Dynamics of selected MHC class I and II molecule expression in the course of HPV positive CIN treatment with the use of human recombinant IFN-gamma

BACKGROUND: Studies consistently reveal downregulation of major histocompatibility complex (MHC)-I molecules or/and selective loss of individual MHC-I alleles and upregulation of MHC-II molecules in the areas of cervical intraepithelial neoplasia (CIN) and in cervical cancers. In vitro studies demonstrated the interferon-gamma (IFN-gamma) potential of MHC class I and II molecule upregulation followed by increased cytolytic response against some cervical cancer cell lines. AIM OF THE STUDY: In vivo assessment of the correlation between regression/persistence state of CIN and the IFN-gamma-induced changes in both class of selected MHC molecule expression. METHODS: Seventeen subjects with CIN I/CIN II associated with high-risk HPV infection underwent uniform IFN-gamma treatment (four intracervical injections over 2-day interval for a total dose of 6,000,000 IU). Immunohistochemical staining has been performed within cervical punch biopsy specimens with the use of monoclonal antibody reacting with HLA-DR, HLA-HC and HLA-Bw4, and the mean proportion of given molecules expressing keratinocytes was counted before, immediately after and 2 months after IFN-gamma treatment RESULTS: The analysis revealed a rapid and significant increase of the HLA-Bw4 proportion in response to IFN-gamma, persistent in the group of complete responders (with CIN clearance). No significant changes in the proportion of HLA-HC 10 positive cells in response to IFN-gamma administration was demonstrated, nor a significant increase in HLA-DR positivity; however, the transient trend towards increasing the proportion of HLA-DR immediately after treatment completion was observed. CONCLUSIONS: Upregulation of selected MHC class I allele expression, but not necessary MHC class II or heavy chain fragments of MHC-I, induced by IFN-gamma correlates with the resolution of cervical intraepithelial lesions and high-risk HPV DNA clearance in vivo.     

Expression of matrix metalloproteinase-2 in preinvasive and invasive carcinoma of the uterine cervix

PURPOSE: To study the immunohistochemical expression of matrix metalloproteinase-2 (MMP-2) in preinvasive and invasive carcinoma of the uterine cervix so as to demonstrate whether the expression of MMP-2 is an early or late event in the process of dedifferentiation and cancer progression. METHODS: A total number of 50 samples of cervical tissue were studied for MMP-2 immunoreactivity. The cases were selected to include ten normal cases used as a control group, 20 CIN cases and 20 cervical carcinoma cases. The CIN group was subdivided into CIN1 (n = 7), CIN2 (n = 6) and CIN3 (n = 7), while the carcinoma group was represented by squamous cell carcinoma (n = 16) and adenocarcinoma (n = 4). RESULTS: MMP-2 expression was totally absent in control cervices and low-grade squamous intraepithelial lesions, while high-grade squamous intraepithelial neoplasia and invasive carcinoma showed up-regulation of MMP-2 expression with no significant difference concerning the type of carcinoma. This overexpression of MMP-2 points to the possibility that it is an early marker of tumor progression in cervical carcinoma. CONCLUSIONS: MMP-2 has a key role in extracellular matrix degradation and invasion in carcinoma of the uterine cervix. Its expression in high-grade squamous intraepithelial lesions may denote a potential risk for invasion and metastasis.     

Immunohistochemical study of ras oncogene expression in endometrial and cervical human lesions

The Y13 259 monoclonal antibody to the ras p21 protein was used in an immunohistochemical assay to study the levels of ras p21 in human uterine lesions as compared to normal tissue. Out of 73 hysterectomies obtained we have examined ras p21 expression in separately made sections from the endometrium, the cervix and leiomyomas found in the same specimens. A total of 155 tissue sections were finally evaluated and included: 55 endometrial mucosae (normal, hyperplastic and atrophic), 13 leiomyomas, 60 cervicitis (mild, moderate and severe with or without dysplasia), 3 in situ and 7 invasive carcinoma of the cervix, 12 invasive adenocarcinoma of the endometrium and 5 endometrial adenocarcinomas, which involved the cervical canal. Out of the 73 hysterectomy specimens 27 lesions were malignant and showed elevated expression of ras p21. The remaining 128 were normal or atrophic mucosae and benign or premalignant lesions, which were mostly negative. However, all cases of severe cervicitis and dysplasias and 6 out of the 12 hyperplastic endometrial lesions were found to be moderately or highly positive. Our results suggest that elevated expression of ras oncogenes may play an important role in the development of human uterine lesions.     

