for colorectal carcinomas. Laminin-5 has previously
been shown to be a ligand for the integrins 3ß1, 6ß1, 6ß4, and
2ß1 (18,30-32). Sordat et al. (27)
showed a decrease in the level of 6ß4 integrin in colorectal cancer, together with
increased laminin-5 expression.
In this study, we have evaluated expression of the 2 chain of laminin-5 as a potential
marker for early invasiveness in clinical lesions. Analyses of 90 lesions varying in neoplastic
advancement from mild dysplasia to invasive carcinoma demonstrated association of expression of
the 2 chain with invasive potential.
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MATERIALS AND METHODS |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionNotesReferences |
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Tissue Samples
Stored biopsy material from 14 women with cervical lesions diagnosed at the Department of
Pathology, Sabbatsberg Hospital, Stockholm, Sweden, from 1970 through 1977 and in 1992 and
from 47 women diagnosed at the Department of Pathology, Karolinska Hospital, Stockholm,
Sweden, from 1992 through 1998 was used in this study. The study protocol was cleared by the
ethical committee of the Stockholm County Council. The biopsy material was formaldehyde fixed,
paraffin embedded, and diagnosed on hematoxylin-eosin (H-E)-stained tissue sections. The
evaluated material consisted of four lesions of mild dysplasia (CIN 1), 19 lesions of moderate
dysplasia (CIN 2), 32 lesions of severe dysplasia or carcinoma in situ (CIN 3), 15 lesions
of microinvasive cancer, and 20 lesions of frankly invasive cancer. For some women with multiple
diagnoses (e.g., coexisting CIN 1, CIN 3, and microinvasiveness), more than one lesion was
investigated. From one of the patients with invasive cancer, specimens of lymph node metastases
in the pelvic wall and metastases in the pleura were studied. From each specimen, four
consecutive sections (4 µm thick) were cut and put onto specially treated slides (Menzel
Superfrost plus) for immunohistochemical studies of the 2 chain of laminin-5, Ki-67, and
cyclin A. Sections for H-E staining were cut before and after the other sections to confirm the
diagnosis.
All cases were selected by original histopathologic diagnosis, and the original diagnoses as well as the representativity of the sections used for histochemical studies were reviewed by two pathologists (E. Eriksson and G. Auer) and translated into the CIN grading system according to the procedure of Richart (6) before immunohistochemical staining was performed. Invasiveness was graded according to the International Federation of Gynecology and Obstetrics (FIGO) classification system (33) as follows: cancer in situ (FIGO 0), microinvasive cancer (FIGO IA), and frankly invasive cancer (FIGO IB).
Immunohistochemistry
Preparation and characterization of polyclonal antibodies raised in rabbit against a fusion
protein containing the C terminus of the laminin 2 chain (containing amino acid residues,
Nos. 1017-1178) and glutathione S-transferase were performed according to methods
described earlier (34).
Immunohistochemistry was performed by use of the standard horseradish peroxidase
avidin-biotin complex (ABC) technique (Elite Standard Kit, cat. PK-6100; Vector Laboratories,
Inc., Burlingame, CA). The sections were first deparaffinized, rehydrated, and microwave treated
in 0.01 M sodium citrate buffer (pH 6) for 10 minutes at 500 W. After the sections were
rinsed in Tris-buffered saline (TBS) (pH 7.6), the endogenous peroxidase activity was blocked by
immersion of the slides in 0.5% hydrogen peroxide in distilled water for 30 minutes and
unspecific staining was prevented by use of 1% bovine serum albumin (BSA) in TBS for 20
minutes. After incubation overnight at 4 °C with the rabbit 2 chain antibodies diluted 1
: 200 in 1% BSA (
2 µg/mL), a biotinylated antirabbit immunoglobulin G (diluted
1 : 200) was applied for 30 minutes, followed by incubation in the avidin-biotin-peroxidase
complex for 30 minutes. The peroxidase reaction was developed by use of diaminobenzidine
tetrahydrochloride (0.6 mg/mL) with 0.03% H2O2 for 6 minutes.
