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Gene Expression Profile in Endometrioid Endometrial Carcinoma
Gynecologic Oncology 83, 175–176 (2001) doi:10.1006/gyno.2001.6449, available online at http://www.idealibrary.com on
EDITORIAL Gene Expression Profile in Endometrioid Endometrial Carcinoma Dirk Gu¨nter Kieback 1 and Dagmar-Christiane Fischer Department of Obstetrics and Gynecology I, Freiburg University Medical Center, Hugstetter Strasse 55, D-79106 Freiburg, Germany
Endometrial cancer is the most common cancer of the female genital tract with endometrioid (type 1) and serous (type 2) being the most common cell types. These tumor entities differ with respect to their frequency (about 80% are type 1), etiology, and prognosis with the more aggressive serous carcinoma arising from atrophic rather than hyperplastic epithelium. Serous endometrium carcinomas occur almost exclusively in postmenopausal women (⬎60 years) and are unrelated to estrogen stimulation. In contrast, endometrioid endometrial carcinomas are associated with hormonal imbalance, hyperlipidemia, and obesity. Precancerous lesions have been identified for both types of endometrial carcinoma, and different pathways describing the transition from normal endometrium to carcinoma have been postulated [1]. On the molecular level, serous carcinomas are frequently associated with mutation-induced loss of p53 function. Endometrioid endometrial carcinomas are characterized by microsatellite instability (MI), reduced or missing expression of PTEN (phosphatase and tensin homologue deleted from chromosome 10, also known as MMAC1, mutated in multiple advanced cancers or TEP1, TGF- regulated and epithelial cell-enriched phosphatase), and mutations of either k-ras and/or -catenin genes [2, 3]. Most interestingly, loss of PTEN expression is rather common in premalignant lesions of cycling endometrium, thus indicating that this is likely to be an early event in endometrial tumorigenesis [4, 5]. In glioblastoma, prostate carcinoma, and other cancers, inactivation of PTEN is associated with late-stage, more aggressive, and usually metastatic tumors emphasizing the biological plausibility of its role in endometrial cancer [3]. It is now widely accepted that cancerogenesis is a multistep process. Numerous studies have shown that the overexpression of oncogenes with their disturbed or constitutively activated signal transduction cascades alone or in combination with the mutation-induced silencing of tumor suppressor genes is associated with malignant transformation [6 – 8]. Even though the expression of only a few genes is likely to be directly affected by mutation, the cellular phenotype is the consequence of complex aberrations influencing the expression of a far greater 1
To whom correspondence and reprint requests should be addressed. Fax: 0049-761-270 2932. E-mail: [email protected].
number of genes. The simultaneous hybridization of labeled cDNA to an array of oligonucleotides representative for several thousand genes (oligonucleotide microarray) permits the identification and quantification of expressed genes. The comparison of gene expression patterns (the transcriptome) in cells or tissues representing distinct phenotypes, e.g., normal and malignant cells, will help to link the cellular phenotype with the transcriptome [9]. In the lead article of this issue of Gynecologic Oncology, Mutter et al. [10] have used this approach to compare gene expression patterns of normal (two samples each from proliferative and secretory endometrium) and of malignant (10 endometrioid adenocarcinomas of different grade, MI status, and PTEN expression) endometrial tissues. After application of several statistical models, a list of 50 genes was generated that were either induced or suppressed in endometrioid endometrial cancers. Even though loss of PTEN expression was identified previously as a potent and early marker for precancerous lesions, it did not qualify as one of the top 50 discriminators [5]. This is most likely due to the heterogeneity within the cancer group indicating that the comparison of normal and fully malignant tissues alone is rather unlikely to detect changes in gene expression patterns that are related to the process of malignant transformation itself. Moreover, even among the resulting discriminators, an induction or suppression of gene expression of more than 10-fold was rarely seen. This further supports the hypothesis that in addition to rather few mutational genetic events responsible for induction and maintenance of the malignant phenotype, subtle changes of the transcriptome occur leading to a widespread deregulation of cellular functions. Whereas in endometrial carcinomas only a few genes are expressed at a higher level than in normal endometrial tissue, many more showed reduced expression levels. The genes discriminating between normal and canceroid tissue are related to a variety of different functions like cell cycle progression, cell– cell interaction, hormone response, and amino acid metabolism or encode components of the extracellular matrix and the cytoskeleton. Most interestingly, endometrioid adenocarcinomas showed a rather sharp decrease in the expression level of progestagen-
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0090-8258/01 $35.00 Copyright © 2001 by Academic Press All rights of reproduction in any form reserved.
