Expression of c-Kit (CD117) in Benign and Malignant Human Endometrial Epithelium.
In the United States, endometrial cancer is the most common malignancy of the female genital tract, resulting in approximately 36 000 new cases and 6300 cancer deaths per year. Endometrioid carcinoma, by far the most prevalent histologic subtype of endometrial cancer, is typically a slow-growing neoplasm neoplasm or tumor, tissue composed of cells that grow in an abnormal way. Normal tissue is growth-limited, i.e., cell reproduction is equal to cell death. , developing predominantly in perimenopausal perimenopausal adjective Referring to a period of a ♀'s life–age 45 to 55-ish–in which menstrual periods become irregular; perimenopause is immediately before, during and after menopause. See Menopause. and postmenopausal women, but not uncommonly also in premenopausal pre·me·no·paus·al
Of or relating to the years or the stage of life immediately before the onset of menopause.
premenopausal adjective women. Epidemiological and microscopic studies have shown that the majority of endometrioid carcinomas develop through a sequence of increasingly complex and cytologically atypical hyperplasias under the influence of estrogen.
Molecular abnormalities frequently observed in endometrioid carcinoma include early PTEN PTEN Protein Tyrosine Phosphatase
PTEN Phosphatase and Tensin Homolog
PTEN Prime Time Entertainment Network (television network) and K-ras mutations, microsatellite instability, and late p53 mutations.[3-9] While it is well documented that endometrial endometrial /en·do·me·tri·al/ (en?do-me´tre-il) pertaining to the endometrium.
n relating to the end-ometrium or cavity of the uterus. epithelial cells express estrogen receptors, the mechanism by which this hormone exerts its influence in the development of endometrioid carcinoma is poorly understood. When unopposed, estrogens Estrogens
Hormones produced by the ovaries, the female sex glands.
Mentioned in: Acne, Polycystic Ovary Syndrome
n. are believed to serve as a promoting influence, resulting in persistent epithelial proliferation predisposing the endometrium endometrium /en·do·me·tri·um/ (-me´tre-um) pl. endome´tria the mucous membrane lining the uterus.
n. pl. to acquiring significant genetic alterations. Recent data also suggest that estrogen metabolites may be directly and indirectly genotoxic genotoxic /ge·no·tox·ic/ (je´no-tok?sik) damaging to DNA: pertaining to agents known to damage DNA, thereby causing mutations, which can result in cancer.
The proto-oncogene c-kit encodes a 145-kd transmembrane transmembrane /trans·mem·brane/ (trans-mem´bran) extending across a membrane, usually referring to a protein subunit that is exposed on both sides of a cell membrane.
adj. tyrosine kinase receptor (CD117), the ligand of which is stem cell factor stem cell factor
A cytokine that promotes the differentiation and growth of hematopoietic stem cells into other types of cells. (SCF SCF Service Canadien des Forêts (Canadian Forest Service)
SCF Stem Cell Factor
SCF Scientific Committee on Food (European Commission)
SCF Service Canadien de la Faune ).[13-15] Expression of c-Kit is weak to moderate in a wide variety of normal, benign, and malignant tissues.[16-18] In a subset of mast cell disorders and gastrointestinal stromal cell tumors,[20,21] over-expression has been linked to either an activating or dominant-inactivating c-kit mutation. Besides a mutational mechanism, it has been proposed that c-kit, together with SCE SCE (in Scotland) Scottish Certificate of Education
SCE n abbr (= Scottish Certificate of Education) → Schulabschlusszeugnis in Schottland may also contribute to tumor development via autocrine autocrine /au·to·crine/ (-krin) denoting a mode of hormone action in which a hormone binds to receptors on and affects the function of the cell type that produced it.
adj. growth stimulation, paracrine paracrine /para·crine/ (par´ah-krin)
1. denoting a type of hormone function in which hormone synthesized in and released from endocrine cells binds to its receptor in nearby cells and affects their function.
2. growth stimulation, or both. It is currently unclear whether c-Kit is expressed in endometrial tissues. Contrary to previous data,[23-26] Arber et al have recently demonstrated by immunohistochemistry that endometrial adenocarcinomas (8/8) and hyperplastic endometria en·do·me·tri·a
Plural of endometrium. (2/2) express CD117. To better define and help resolve these conflicting findings, we evaluated the expression of this growth factor receptor A growth factor receptor is a receptor which binds to growth factor. External links
• • in endometrial tissues using both immunohistochemistry and immunoprecipitation followed by Western blot analysis West·ern blot analysis
An electrophoretic procedure for separating proteins. .