Association of human leukocyte antigen and T cell message with human papillomavirus 16–positive cervical neoplasia in Japanese women

To investigate whether an association exists between human leukocyte antigen (HLA) haplotype and cervical neoplasia within the Japanese population, we analyzed the human papillomavirus (HPV) genotypes, the HLA class I specificities and class II alleles, and the T-cell responses in the lesions of patients with cervical neoplasia. Eighty-one patients, consisting of 62 cervical intraepithelial neoplasia (CIN) lesions and 19 invasive cervical cancers (ICC), were examined. The frequencies of HPV infection in the CIN I/II and CIN III/ICC groups were 68.0% (17/25) and 80.4% (45/56), respectively. All patients and 138 local Japanese controls were analyzed for HLA-A, HLA-B, HLA-DRB1, and HLA-DQB1. For major histocompatibility complex (MHC) class II HLA-DRB1 alleles, the frequency of DRB1*0901 was significantly elevated in HPV 16-positive CIN III/ICC patients compared with controls (59.3% versus 29.7%, P = 0.0031, OR = 3.44). Similarly for the HLA-DQB1 alleles, a significant increase in the DQB1*03032 frequency was observed in HPV 16-positive CIN III/ICC patients compared with controls (59.3% versus 28.3%, P = 0.0018, OR = 3.69). In the analysis of the T-cell responses in the lesions, Fas ligand was detected at a decreased frequency in HPV 16-positive CIN III/ICC patients with the HLA-DRB1*0901-DQB1*03032 haplotype. The presence of helper T cell-specific messenger RNAs in the cervical lesions supports an association among MHC class II, helper T cells, the immune response to HPV, and the development of cervical carcinoma. Accordingly, a specific MHC class II haplotype, DRB1*0901-DQB1*03032, may be a risk factor for cervical carcinoma in the Japanese population.     

Clinical significance of numerical aberrations on chromosome 17 in uterine cervical and endometrial neoplasias

In order to determine the clinical significance of numerical aberrations on chromosome 17 in uterine cervical and endometrial neoplasias, we investigated 140 cell specimens obtained from the uterine cervix and endometrium using the fluorescence in situ hybridization (FISH) method. These specimens consisted of ten normal cervical epithelium (NCE), 16 cervical intraepithelial neoplasias (CIN 1), 15 CIN 2, 35 CIN 3, 11 early invasive squamous cell carcinoma of the uterine cervix (early invasive SCC), 11 invasive SCC, 13 normal endometrium (NE), 17 endometrial hyperplasias (EH), and 12 endometrial ademocarcinomas (EA). After Papanicolaou staining on these specimens was decolorized, FISH was performed using chromosome 17 specific repetitive DNA probes. Signals of centromere of chromosome 17 in marked atypical cells were counted using a fluorescence microscope. There was a significant difference in the rate of cells with one signal on chromosome 17 between CIN 1 (7.1+/-0.7%) or 2 (7.0+/-0.5%) and CIN 3 (12.6+/-0.9%) (p<0.01), and also between CIN 3 and early invasive SCC (19.6+/-1.0%) (p<0.01). The rate of cells with three signals was significantly increased when the uterine cervical lesions were progressive to CIN 3 (p<0.01). Cells with five or more signals occurred only in early invasive SCC and invasive SCC. There was a significant difference in the rate of cells with three signals between EH (4.8+/-0.6%) and EA (11.4+/-2.1%) (p<0.05). Cells with five or more signals occurred only in EA. Examination of the numerical aberrations on chromosome 17 in uterine cervical and endometrial neoplasias has been suggested to be useful as an additional method for the differential diagnosis of these lesions.     

Is it safe to prescribe hormonal contraception and replacement therapy to patients with premalignant and malignant uterine cervices?