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EDITORIAL
associated endometrial protein, alternative splice variant 2 (PAEP, as2), and insulin-like growth factor 1 (IGF-1, somatomedin C) by factors of 158 and 42, respectively. PAEP, also known as placental protein 14 (glycodelin), pregnancy-associated endometrial ␣-2 globulin, or ␣-uterine protein, is the main protein synthesized and secreted from the endometrium during the secretory phase and belongs to the lipocalin superfamily [11–13]. The 34-kDa IGF-1 binding protein (34-kDa IGF-BP), also termed placenta protein 12 (pp12), is likely to be a splice variant of PAEP [14]. IGF-1 and IGF-2 are important for growth and development and their availability is tightly regulated via interaction with their cognate receptors and a variety of specific binding proteins [15]. Endometrial cells express the genes of the IGF system, which is believed to be the major mediator of steroid hormone action in this tissue [16]. To make the story even more complicated, hyperinsulinemia, a condition strongly associated with type 1 endometrial carcinoma, inhibits the expression of IGF-1 binding protein in the endometrium, thus increasing the concentration of free IGF-1 [17, 18]. The resulting steroid receptor-mediated cell proliferation activated via IGF drives overstimulation by a second pathway independent of steroid hormone action. One might speculate that the IGF system may be the predominant factor in serous endometrial cancerogenesis where hormone-driven endometrial hyperplasia is mostly absent. The results presented by Mutter et al. [10] highlight a number of genes, whose function should be further elucidated not only in endometrioid endometrial cancer but also in normal and premalignant endometrium in order to better understand the most likely tissue and cell-type-specific process of cancerogenesis. An examination of serous endometrial carcinoma and the comparison of its gene expression pattern with endometrioid lesions may in the future generate important insights into tissue-specific pathways of cancerogenesis.
2. Matias-Guiu X, Catasus L, Bussaglia E, et al. Molecular pathology of endometrial hyperplasia and carcinoma. Hum Pathol 2001;32:569 –77. 3. Di Cristofano A, Pandolfi PP. The multiple roles of PTEN in tumor suppression. Cell 2000;100:387–90. 4. Mutter GL. Histopathology of genetically defined endometrial precancers. Int J Gynecol Pathol 2000;19:301–9. 5. Mutter GL, Lin MC, Fitzgerald JT, et al. Altered PTEN expression as a diagnostic marker for the earliest endometrial precancers. J Natl Cancer Inst 2000;92:924 –30. 6. Hunter T. Signaling—2000 and beyond. Cell 2000;100:113–27. 7. Hunter T. Oncoprotein networks. Cell 1997;88:333– 46. 8. Hanahan D, Weinberg RA. The hallmarks of cancer. Cell 2000;100:57–70. 9. Polyak K, Riggins GJ. Gene discovery using the serial analysis of gene expression technique: implications for cancer research. J Clin Oncol 2001;19:2948 –58. 10. Mutter GL, Baak JPA, Fitzgerald JT, Gray R, Neuberg D, Kust GA, Gentleman R, Gullans SR, Wei L-J, Wilcox M. Global expression changes of constitutive and hormonally regulated genes during endometrial neoplastic transformation. Gynecol Oncol 2001;82:177–185. 11. Garde J, Bell SC, Eperon IC. Multiple forms of mRNA encoding human pregnancy-associated endometrial alpha 2-globulin, a beta-lactoglobulin homologue. Proc Natl Acad Sci USA 1991;88:2456 – 60. 12. Julkunen M, Seppala M, Janne OA. Complete amino acid sequence of human placental protein 14: a progesterone-regulated uterine protein homologous to beta-lactoglobulins. Proc Natl Acad Sci USA 1988;85:8845–9. 13. Chan P, Simon-Chazottes D, Mattei MG, et al. Comparative mapping of lipocalin genes in human and mouse: the four genes for complement C8 gamma chain, prostaglandin-D-synthase, oncogene-24p3, and progestagen-associated endometrial protein map to HSA9 and MMU2. Genomics 1994;23:145–50. 14. Rutanen EM, Koistinen R, Seppala M, et al. Progesterone-associated proteins PP12 and PP14 in the human endometrium. J Steroid Biochem 1987;27:25–31. 15. Le Roith D, Scavo L, Butler A. What is the role of circulating IGF-I? Trends Endocrinol Metab 2001;12:48 –52. 16. Stoll BA. New metabolic– endocrine risk markers in endometrial cancer. Br J Obstet Gynaecol 1999;106:402– 6.
REFERENCES
17. Nagamani M, Stuart CA, Dunhardt PA, et al. Specific binding sites for insulin and insulin-like growth factor I in human endometrial cancer. Am J Obstet Gynecol 1991;165:1865–71.
1. Sherman ME. Theories of endometrial carcinogenesis: a multidisciplinary approach. Mod Pathol 2000;13:295–308.
18. Giudice LC. Growth factors and growth modulators in human uterine endometrium: their potential relevance to reproductive medicine. Fertil Steril 1994;61:1–17.