MATERIALS AND METHODS
Formalin-fixed, paraffin-embedded tissues from 7 endometrial hyperplasias, 14 proliferative endometria, and 14 secretory endometria were immunohistochemically analyzed for CD117 expression. Four-micrometer tissue sections were deparaffinized in xylene xylene (zī`lēn) or dimethylbenzene (dī'mĕthəlbĕn`zēn), C6H4(CH3)2 , rehydrated in graded alcohols, and washed in phosphate-buffered saline. The tissue sections were heated in a microwave in 10 mmol/L citrate buffer solution for antigen retrieval at pH 6.0 in a thermoresistant container for 12 minutes and cooled for 20 minutes. Endogenous peroxidase peroxidase /per·ox·i·dase/ (per-ok´si-das) any of a group of iron-porphyrin enzymes that catalyze the oxidation of some organic substrates in the presence of hydrogen peroxide.
n. activity was quenched in 0.3% hydrogen peroxide for 10 minutes. The sections were then incubated for 45 minutes at room temperature with a c-Kit monoclonal antibody that does not bind to the SCF binding site (clone K45; 1:20 dilution, NeoMarkers, Fremont, Calif). Saline was applied instead of primary antibody as a negative control. Antigen-antibody complexes were visualized using a streptavidin-biotin staining technique (Vector Laboratories, Burlingame, Calif) according to the manufacturer's recommendations. Diaminobenzidine was used as a chromogen chromogen /chro·mo·gen/ (kro´mah-jen) any substance giving origin to a coloring matter.
1. A substance that lacks definite color but may be transformed into a pigment. , and hematoxylin hematoxylin /he·ma·tox·y·lin/ (he?mah-tok´si-lin) an acid coloring matter from the heartwood of Haematoxylon campechianum; used as a histologic stain and also as an indicator. served as a counterstain counterstain /coun·ter·stain/ (-stan) a stain applied to render the effects of another stain more discernible.
n. . Human small cell lung carcinoma cell lines H526 and H526A (generously provided by Geoffrey Krystal, MD) served as positive controls. The immunostaining results were recorded with respect to intensity (1+ to 3+) and distribution of staining (focal indicates [is less than]10% of cells; intermediate, [is greater than]10% but [is less than]50% of cells; and diffuse, [is greater than]50% of cells).
One endometrial polyp, obtained from a case of cryopreserved endometrioid carcinoma, and 9 frozen archived endometrioid endometrial carcinomas were also analyzed by immunohistochemistry in order to examine expression of CD117 in malignant endometria, as well as to identify suitable cases for CD117 immunoprecipitation and Western blot analysis (selection criteria and blotting methodology are described below). Five-micrometer tissue sections were fixed in acetone acetone (ăs`ĭtōn), dimethyl ketone (dīmĕth`əl kē`tōn), or 2-propanone (prō`pənōn), CH3COCH3 for 10 minutes, air dried, re-hydrated in graded alcohols, and washed in phosphate-buffered saline. Following a 10-minute incubation in 0.3% hydrogen peroxide, the tissue sections were rinsed in saline and then incubated for 45 minutes with either a c-Kit monoclonal antibody (clone K45, 1:20 dilution) or saline, and processed as described above. As with the formalin-fixed tissues, immunostaining results were recorded with respect to intensity and distribution.
Immunoprecipitation and Western Blot Analyses
Cell lysates were prepared from thick (about 60-[micro]m) sections of endometrial tissue using the same frozen tissue blocks previously analyzed by immunohistochemistry for CD117 expression. Cases were selected that consisted predominantly of tumor with relatively few mast cells and histiocytes (both c-Kit-expressing cell types). Tissue sections were lysed in 20 mmol/L Tris-HCl (pH 7.4), 50 mmol/L sodium chloride, 1% Nonidet P-40, and a cocktail of protease inhibitors (Boehringer-Mannheim, Mannheim, Germany) for 30 minutes on ice. Following centrifugation for 30 minutes at 14 000 g, protein concentrations were measured using a Bradford-based colorimetric col·or·im·e·ter
1. Any of various instruments used to determine or specify colors, as by comparison with spectroscopic or visual standards.
2. assay (Bio-Rad, Hercules, Calif). Equal amounts of protein (1 mg) from 2 endometrial carcinomas and 1 endometrial polyp were immunoprecipitated overnight at 4 [degrees] C with either 1 [micro]g c-Kit monoclonal antibody (clone K45) or saline, and then incubated with protein A/G PLUS agarose (Santa Cruz Biotechnology, Santa Cruz, Calif) for 1 hour at 4 [degrees] C. Antigen-antibody complexes were extensively washed, separated by sodium dodecyl sulfate-polyacrylamide gel electrophoresis, electrotransferred onto Hybond ECL (Emitter-Coupled Logic) A digital circuit composed of bipolar transistors in which the emitter ends are wired together. ECL gates switch faster than TTL gates, but consume more power. See TTL, I2L and bipolar.