The levels of estrogen and progesterone receptors in normal and abnormal uterine cervices were determined. The study group consisted of 14 patients with cervical intraepithelial neoplasia (CIN III) and 7 patients with invasive carcinoma of the cervix (stage IB-IIA). The control group included 23 patients who underwent total abdominal hysterectomy for menorrhagia, leiomyoma, etc. The concentration of total estrogen receptors in premalignant and malignant cervices did not differ from the patients with benign conditions of the cervix. The concentration of progesterone receptors was significantly higher in the nonaffected cervices than in the patients with preinvasive and invasive carcinoma of the cervix (P less than 0.05). We have shown that estrogen receptor concentrations do not differ between women with normal and abnormal uterine cervices. Therefore, we feel that the contraceptive pill is not contraindicated in women who have been treated for CIN III. We also maintain that hormone replacement therapy should be given, when indicated, to women who have been castrated following surgery and/or radiotherapy for invasive carcinoma of the cervix.     

The role of p53, Bcl-2 and Ki-67 in premalignant cervical lesions and cervical cancer

PURPOSE: The aim of this study was to determine the role of p53, Bcl-2 and Ki-67 expression in the carcinogenesis of cervical carcinoma and aggressiveness of cervical intraepithelial neoplasia (CIN). METHODS: The pathology specimens of 63 patients with a diagnosis of normal squamous epithelium (22 cases), CIN I (14), CIN II (5), CIN III (8) and squamous cell carcinoma (14) were evaluated immunohistochemically for the expression of p53, Bcl-2 and Ki-67 in paraffin sections. RESULTS: The expression of p53 and Ki-67 increased proportionally to the grade of CIN and cervical cancer, but only the increase of p53 expression was statistically significant (p = 0.002). There was no significant correlation between Bcl-2 expression and premalignant and malignant cervical lesions. CONCLUSION: p53 expression may have a role in the carcinogenesis of squamous cell cervical carcinoma whereas Bcl-2 expression has no role. Ki-67 expression can not be used in determining the aggressiveness of CIN lesions.     

Nucleolar organizing regions in human papillomavirus infection and in cervical intraepithelial neoplasia.

The Ag-NOR staining technique for nucleolar organizer regions (Ag-NORs) was applied to 37 biopsies of the uterine cervix taken from colposcopically abnormal areas. Histological examination of the sections showed that 13 patients had condylomatous lesions without atypia, 15 had CIN I, 4 had CIN II, 3 had CIN III and 2 carcinoma in situ. The mean numbers of Ag-NORs in parabasal and basal cells of squamous epithelium increased progressively from CIN I to CIN III-CIS. There was no significant difference between the Ag-NOR count in condylomatous lesions and CIN I. Significant differences were found between the number of Ag-NORs in condylomatous lesions and in the various grades of CIN. The Ag-NOR technique is useful in the diagnosis of cervical intraepithelial neoplasia and confirms the need to regard condylomata of the uterine cervix as intraepithelial neoplasia grade I and recommend these patients for follow-up.     

Squamous carcinoma of the uterine cervix with CIN 3-like growth pattern: An under-diagnosed lesion

Abstract. Al-Nafussi AI, Monaghan H. Squamous carcinoma of the uterine cervix with CIN 3-like growth pattern: An under-diagnosed lesion.
Invasive squamous carcinomas of the cervix have traditionally been classified into keratinizing, non-keratinizing, verrucous, warty (condylomatous), papillary transitional (squamo-transitional), and lymphoepithelioma-like carcinomas. The majority of these tumors are easily recognized. We present for the first time the pathological appearances of six cases of invasive squamous carcinoma with growth pattern simulating tangentially cut CIN 3 involving endocervical glandular crypts/clefts. In all cases initial diagnosis on biopsy and/or loop excision was thought to be CIN 3, perhaps with suspicion of early invasion. On further excision and/or on clinical grounds the tumors were frankly invasive. We propose the use of the term squamous carcinoma with "CIN 3-like growth pattern" for such lesions. This is in order to avoid misinterpretation as CIN 3 with subsequent inappropriate management of patients with this type of tumor.     