EDITORIAL Gene Expression Profile in Endometrioid Endometrial Carcinoma Dirk Gu¨nter Kieback 1 and Dagmar-Christiane Fischer Department of Obstetrics and Gynecology I, Freiburg University Medical Center, Hugstetter Strasse 55, D-79106 Freiburg, Germany
Endometrial cancer is the most common cancer of the female genital tract with endometrioid (type 1) and serous (type 2) being the most common cell types. These tumor entities differ with respect to their frequency (about 80% are type 1), etiology, and prognosis with the more aggressive serous carcinoma arising from atrophic rather than hyperplastic epithelium. Serous endometrium carcinomas occur almost exclusively in postmenopausal women (⬎60 years) and are unrelated to estrogen stimulation. In contrast, endometrioid endometrial carcinomas are associated with hormonal imbalance, hyperlipidemia, and obesity. Precancerous lesions have been identified for both types of endometrial carcinoma, and different pathways describing the transition from normal endometrium to carcinoma have been postulated [1]. On the molecular level, serous carcinomas are frequently associated with mutation-induced loss of p53 function. Endometrioid endometrial carcinomas are characterized by microsatellite instability (MI), reduced or missing expression of PTEN (phosphatase and tensin homologue deleted from chromosome 10, also known as MMAC1, mutated in multiple advanced cancers or TEP1, TGF- regulated and epithelial cell-enriched phosphatase), and mutations of either k-ras and/or -catenin genes [2, 3]. Most interestingly, loss of PTEN expression is rather common in premalignant lesions of cycling endometrium, thus indicating that this is likely to be an early event in endometrial tumorigenesis [4, 5]. In glioblastoma, prostate carcinoma, and other cancers, inactivation of PTEN is associated with late-stage, more aggressive, and usually metastatic tumors emphasizing the biological plausibility of its role in endometrial cancer [3]. It is now widely accepted that cancerogenesis is a multistep process. Numerous studies have shown that the overexpression of oncogenes with their disturbed or constitutively activated signal transduction cascades alone or in combination with the mutation-induced silencing of tumor suppressor genes is associated with malignant transformation [6 – 8]. Even though the expression of only a few genes is likely to be directly affected by mutation, the cellular phenotype is the consequence of complex aberrations influencing the expression of a far greater 1
To whom correspondence and reprint requests should be addressed. Fax: 0049-761-270 2932. E-mail: [email protected].
number of genes. The simultaneous hybridization of labeled cDNA to an array of oligonucleotides representative for several thousand genes (oligonucleotide microarray) permits the identification and quantification of expressed genes. The comparison of gene expression patterns (the transcriptome) in cells or tissues representing distinct phenotypes, e.g., normal and malignant cells, will help to link the cellular phenotype with the transcriptome [9]. In the lead article of this issue of Gynecologic Oncology, Mutter et al. [10] have used this approach to compare gene expression patterns of normal (two samples each from proliferative and secretory endometrium) and of malignant (10 endometrioid adenocarcinomas of different grade, MI status, and PTEN expression) endometrial tissues. After application of several statistical models, a list of 50 genes was generated that were either induced or suppressed in endometrioid endometrial cancers. Even though loss of PTEN expression was identified previously as a potent and early marker for precancerous lesions, it did not qualify as one of the top 50 discriminators [5]. This is most likely due to the heterogeneity within the cancer group indicating that the comparison of normal and fully malignant tissues alone is rather unlikely to detect changes in gene expression patterns that are related to the process of malignant transformation itself. Moreover, even among the resulting discriminators, an induction or suppression of gene expression of more than 10-fold was rarely seen. This further supports the hypothesis that in addition to rather few mutational genetic events responsible for induction and maintenance of the malignant phenotype, subtle changes of the transcriptome occur leading to a widespread deregulation of cellular functions. Whereas in endometrial carcinomas only a few genes are expressed at a higher level than in normal endometrial tissue, many more showed reduced expression levels. The genes discriminating between normal and canceroid tissue are related to a variety of different functions like cell cycle progression, cell– cell interaction, hormone response, and amino acid metabolism or encode components of the extracellular matrix and the cytoskeleton. Most interestingly, endometrioid adenocarcinomas showed a rather sharp decrease in the expression level of progestagen-
175
0090-8258/01 $35.00 Copyright © 2001 by Academic Press All rights of reproduction in any form reserved.
