Increased expression of transforming growth factor β isoforms and basic fibroblast growth factor in complex hyperplasia and adenocarcinoma of the endometrium: Evidence for paracrine and autocrine action

Leslie I. Gold, Babita Saxena, Khush R. Mittal, Michael Marmor, Sunanda Goswami, Lila Nactigal, Murray Korc, Rita I. Demopoulos

Research output: Contribution to journalArticle

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Abstract

Endometrial carcinoma is associated with antecedent simple and complex hyperplasia, and the endometrium is a target tissue for the action of cytokines and growth factors. Transforming growth factor (TGF)-βs are potent cellular growth and differentiation regulatory factors. Therefore, we investigated the potential role for TGF-βs in the normal proliferative endometrium and its possible involvement in the transition to complex hyperplasia and progression to endometrial carcinoma. The angiogenic and mitogenic growth factor, basic fibroblast growth factor, was used for comparison. Differential TGF-β isoform-specific immunoreactivity was observed in the normal endometrium, which is composed of glandular and stromal cells. There was an increase in TGF-β3 but not TGF-β1 or TGF-β2 in the glandular epithelium from the proliferative to the secretory phase of the menstrual cycle. Immunostaining for TGF-β2 was more intense in the stroma than the glands. In contrast, TGF-β1 and TGF-β3 were near equal intensity in these two endometrial compartments, TGF-β3 being the most intense. The glandular epithelium demonstrated a statistically significant stepwise increase in the expression of all three TGF-βs progressing from the normal proliferative endometrium to simple hyperplasia and on to complex hyperplasia. However, the stromal cells maintained approximately the same level of immunoreactivity for TGF-β in all these samples. In comparing proliferative endometrium with complex hyperplasia, there was a 5.1- , 3.4- , and 2.6-fold increase in immunostaining in the glands for TGF-β1, TGF-β2, and TGF-β3, respectively (P ≤ 0.001). There was no further increase in immunoreactivity with progression from preneoplastic complex hyperplasia to carcinoma. Immunoreactive basic fibroblast growth factor was slight in normal endometrium and simple hyperplasia. There was a 4.6- and 4.2-fold increase in immunostaining observed in complex hyperplasia compared with proliferative endometrium in the glandular (P ≤ 0.0054) and stromal (P ≤ 0.0053) cells, respectively, with no further increase in carcinoma. By in situ hybridization, an increase in mRNA for all TGF-β isoforms paralleled TGF-β immunoreactivity. However, in contrast to the increased immunostaining in the glands in complex hyperplasia, there was remarkably more mRNA in the stromal cell compartment. The discordant expression of mRNA and protein was only observed in the pathological endometrium since both were more highly expressed in the stromal cells in normal proliferative endometrium. This result suggests that there may be a greater paracrine than autocrine mechanism of TGF-β action in the pathological state. Furthermore, the simultaneous overexpression or accumulation of TGF-β isoforms and basic fibroblast growth factor, especially in glandular epithelium, with progression from the normal to the hyperplastic state may indicate dysregulated growth control, which may contribute to the development of endometrial carcinoma.

Original languageEnglish (US)
Pages (from-to)2347-2358
Number of pages12
JournalCancer Research
Volume54
Issue number9
StatePublished - May 1 1994
Externally publishedYes

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Transforming Growth Factors
Fibroblast Growth Factor 2
Endometrium
Hyperplasia
Protein Isoforms
Adenocarcinoma
Stromal Cells
Endometrial Neoplasms
Epithelium
Messenger RNA
Intercellular Signaling Peptides and Proteins
Growth Differentiation Factors
Carcinoma
Luteal Phase

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Increased expression of transforming growth factor β isoforms and basic fibroblast growth factor in complex hyperplasia and adenocarcinoma of the endometrium : Evidence for paracrine and autocrine action. / Gold, Leslie I.; Saxena, Babita; Mittal, Khush R.; Marmor, Michael; Goswami, Sunanda; Nactigal, Lila; Korc, Murray; Demopoulos, Rita I.

In: Cancer Research, Vol. 54, No. 9, 01.05.1994, p. 2347-2358.