1. nitrocellulose nitrocellulose, nitric acid ester of cellulose (a glucose polymer). It is usually formed by the action of a mixture of nitric and sulfuric acids on purified cotton or wood pulp. membrane (Amersham, Arlington Heights, Ill), and then immunoblotted with c-Kit monoclonal antibodies (clone K45 monoclonal and clone 1.D9.3D6 monoclonal, Roche/Boehringer Mannheim, Indianapolis, Ind) followed by horseradish horseradish
Hardy perennial plant (Armoracia lapathifolia) of the mustard family, native to Mediterranean lands and grown throughout the temperate zones. Its hotly pungent, fleshy root is used as a condiment and is traditionally considered medicinal. peroxidase-labeled anti-mouse IgG (Vector). A luminol-based chemiluminescent reaction (ECL Reagent; Amersham) allowed for the identification of horseradish peroxidase-labeled secondary antibody. For positive controls, H526 cell lysates were either immunoprecipitated (100 [micro]g protein) as described or directly loaded onto the gel (40 [micro]g protein) along with the immunoprecipitated endometrial proteins.
The immunohistochemical results for CD117 expression in formalin-fixed, paraffin-embedded benign endometrial tissue are summarized in Table 1. Thirteen (93%) of the proliferative endometria were positively immunostained for CD117, of which 5 cases had intense, focal cytoplasmic staining within epithelial cells (Figure 1), 6 cases exhibited intense membrane staining correlating with the terminal bar of isolated ciliated cil·i·at·ed
Covered with short, hair-like protrusions, like B. coli and certain other protozoa. The cilia or hairs help the organism to move. epithelial cells (Figure 2), and 2 cases had both cytoplasmic and terminal bar staining. Eleven (79%) of the secretory endometria expressed CD117; however, cytoplasmic staining of epithelial cells was less intense (Table 1), and only 1 case had membrane staining similar to that noted in ciliated cells of the proliferative endometria. Four (57%) of the endometrial hyperplasias stained positively for CD117. In all 4 cases, 3 simple hyperplasias and 1 complex atypical hyperplasia, an intense cytoplasmic staining reaction was observed (Figure 3). The cytoplasmic staining in both the hyperplasias and proliferative endometria was characterized by a paranuclear reaction, predominantly in the subnuclear/ basal compartment, but also in the supranuclear su·pra·nu·cle·ar
1. Located above the level of the motor neurons of the spinal or cranial nerves. Used to indicate disorders of movement caused by destruction or functional impairment of brain structures, such as the motor cortex, region. Consistent with previous data,[18,28] mast cells and to a lesser degree endothelial cells within the endometrium and myometrium myometrium /myo·me·tri·um/ (-me´tre-um) the tunica muscularis of the uterus.myome´trial
The muscular wall of the uterus. were positively immunostained, thereby providing an internal positive control for each case. Histiocytes also stained positively for CD117. No staining reaction was ever detected following omission of the primary antibody.
[Figure 1-3 ILLUSTRATION OMITTED]
[TABULAR DATA 1 NOT REPRODUCIBLE IN ASCII ASCII or American Standard Code for Information Interchange, a set of codes used to represent letters, numbers, a few symbols, and control characters. Originally designed for teletype operations, it has found wide application in computers. ]
We then immunohistochemically analyzed 9 randomly selected, frozen endometrioid carcinomas and 1 endometrial polyp that arose in association with endometrioid carcinoma (the carcinoma was not represented in the cryopreserved tissues) to determine whether malignant epithelia ep·i·the·li·a
A plural of epithelium. also expressed CD117. As shown in Table 2, the polyp polyp, in medicine, a benign tumor occurring in areas lined with mucous membrane such as the nose, gastrointestinal tract (especially the colon), and the uterus. Some polyps are pedunculated tumors, i.e. and 4 of 9 carcinomas expressed CD117. Immunostaining was localized to the cytoplasm of endometrial epithelial cells and varied in intensity from moderate to intense (Figure 4, A). We then analyzed 3 of these same cryopreserved tissues by immunoprecipitation followed by Western blotting. Our intent was to evaluate the molecular weight and amount of CD117 in endometrial tissue to confirm antibody specificity, as well as to potentially identify aberrant forms (ie, truncations) of this growth factor receptor in endometria. One case of endometrioid carcinoma (case 2) and the endometrial polyp (case 3) were selected for analysis based on their intense CD117 immunostaining reaction and relatively low numbers of mast cells and histiocytes. Also included was a single case of endometrioid carcinoma (case 1), which had undetectable CD117 expression within the tumor by immunohistochemistry and relatively low numbers of mast cells and histiocytes. As shown in Figure 4, B, a 145-kd band corresponding to full length c-CD117 is present in all samples, with substantially more in carcinoma case 2 than in carcinoma case 1, a finding highly consistent with our immunostaining data (Figure 4, A). The endometrial polyp (case 3) had a more prominent 145-kd band than the negatively stained carcinoma; however, the level of expression was less than that of the CD117-overexpressing carcinoma. The faint 145-kd band in carcinoma case 1 likely represents expression of c-Kit by residual mast cells, histiocytes, and endothelial cells. Nonspecific nonspecific /non·spe·cif·ic/ (non?spi-sif´ik)
1. not due to any single known cause.