TBS was used for rinsing between steps. After counterstaining with Mayers' hematoxylin,
the slides were dehydrated and mounted with a xylene-soluble mounting medium. As a control of
specificity of the method, the laminin 2 chain antibody was replaced with BSA, and the
same procedure was performed on adjacent sections. Only cells with a distinct cytoplasmic
immunoreaction were considered laminin-5 2 chain positive. To declare a lesion positive,
more than 1% of the cells had to show this specific immunostaining.
The Ki-67 antigen, a proliferation-associated nuclear protein, was detected by the monoclonal mouse antibody MIB-1 (Immunotech S.A., Marseille, France; diluted 1 : 150 in 1% BSA), and cyclin A analysis was performed with a monoclonal mouse antibody to human cyclin A protein (Novocastra Laboratories Ltd., Newcastle upon Tyne, U.K.; diluted 1 : 100 in 1% BSA). The MIB-1 antibody allows discrimination between nonproliferating cells and proliferating cells in all phases of the cell cycle, whereas the cyclin A antibody targets the committed cells—i.e., cells that are committed to completing the cell cycle.
The evaluation of the immunohistochemical reactions was done by two investigators working independently of each other.
Statistical Analysis
A chi-squared test for trend (35) was used to analyze the association
between positivity for laminin-5 2 chain staining and invasiveness of cervical lesions. A
two-sided P value was calculated on the basis of the chi-squared test. Since there were
only four lesions with CIN 1, CIN 1 and CIN 2 were grouped together.
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RESULTS |
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Fig. 1
summarizes the results of laminin
2 chain immunoreactivity in 90 paraffin-embedded lesions from the
uterine cervix. Only one (see below) of 23 CIN 1 and CIN 2
lesions tested positive for the laminin-5 2 chain by use of a
polyclonal antibody. Twenty-one of 32 CIN 3 lesions were negative for
laminin-5 2 (Fig. 2, A and B). All lesions
with invasive and microinvasive cancers (total, 35 lesions) were positive.
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On treatment with MIB-1 antibodies to Ki-67 and antibodies to cyclin A, histologic sections of CIN 1 and CIN 2 lesions showed proliferative activity in the parabasal cell layers, with no activity in the basal cells. Cells that were positive for the laminin
2 chain in the CIN
3-diagnosed material were in close conjunction with the basement membrane. The staining was
weak to moderate and cytoplasmic (Fig. 2,
C and D). In some CIN 3
specimens, positive cells in the epidermal layer overlying the lesion were visible that were
probably participating in wound healing. In the CIN 3 lesions, proliferative activity was observed
mainly in the parabasal and intermediate layers. The degree of proliferative activity was
independent of the laminin 2 chain positivity.
In the specimens with microinvasive and frankly invasive cancers, immunohistochemical
staining of laminin 2 chain was mainly confined to the cancer cells at the invasion front of
the tumor. The staining was moderate to strong and exclusively cytoplasmic (Fig. 2, E-H). Proliferative activity was seen throughout the tumor areas but had no specific
association with the peripheral 2 chain-positive cancer cells.
By use of a variation of the chi-squared test (35), a statistically
significant association between grade or degree of invasiveness of cervical lesions and laminin
2 positivity was observed (two-sided P<.001; see Table 1).
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One of the lesions diagnosed as CIN 2 tested strongly positive for the
2 chain. Most of
the positive cells were strongly stained and peripherally located (Fig. 3,
B). Morphologically, the specimen consisted of fragments of strongly chronically inflamed mucosa
from the portio tissue of the cervix, covered with inverting metaplastic and degenerative
squamous epithelia. The interpretation of the histopathologic picture of the epithelium was
difficult because of massive presence of inflammatory cells and was diagnosed as only moderate
squamous cell atypia (Fig. 3, A). However, about 1 month later, a cervical
cone biopsy from the same patient was diagnosed as microinvasive cancer. This later specimen
showed a strong cytoplasmic staining for the laminin 2 chain and also a tendency to
extracellular staining (Fig. 3, C and D).