Detection of HPV DNA in the uterine cervical lesions by polymerase chain reaction and in situ hybridization]

Human papillomavirus (HPV) is found in close association with carcinogenesis of the uterine cervix. We applied a new in vitro gene amplification technology, the polymerase chain reaction (PCR) to detect HPV 16 and 18 in cervical exfoliated cells. HPV infections were detected in 5 (16%) of 31 women with no pathological lesions of the uterine cervix (normal), 16 (24%) of 67 with cervical intraepithelial neoplasia (CIN) and 6 (38%) of 16 with invasive cervical cancer. Moreover, 10% formalin-fixed and paraffin-embedded tissue sections were prepared from the uterine cervix of these 27 women with PCR-proven HPV infection and were examined for the histological localization of HPV-DNA by in situ hybridization with biotin-labeled DNA probes of HPV types 6/11, 16/18 and 31/33/35. HPV-DNA type 16/18 was detected in 3 of 5 normal women, 2 of 4 CINs I, 2 of 3 CINs II, 6 of 9 CINs III and 6 of 6 invasive cervical cancers. HPV-DNA type 6/11 was detected in 6 of 6 condylomas. Viral DNA sequence was detected in the superficial cells of CIN I and II, and it was distributed through entire thickness layer of undifferentiated cells derived from CIN III and squamous cell carcinoma. In addition, the staining intensity became weak as the lesion progressed. These differences between lesions might be due to the difference in the viral form in the nuclei, ie whether an episomal or integrated form. Thus, an in situ hybridization technique with a biotin-labeled DNA probe as well as the PCR method is useful for the detection of HPV in clinical samples.     

Frequent expression of beta-human chorionic gonadotropin (beta-hCG) in squamous cell carcinoma of the cervix.

Human chorionic gonadotropin (beta-hCG) has been detected within tissue homogenates, culture fluid, and sera of patients with squamous cell carcinoma of the cervix. Studies regarding in vivo localization of beta-hCG in squamous cell carcinoma of the cervix are scant and conflicting. Cervical samplings (biopsy and/or curettage specimens) of 63 cases of poorly differentiated invasive squamous cell carcinoma of the cervix were initially stained by the immunoperoxidase technique for the presence of beta-hCG and human placental lactogen (hPL). Based on beta-hCG reactivity, patients were divided into beta-hCG-positive and beta-hCG-negative groups. Thirty-three of the 63 (52%) cases showed localization of beta-hCG in tumor cells. Subsequent specimens of patients, who underwent surgical treatment, were likewise examined for beta-hCG reactivity. These surgical specimens showed focal beta-hCG reactivity in the beta-hCG-positive group only. The beta-hCG reactivity was seen in both high-grade SIL (CIN III), invasive squamous cell carcinoma, and its metastases. The focal beta-hCG reactivity was predominantly confined to the peripheral tumor cells at the stromal-epithelial interface in noninvasive and invasive lesions. Intensity of immunostaining was moderate to strong. The beta-hCG staining was observed in different cancer stages and in various age groups. No hPL reactivity was seen in any cases. Poorly differentiated squamous cell carcinoma of uterine cervix showing immunoreactivity for beta-hCG should be distinguished from choriocarcinoma and other trophoblastic tumors.     

The possible role of p53 and bcl-2 expression in cervical carcinomas and their premalignant lesions

OBJECTIVE: The purpose of this study was to assess the expression and clinical significance of bcl-2 and p53 in the progression of cervical neoplasias. METHODS: One hundred seventy-one cervical specimens, consisting of normal cervical epithelium (n = 13), lesions with histological features of HPV infection (n = 14), CIN (cervical intraepithelial neoplasia) lesions (n = 63), and cervical carcinomas (n = 81) were examined immunohistochemically in paraffin sections. RESULTS: Twenty-three specimens showed p53 expression [3/20 (15%) CIN III, 18/63 (29%) ISCC (invasive squamous cervical carcinoma), and 2/18 (11%) adenocarcinomas] while 63 cases expressed the bcl-2 gene [10/13 (77%) normal, 0/14(0%) condylomas, 6/23 (26%) CIN I, 9/20 (45%) CIN II, 15/20 (75%) CIN III, 18/63 (29%) ISCC, and 5/18 (28%) adenocarcinomas]. The expression of bcl-2 was found to increase in direct relation to the grade of CIN (P = 0.02) whereas such a trend was not observed for p53. p53 was not detected in normal or premalignant lesions (except 3 out of 20 cases of CIN III). There was no significant correlation between the expression of p53 and the histological type of cervical carcinoma, even though expression of p53 was higher in ISCC than in adenocarcinomas (29% vs 11%, respectively). In cervical cancer patients, expression of bcl-2 was correlated to a greater than 5-year survival (P < 0.01) while no prognostic significance of p53 expression was found. CONCLUSION: Evaluation of bcl-2 expression may provide additional and independent prognostic information for the clinical course of the disease and therefore to be developed as a prognostic indicator for cervical cancer.     