176
EDITORIAL
associated endometrial protein, alternative splice variant 2 (PAEP, as2), and insulin-like growth factor 1 (IGF-1, somatomedin C) by factors of 158 and 42, respectively. PAEP, also known as placental protein 14 (glycodelin), pregnancy-associated endometrial ␣-2 globulin, or ␣-uterine protein, is the main protein synthesized and secreted from the endometrium during the secretory phase and belongs to the lipocalin superfamily [11–13]. The 34-kDa IGF-1 binding protein (34-kDa IGF-BP), also termed placenta protein 12 (pp12), is likely to be a splice variant of PAEP [14]. IGF-1 and IGF-2 are important for growth and development and their availability is tightly regulated via interaction with their cognate receptors and a variety of specific binding proteins [15]. Endometrial cells express the genes of the IGF system, which is believed to be the major mediator of steroid hormone action in this tissue [16]. To make the story even more complicated, hyperinsulinemia, a condition strongly associated with type 1 endometrial carcinoma, inhibits the expression of IGF-1 binding protein in the endometrium, thus increasing the concentration of free IGF-1 [17, 18]. The resulting steroid receptor-mediated cell proliferation activated via IGF drives overstimulation by a second pathway independent of steroid hormone action. One might speculate that the IGF system may be the predominant factor in serous endometrial cancerogenesis where hormone-driven endometrial hyperplasia is mostly absent. The results presented by Mutter et al. [10] highlight a number of genes, whose function should be further elucidated not only in endometrioid endometrial cancer but also in normal and premalignant endometrium in order to better understand the most likely tissue and cell-type-specific process of cancerogenesis. An examination of serous endometrial carcinoma and the comparison of its gene expression pattern with endometrioid lesions may in the future generate important insights into tissue-specific pathways of cancerogenesis.
2. Matias-Guiu X, Catasus L, Bussaglia E, et al. Molecular pathology of endometrial hyperplasia and carcinoma. Hum Pathol 2001;32:569 –77. 3. Di Cristofano A, Pandolfi PP. The multiple roles of PTEN in tumor suppression. Cell 2000;100:387–90. 4. Mutter GL. Histopathology of genetically defined endometrial precancers. Int J Gynecol Pathol 2000;19:301–9. 5. Mutter GL, Lin MC, Fitzgerald JT, et al. Altered PTEN expression as a diagnostic marker for the earliest endometrial precancers. J Natl Cancer Inst 2000;92:924 –30. 6. Hunter T. Signaling—2000 and beyond. Cell 2000;100:113–27. 7. Hunter T. Oncoprotein networks. Cell 1997;88:333– 46. 8. Hanahan D, Weinberg RA. The hallmarks of cancer. Cell 2000;100:57–70. 9. Polyak K, Riggins GJ. Gene discovery using the serial analysis of gene expression technique: implications for cancer research. J Clin Oncol 2001;19:2948 –58. 10. Mutter GL, Baak JPA, Fitzgerald JT, Gray R, Neuberg D, Kust GA, Gentleman R, Gullans SR, Wei L-J, Wilcox M. Global expression changes of constitutive and hormonally regulated genes during endometrial neoplastic transformation. Gynecol Oncol 2001;82:177–185. 11. Garde J, Bell SC, Eperon IC. Multiple forms of mRNA encoding human pregnancy-associated endometrial alpha 2-globulin, a beta-lactoglobulin homologue. Proc Natl Acad Sci USA 1991;88:2456 – 60. 12. Julkunen M, Seppala M, Janne OA. Complete amino acid sequence of human placental protein 14: a progesterone-regulated uterine protein homologous to beta-lactoglobulins. Proc Natl Acad Sci USA 1988;85:8845–9. 13. Chan P, Simon-Chazottes D, Mattei MG, et al. Comparative mapping of lipocalin genes in human and mouse: the four genes for complement C8 gamma chain, prostaglandin-D-synthase, oncogene-24p3, and progestagen-associated endometrial protein map to HSA9 and MMU2. Genomics 1994;23:145–50. 14. Rutanen EM, Koistinen R, Seppala M, et al. Progesterone-associated proteins PP12 and PP14 in the human endometrium. J Steroid Biochem 1987;27:25–31. 15. Le Roith D, Scavo L, Butler A. What is the role of circulating IGF-I? Trends Endocrinol Metab 2001;12:48 –52. 16. Stoll BA. New metabolic– endocrine risk markers in endometrial cancer. Br J Obstet Gynaecol 1999;106:402– 6.
REFERENCES
17. Nagamani M, Stuart CA, Dunhardt PA, et al. Specific binding sites for insulin and insulin-like growth factor I in human endometrial cancer. Am J Obstet Gynecol 1991;165:1865–71.
1. Sherman ME. Theories of endometrial carcinogenesis: a multidisciplinary approach. Mod Pathol 2000;13:295–308.
18. Giudice LC. Growth factors and growth modulators in human uterine endometrium: their potential relevance to reproductive medicine. Fertil Steril 1994;61:1–17.