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Sections from samples of a local lymph node metastasis and a pleural metastasis from the same patient are shown in Fig. 3,
E-H. The lymph nodes demonstrated a
small number of 2 chain-positive cancer cells (Fig. 3, F), while the
pleural metastasis showed peripherally situated cancer cells with strong cytoplasmic laminin
2 positivity (Fig. 3, G and H). Proliferative activity was shown
throughout the metastases by the strong positivity for both the MIB-1 and cyclin A antibodies. |
DISCUSSION |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionNotesReferences |
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In this study, we used a polyclonal antibody against the recombinant
2 chain of laminin-5 to examine the location of this protein among
90 lesions comprising both precancerous stages and frank cancer of the
uterine cervix. The goal was to identify a marker of early invasiveness
and possibly identify the CIN 3 lesions that were at increased risk of
progressing to invasive carcinoma. Pyke et al. (24)
demonstrated by immunohistochemistry, by use of a polyclonal antibody,
the localization of laminin 2 chain protein in cancer cells in all
cases studied of colon adenocarcinomas and squamous cell carcinomas of
the skin and cervix but not in sarcomas. They also showed that, by
in situ hybridization, the distribution of laminin-5-positive
cancer cells at the invasion front in colon carcinomas was identical to
that of the receptor for urokinase plasminogen activator (uPAR). An
earlier study by Pyke et al. (36) proposed that binding of the
ligand for uPAR promotes the cancer cell invasion process by activation
of plasminogen, leading to degradation of extracellular matrix. The
coexpression of the 2 chain of laminin-5 and uPAR suggested
laminin-5 as a marker of invasive cancer in some human cancers
(24). Sordat et al. (27) (studying colorectal
neoplasia) and Pyke et al. (24) (studying colon carcinoma)
observed budding cancer cells with the accumulation of laminin-5 2
chains in the cytoplasm. In contrast, extracellular 2 expression
has been reported in gastric cancer in basement membranes surrounding
cancer cells (37). The high incidence of cervical cancer worldwide, almost half a million a year, with a mortality of about 50%, constitutes a major public health problem (1). With regard to diagnosis, differentiation between CIN 3, microinvasive, and frankly invasive cancer is an important and difficult question to answer in some cases. Microinvasive cancer is defined according to the FIGO classification system (33) as a lesion no wider than 7 mm in which neoplastic epithelium invades the stroma in one or more places to a depth of 5 mm or less below the basement membrane of the epithelium. The frequent occurrence of inflammation in the endocervix often makes it difficult to determine whether the diagnosis is CIN 3 (FIGO 0) or microinvasive cancer (FIGO IA), since the border of the epithelia is often uneven or indistinct. Depending on the diagnosis, the patient will receive different treatments. With a diagnosis of CIN 3, a laser treatment or conization will be performed followed by regular controls, in Sweden first every 6 months up to 2 years and then once a year up to 5 years. If microinvasive cancer is diagnosed, the treatment will be a simple hysterectomy. In contrast, frankly invasive cancer (FIGO IB) is treated with radical hysterectomy and bilateral pelvic lymphadenectomy. Thus, a sensitive diagnostic procedure is a prerequisite for appropriate therapy. According to the classic works of Petersen (7) and Kottmeier (38), 30%-70% of all cervical carcinoma in situ lesions had progressed to invasive carcinoma after 10 years of observation. Mean intervals between the time of detection of carcinoma in situ and invasive carcinoma ranged from 8 to 20 years in different studies. The latency period can vary with age, and progression may be more rapid in elderly women than in younger women (39). A 40-year study of repeated screening of a younger and an older age group of women estimated regression rates for carcinoma in situ to be 72% and 47%, respectively (40).