E-cadherin expression during progression of squamous intraepithelial lesions in the uterine cervix

Alterations of E-cadherin expression in cervical intraepithelial neoplasias and invasive carcinomas of the uterine cervix have been described by some authors but their clinical significance has not yet been clarified. Archival specimens of 27 normal cervical epithelia, 15 atypical cells of undetermined origin (ASCUS), 53 low-grade squamous intraepithelial lesions (LSIL), 19 high-grade squamous intraepithelial lesions (HSIL) and six invasive squamous carcinomas were evaluated for E-cadherin expression. The cytological material was processed using liquid based cytology (ThinPrep technique) and immunostained for E-cadherin. All HPV infections (koilocytes) showed strong cell membranous E-cadherin expression. In HSIL a strong decrease in E-cadherin expression and heterogeneous distribution was noticed. In the relatively small number of squamous cell carcinomas of the cervix studied, a significant decrease or loss in E-cadherin expression, predominantly cytoplasmic, was noted. We concluded that decreased E-cadherin expression appears to be a useful parameter of malignant potential of cervical lesions. E-cadherin immunoexpression could provide an additional criterion in correlation with cyto- and histomorphology and colposcopy to define high grade CIN lesions.     

子宫颈癌组织中水通道蛋白8和bcl-2蛋白的表达及其相关性

目的 探讨水通道蛋白(AQP)8、bcl-2蛋白在宫颈癌组织中的表达及其相关性.方法 采用免疫组化Envision二步法检测AQP8和bcl-2蛋白在74例宫颈癌(其中鳞癌46例、腺癌28例)、34例宫颈上皮内瘤变(CIN)和15例正常宫颈组织中的表达情况,并分析两者的相关性.结果 AQP8和bcl-2蛋白主要在CIN异型细胞和宫颈癌细胞的细胞质内表达,AQP8蛋白在宫颈鳞癌、腺癌、CIN和正常宫颈组织中的阳性表达率分别为98%、61%、71%和53%,鳞癌高于腺癌、CIN和正常宫颈组织,差异有统计学意义(P＜0.01);腺癌与CIN、正常宫颈组织比较,CIN与正常宫颈组织比较,差异均无统计学意义(P＞0.05).bcl-2蛋白在宫颈鳞癌、腺癌、CIN和正常宫颈组织中的阳性表达率分别为74%、71%、53%和20%,鳞癌与腺癌组织比较,差异无统计学意义(P＞0.05);鳞癌、腺癌高于CIN、正常宫颈组织,CIN也高于正常宫颈组织,差异均有统计学意义(P＜0.01).AQP8和bcl-2蛋白在宫颈癌组织中的表达呈明显正相关(rs=0.463,P=0.000).结论 AQP8和bcl-2蛋白在宫颈癌组织中的表达呈明显正相关,AQP8蛋白表达上调可能与宫颈癌的发生、发展有一定的关系.     

Abnormal distribution of E-cadherin and beta-catenin in different histologic types of cancer of the uterine cervix