2. not directed against a particular agent, but rather having a general effect.
1. bands with varying degrees of intensity were present in all lanes of CD1107-immunoprecipitated samples, including a cell lysate ly·sate
The cellular debris and fluid produced by lysis. prepared from the positive control cell line, H526.
[Figure 4 ILLUSTRATION OMITTED]
[TABULAR DATA 2 NOT REPRODUCIBLE IN ASCII]
In this study we demonstrated in situ expression of CD117 in benign endometria. Although these data are consistent with a study by Arber et al, we did not detect immunostaining in endometrial stromal cells, as previously described in normal endometrial tissue and decidua decidua /de·cid·ua/ (de-sid´u-ah) the endometrium of the pregnant uterus, all of which, except the deepest layer, is shed at parturition. .[24,25] We are aware of 4 independent studies that have been unable to detect CD117 by immunohistochemistry in normal endometrial epithelial tissue.[16,24-26] A close examination of the methodologies employed in the different studies reveals that when a citrate antigen-retrieval step was used with formalin-fixed, paraffin-embedded tissues, CD117 staining was detectable (our data and reference 18), whereas when cryopreserved tissues were immunostained using a standard protocol (ie, no antigen retrieval with frozen samples), staining was scored as negative.[16,24-26] Therefore, in benign endometria in which levels of c-Kit expression may be lower relative to the carcinomas, antigen retrieval may be necessary to increase the sensitivity of the assay. Moreover, tissue architecture is often compromised and background levels are higher in cryopreserved tissues, making immunohistochemical interpretation difficult if expression levels are low.
Perhaps one of the most interesting findings in this study was that in benign endometrial tissue, CD117 immunostaining tended to be more intense and/or more frequently observed in epithelial cells of hyperplastic and proliferative endometria when compared with secretory endometria. Because CD117 is generally regarded as a plasma membrane-bound protein, we expected the staining to be localized predominantly on the cell surface. However, membrane staining was less common than cytoplasmic staining in benign endometria, as reported previously by us and others. Predominantly cytoplasmic c-Kit immunostaining has also been described in a number of other normal human tissues. The significance of both the spatial focality and cellular localization Customizing software and documentation for a particular country. It includes the translation of menus and messages into the native spoken language as well as changes in the user interface to accommodate different alphabets and culture. See internationalization and l10n. of CD117 immunostaining in benign endometria remains to be determined. The specific and distinctive staining pattern of ciliated epithelial cells, known to increase in prominence under the influence of estrogen, and the relatively more intense staining of proliferative and hyperplastic endometrium suggest a possible relationship between estrogens and CD117 expression in endometrial tissue. Although merely speculative at this juncture, we hypothesize that c-Kit expression in endometrial epithelium may be up-regulated in an hyperestrogenic milieu. Together with its ligand (SCF), which is expressed in endometrial stromal cells and present in sera of blood, c-kit could then potentially allow for growth regulation in either a paracrine or endocrine manner, resulting in increased proliferation of glandular glandular /glan·du·lar/ (glan´du-ler)
1. pertaining to or of the nature of a gland.
1. epithelial cells and placing that epithelium at increased risk of acquiring neoplasia-fomenting mutations. Further investigation into our hypothesis of an estrogen-driven, c-kit/SCF model of endometrial tumorigenesis tumorigenesis /tu·mor·i·gen·e·sis/ (-jen´e-sis) oncogenesis.
Formation or production of tumors. is pending the availability of reliable SCF antibodies and the conduction of in vitro studies.