In our study, all microinvasive and frankly invasive cancers showed laminin 2 chain
positivity, with the immunoreactivity located almost exclusively in the cytoplasm of the cancer
cells at the invasive front of the cancer, in agreement with the findings of Pyke et al. (24) and Sordat et al. (27). In 11 of 32 lesions with CIN 3,
cytoplasmic laminin 2 chain positivity was demonstrated in the cells close to the basement
membrane. All mildly and moderately dysplastic lesions (CIN 1 and 2) were
immunohistochemically negative for laminin 2, with the important exception of the one CIN
2 lesion that 1 month thereafter proved to be microinvasive cancer, which was originally difficult
to diagnose because of the presence of inflammatory cells. By means of hematoxylin staining, the
invasive cells could easily have been overlooked, but they were clearly identifiable by the laminin
2 staining.
In contrast to other reports (18,24), we detected no laminin 2
chain immunoreactivity in the basement membrane of normal cervical tissue adjacent to
carcinomatous areas with our method. A possible explanation could be that the antibody has
difficulty reaching the highly cross-linked laminin-5 protein in the native basement membrane.
The investigation of our material with the proliferation markers Ki-67, designed to allow
discrimination between nonproliferating and proliferating cells, and cyclin A, which identified
committed cells, clearly showed that proliferative activity increased with increasing advancement
of CIN 3 and invasive cervical lesions. In both types of lesions, the degree of proliferative activity
was independent of laminin 2 positivity. In the invasive cancers showing a lower degree of
differentiation, the proliferative activity was detected throughout the tumor sections but showed
no spatial association with the laminin 2-positive cancer cells located peripherally.
Because of the diagnostic problems in distinguishing between CIN 3 and microinvasive cancer
in cervical lesions, there will often be an overtreatment or undertreatment of the patients, which
may cause extensive suffering for the patients and high costs for the health care system. It is
obvious that there is need for a marker that could identify early the CIN 3 lesions that are likely to
progress and develop into invasive carcinomas. This study has shown that our
immunohistochemical method, by use of a polyclonal antibody against the recombinant 2
chain of laminin-5, is able to distinguish between lesions with and without invasive capacity. This
method could be useful in the histopathologic diagnosis of cervical cancer.
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NOTES |
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Editor's note: K. Tryggvason holds stock in BioStratum Inc., Research Triangle Park, NC, a company developing basement membrane technology-related therapies and diagnostic applications and is currently conducting research sponsored by this company.
Supported by the Swedish Cancer Society and the Cancer Society in Stockholm, Sweden.
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Manuscript received May 10, 1999; revised September 1, 1999; accepted September 8, 1999.
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M. Katayama, N. Sanzen, A. Funakoshi, and K. Sekiguchi Laminin {gamma}2-Chain Fragment in the Circulation: A Prognostic Indicator of Epithelial Tumor Invasion Cancer Res., January 1, 2003; 63(1): 222 - 229. [Abstract] [Full Text] [PDF]
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T. Niki, T. Kohno, S. Iba, Y. Moriya, Y. Takahashi, M. Saito, A. Maeshima, T. Yamada, Y. Matsuno, M. Fukayama, et al. Frequent Co-Localization of Cox-2 and Laminin-5 {gamma}2 Chain at the Invasive Front of Early-Stage Lung Adenocarcinomas Am. J. Pathol., March 1, 2002; 160(3): 1129 - 1141. [Abstract] [Full Text] [PDF]
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J. Hao, L. Jackson, R. Calaluce, K. McDaniel, B. L. Dalkin, and R. B. Nagle Investigation into the Mechanism of the Loss of Laminin 5 ({{alpha}}3{beta}3{{gamma}}2) Expression in Prostate Cancer Am. J. Pathol., March 1, 2001; 158(3): 1129 - 1135. [Abstract] [Full Text] [PDF]
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