OBJECTIVE: The goal of this study was to analyze the cellular distribution and possible alterations of beta-catenin and E-cadherin proteins in different histologic types of uterine cervical cancer and precursor lesions, compared to normal controls. METHODS: We performed an immunochemical staining analysis of the cellular distribution of beta-catenin and E-cadherin proteins in biopsy samples from 20 normal exocervical squamous epithelium, 43 premalignant lesions, and a large series of 126 invasive tumors of different histologic types that included 68 squamous carcinomas, 31 adenosquamous carcinomas, and 27 adenocarcinomas. Statistical significance was evaluated by the chi-square or Fisher's Exact test. RESULTS: We observed beta-catenin abnormally distributed in the cytoplasm of 62% of premalignant lesions and more than 70% of invasive cancers, statistically significant when compared with normal tissue (P < 0.05). Similarly, we found that E-cadherin exhibit a significant abnormal distribution in the cytoplasm of 58% of premalignant lesions (P < 0.05) and in more than 71% of squamous carcinoma and adenosquamous carcinoma when compared with normal tissue (P < 0.05). We found no differences in the distribution of E-cadherin between adenocarcinomas compared with control samples. Interestingly, we found that both, beta-catenin and E-cadherin, were absent in the membrane of nearly 40% premalignant lesions. Nuclear staining of beta-catenin was rarely seen in any cases, contrary to what has been reported for this and other neoplasias. CONCLUSION: Our findings indicate that cellular alterations of both beta-catenin and E-cadherin are frequent in tumors of the uterine cervix of different histologic types, and support a role for these proteins in cervical cancer development.     

Cyclic variation of major histocompatibility complex class II antigen expression in the human fallopian tube epithelium.

OBJECTIVE: To systematically investigate the expression of major histocompatibility complex (MHC) class II antigens (human leukocyte antigens, HLA-DR, -DP, and -DQ) on columnar epithelium in the fallopian tube during the menstrual cycle. STUDY DESIGN: Biopsies were collected from the fallopian tube during laparotomy sterilization and immunoperoxidase staining was performed. SETTINGS: Departments of Gynecology and Obstetrics and Clinical Immunology and Transfusion Medicine, Uppsala University, Uppsala, Sweden. PATIENTS: Twenty healthy fertile women undergoing sterilization at different times of the menstrual cycle. INTERVENTIONS: None. MAIN OUTCOME MEASURES: The staining of the columnar epithelium was judged on a 4-graded scale according to the distribution of class II antigens. RESULTS: A widespread preovulatory HLA-DR expression was observed almost completely lining the columnar epithelial cells including the luminal surface, whereas postovulatory the HLA-DR expression was withdrawn from the surface. The HLA-DP and -DQ antigens varied in a similar way, although not as pronounced. CONCLUSIONS: The MHC class II antigen variation in the fallopian tube epithelium seen in this study may indicate a hormonal regulation that could reflect variable need for local immunocompetence during the menstrual cycle: a preovulatory need for immunoreactivity against invading microbes and postovulatory an optimal survival of the foreign preimplantation embryo.     

MMP-1 and MMP-2 in the cervix uteri in different steps of malignant transformation--an immunohistochemical study.

OBJECTIVES: Enzymatic degradation of the extracellular matrix (ECM) represents a key element in the multistage process of tumor invasion and metastasis. This process requires extensive degradation of ECM components such as basement membrane collagen (type IV) and interstitial collagen (type I, II, III). Matrix metalloproteinase-2 (MMP-2) specifically cleaves collagen type IV, the major collagen of the basement membrane. MMP-1 digests interstitial collagen type I and III, the main collagen types of the stromal extracellular matrix. We investigated protein levels of MMP-1 and MMP-2 in different stages of malignant transformation. METHODS: Using the APAAP method we analyzed 10 normal cervical tissues, 11 cervical intraepithelial neoplasia 1 (CIN 1), 8 CIN 2 and 10 CIN 3 lesions, and 15 invasive squamous cell carcinomas. These data were compared with the HPV DNA status tested by hybrid capture II. RESULTS: Only a few isolated epithelial cells stained positively for MMP-1 and MMP-2 in normal cervical tissue and CIN 1 lesions. The CIN 2 and CIN 3 group displayed a heterogeneous distribution of MMP expression. 3 CIN 2 and 8 CIN 3 lesions showed strong MMP-2 and weak MMP-1 expression in the dysplastic epithelial cells. 5 CIN 2 and 2 CIN 3 lesions stained negatively. Invasive carcinomas showed a coexpression for MMP-1 and MMP-2 in malignant epithelial cells and peritumoral stroma cells. All MMP-2-positive cases tested positive for the HPV high-risk group. CONCLUSIONS: The expression of MMP-2 protein in preinvasive lesions of the cervix uteri and a consecutive coexpression of MMP-1 and MMP-2 in invasive cancer suggest a gradually increasing invasive potential. MMP-2 expression, when focally observed in high-grade squamous intraepithelial lesions of the cervix, may indicate tumor areas with an increased risk for invasive growth.     