Here we have also demonstrated by immunohistochemistry the expression of CD117 in a subset of human endometrial carcinomas (4/9) and a carcinoma-related polyp. As with benign endometria, immunostaining was; principally located in the cytoplasm of the carcinomas, consistent with the findings of Arber et al and our previous experience. In contrast, 2 independent studies failed to detect CD117 expression in endometrial carcinomas. In an immunohistochemical study by Matsuda et al, a very small sample set (n = 4) could be the explanation. In the other, failure to detect c-kit mRNA by Northern blotting could have resulted owing to the analysis of total RNA RNA: see nucleic acid.
in full ribonucleic acid
One of the two main types of nucleic acid (the other being DNA), which functions in cellular protein synthesis in all living cells and replaces DNA as the carrier of genetic rather than poly-A-enriched RNA. As expected, data indicate that reverse-transcription polymerase chain reaction polymerase chain reaction (pŏl`ĭmərās') (PCR), laboratory process in which a particular DNA segment from a mixture of DNA chains is rapidly replicated, producing a large, readily analyzed sample of a piece of DNA; the process is is more sensitive at detecting c-kit mRNA transcripts in gastric carcinoma cell lines, suggesting low levels of c-kit message. We cannot, however, explain why 10 frozen endometrial carcinomas analyzed by Natali et al had undetectable CD117 immunostaining. Recognizing the contradictory data regarding expression of CD117 in endometrial carcinomas, we felt it was critical to also perform Western blot analysis with some of the same cryopreserved tumor samples analyzed by immunohistochemistry. Using this approach, we have correlated levels of CD117 immunoprecipitated from lysed endometrial tissue with immunostaining intensity, thereby confirming expression of CD117 in some malignant endometria.
Our Western blot analysis demonstrated that CD117, expressed in the endometrial polyp and carcinoma, is about 145 kd, which is consistent with the size of the full-length CD117 protein. It is most likely that the smaller, fainter bands on the blot (ranging in size front about 80 to 120 kd) represent nonspecific antibody-protein interactions. However, based on the data generated from this study, we cannot exclude the possibility that some of the bands may represent CD117 truncations, as previously described in gastric and colon cancer cells. Moreover, we cannot conclude that full-length CD117 expressed in these endometrial tissues is a functionally normal gene product. Clearly, there are numerous examples, most notably in gastrointestinal stromal cell tumors[20,21] and mastocytosisy,[19,34] of mutations resulting either in a constitutively active or nonfunctional receptor. Examining those endometrioid carcinoma cases with positive immunostaining for c-kit gene mutations is certainly warranted.
Using a monoclonal antibody, we detected CD117 expression in a high percentage of benign endometrium, with the most intense immunostaining in hyperplastic and proliferative endometrium. Our study also demonstrates that CD117 is expressed in a subset of endometrial carcinomas using both immunohistochemistry and Western blot analyses. We feel these findings provide a solid foundation for now addressing an important question: Does c-kit play a role in endometrial carcinogenesis? Based on data generated in this study, we can now focus on a number of relevant issues, namely, the effects of estrogen on levels of CD117 in primary human endometrial epithelial cell cultures, a mutational analysis of c-kit in endometrial carcinomas, and the functionality of this tyrosine kinase receptor in human endometrial carcinoma cell lines.
We thank Geoffrey Krystal, MD, McGuire Virginia Medical Center, Richmond, Va, for kindly providing the small cell lung carcinoma cell lines. We are also indebted to Renee Workman, BS, Tracey Lamb, BA, and Teresa Gainey, BS, for their fine technical support in the immunohistochemical studies.
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Accepted for publication August 8, 2000.
From the Department of Pathology, Medical College of Virginia History
The school was founded in 1838 as the Medical Department of Hampden-Sydney College. It received an independent charter from the General Assembly in 1854 and became the Medical College of Virginia, and shortly thereafter transferred all its property to the Commonwealth at Virginia Commonwealth University Formed by a merger between the Richmond Professional Institute and the Medical College of Virginia in 1968, VCU has a medical school that is home to the nation's oldest organ transplant program. , Richmond, Va (Drs Elmore and Kornstein and Mr Moore); the Department of Pathology, winchester of Greenville, PA, Greenville, SC (Dr Burks).
Presented in part at the US and Canadian Academy of Pathology annual meetings, Washington, DC, March 23-29, 1996, and Orlando, Fla, March 1-7, 1997.
Reprints: Lynne W. Elmore, PhD, Deaprtment of Pathology, Medical College of Virginia at Virginia Commonwealth Universit, Box 980662, Richmond, VA 23298.