An immunohistochemical study on regional immunological response of uterine cervical cancer

An immunohistochemical analysis was performed to detect MHC class I (HLA-ABC) and class II (HLA-DR) antigens expression on cancer cells from 20 patients with carcinoma of the cervix using monoclonal antibodies to HLA-ABC and DR antigens. Locally infiltrating lymphocytes were also examined with anti-Leu 1,-Leu 2a,-Leu 3a, and -Leu 12. Class I and class II antigens expression on cervical cancer cell lines OMC-1 and OMC-4 were examined in the same way, and the effects of Interferon (IFN)-gamma treatment were evaluated with Cell-EIA tests. The results were as follows. 1) Class I antigens were preserved in many cases, but lost in some. 2) Class II antigens were newly expressed in some cases. 3) Among the many infiltrating T cells, Leu 2a-positive cells were predominant in surrounding the cancer nests which preserved class I antigens, and Leu 3a-positive cells were predominant in surrounding the cancer nests which expressed class II antigens. 4) Both OMC-1 and OMC-4 cervical cancer cell lines expressed class I and class II antigens. 5) Cell-EIA tests showed that IFN-gamma treatment enhanced the expression of class I and class II antigens in OMC-1 and OMC-4. These results suggested that the preservation of class I antigens and the expression of class II antigens on cervical cancer cells markedly increase the local immune response in cervical cancer, and IFN-gamma treatment enhances the immune response in vivo.     

肿瘤干细胞相关基因ABCB1、ABCG2表达与宫颈上皮恶变及发展关系的研究

目的:探讨肿瘤干细胞相关基因ABCB1、ABCG2表达与宫颈癌形成及临床病理参数之间的关系。方法:应用组织芯片技术和免疫组织化学检测宫颈浸润癌34例、微小浸润癌30例、CINⅢ30例、宫颈慢性炎症30例患者ABCB1、ABCG2的表达,并与临床病理资料进行相关性分析。结果:ABCB1在浸润癌、微小浸润癌、CINⅢ、宫颈慢性炎症中的阳性表达率分别是为76%(26/34)、60%(18/30)、40%(12/30)、20%(6/30),其阳性表达率随病变级别升高而明显增加;ABCB1在浸润癌中表达水平与肿瘤分化程度、TNM分期、淋巴结转移密切相关(P<0.05),与肿瘤体积无关(P>0.05);ABCG2在浸润癌、微小浸润癌、CINⅢ、宫颈慢性炎症中的阳性表达率分别为80%(27/34)、70%(21/30)、40%(12/30)、30%(9/30),其阳性表达率随病变级别增加而上升;ABCG2表达水平与肿瘤体积、TNM分期密切相关(P<0.05),与淋巴结转移、肿瘤分化程度无关(P>0.05)。结论:ABCB1、ABCG2在促进宫颈癌变过程中发挥主要作用,并且ABCB1的阳性表达是提示宫颈癌预后不良的客观指标。     

Stromal cells play a role in cervical cancer progression mediated by MMP-2 protein

Metalloproteinases, especially metalloproteinase-2 (MMP-2), are known for their role in the degradation of the extracellular matrix. Nevertheless, a thorough understanding of MMP-2 expression in neoplastic lesions of the uterine cervix has yet to be accomplished. This study aimed to analyze the MMP-2 expression in cervical intraepithelial neoplasia III (CIN3) and in cervical squamous cell carcinoma, in tumor cells and adjacent stromal cells. MMP-2 expression was assessed by an immunohistochemical technique. MMP-2 expression was greater in the stromal cells of invasive carcinomas than in CIN3 (p < 0.0001). MMP-2 expression in stromal cells correlates with the clinical stage, gradually increasing as the tumor progresses (p = 0.04). This study corroborates that stromal cells play an important role in tumor invasion and progression, mediated by the progressive enhancement of MMP-2 expression from CIN3 to advanced invasive tumor. The intense MMP-2 expression most probably is associated with poor tumor prognosis.