Research output: Contribution to journalArticle

Gold, Leslie I. ; Saxena, Babita ; Mittal, Khush R. ; Marmor, Michael ; Goswami, Sunanda ; Nactigal, Lila ; Korc, Murray ; Demopoulos, Rita I. / Increased expression of transforming growth factor β isoforms and basic fibroblast growth factor in complex hyperplasia and adenocarcinoma of the endometrium : Evidence for paracrine and autocrine action. In: Cancer Research. 1994 ; Vol. 54, No. 9. pp. 2347-2358.
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abstract = "Endometrial carcinoma is associated with antecedent simple and complex hyperplasia, and the endometrium is a target tissue for the action of cytokines and growth factors. Transforming growth factor (TGF)-βs are potent cellular growth and differentiation regulatory factors. Therefore, we investigated the potential role for TGF-βs in the normal proliferative endometrium and its possible involvement in the transition to complex hyperplasia and progression to endometrial carcinoma. The angiogenic and mitogenic growth factor, basic fibroblast growth factor, was used for comparison. Differential TGF-β isoform-specific immunoreactivity was observed in the normal endometrium, which is composed of glandular and stromal cells. There was an increase in TGF-β3 but not TGF-β1 or TGF-β2 in the glandular epithelium from the proliferative to the secretory phase of the menstrual cycle. Immunostaining for TGF-β2 was more intense in the stroma than the glands. In contrast, TGF-β1 and TGF-β3 were near equal intensity in these two endometrial compartments, TGF-β3 being the most intense. The glandular epithelium demonstrated a statistically significant stepwise increase in the expression of all three TGF-βs progressing from the normal proliferative endometrium to simple hyperplasia and on to complex hyperplasia. However, the stromal cells maintained approximately the same level of immunoreactivity for TGF-β in all these samples. In comparing proliferative endometrium with complex hyperplasia, there was a 5.1- , 3.4- , and 2.6-fold increase in immunostaining in the glands for TGF-β1, TGF-β2, and TGF-β3, respectively (P ≤ 0.001). There was no further increase in immunoreactivity with progression from preneoplastic complex hyperplasia to carcinoma. Immunoreactive basic fibroblast growth factor was slight in normal endometrium and simple hyperplasia. There was a 4.6- and 4.2-fold increase in immunostaining observed in complex hyperplasia compared with proliferative endometrium in the glandular (P ≤ 0.0054) and stromal (P ≤ 0.0053) cells, respectively, with no further increase in carcinoma. By in situ hybridization, an increase in mRNA for all TGF-β isoforms paralleled TGF-β immunoreactivity. However, in contrast to the increased immunostaining in the glands in complex hyperplasia, there was remarkably more mRNA in the stromal cell compartment. The discordant expression of mRNA and protein was only observed in the pathological endometrium since both were more highly expressed in the stromal cells in normal proliferative endometrium. This result suggests that there may be a greater paracrine than autocrine mechanism of TGF-β action in the pathological state. Furthermore, the simultaneous overexpression or accumulation of TGF-β isoforms and basic fibroblast growth factor, especially in glandular epithelium, with progression from the normal to the hyperplastic state may indicate dysregulated growth control, which may contribute to the development of endometrial carcinoma.",
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T2 - Evidence for paracrine and autocrine action

AU - Gold, Leslie I.

AU - Saxena, Babita

AU - Mittal, Khush R.

AU - Marmor, Michael

AU - Goswami, Sunanda

AU - Nactigal, Lila

AU - Korc, Murray

AU - Demopoulos, Rita I.

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N2 - Endometrial carcinoma is associated with antecedent simple and complex hyperplasia, and the endometrium is a target tissue for the action of cytokines and growth factors. Transforming growth factor (TGF)-βs are potent cellular growth and differentiation regulatory factors. Therefore, we investigated the potential role for TGF-βs in the normal proliferative endometrium and its possible involvement in the transition to complex hyperplasia and progression to endometrial carcinoma. The angiogenic and mitogenic growth factor, basic fibroblast growth factor, was used for comparison. Differential TGF-β isoform-specific immunoreactivity was observed in the normal endometrium, which is composed of glandular and stromal cells. There was an increase in TGF-β3 but not TGF-β1 or TGF-β2 in the glandular epithelium from the proliferative to the secretory phase of the menstrual cycle. Immunostaining for TGF-β2 was more intense in the stroma than the glands. In contrast, TGF-β1 and TGF-β3 were near equal intensity in these two endometrial compartments, TGF-β3 being the most intense. The glandular epithelium demonstrated a statistically significant stepwise increase in the expression of all three TGF-βs progressing from the normal proliferative endometrium to simple hyperplasia and on to complex hyperplasia. However, the stromal cells maintained approximately the same level of immunoreactivity for TGF-β in all these samples. In comparing proliferative endometrium with complex hyperplasia, there was a 5.1- , 3.4- , and 2.6-fold increase in immunostaining in the glands for TGF-β1, TGF-β2, and TGF-β3, respectively (P ≤ 0.001). There was no further increase in immunoreactivity with progression from preneoplastic complex hyperplasia to carcinoma. Immunoreactive basic fibroblast growth factor was slight in normal endometrium and simple hyperplasia. There was a 4.6- and 4.2-fold increase in immunostaining observed in complex hyperplasia compared with proliferative endometrium in the glandular (P ≤ 0.0054) and stromal (P ≤ 0.0053) cells, respectively, with no further increase in carcinoma. By in situ hybridization, an increase in mRNA for all TGF-β isoforms paralleled TGF-β immunoreactivity. However, in contrast to the increased immunostaining in the glands in complex hyperplasia, there was remarkably more mRNA in the stromal cell compartment. The discordant expression of mRNA and protein was only observed in the pathological endometrium since both were more highly expressed in the stromal cells in normal proliferative endometrium. This result suggests that there may be a greater paracrine than autocrine mechanism of TGF-β action in the pathological state. Furthermore, the simultaneous overexpression or accumulation of TGF-β isoforms and basic fibroblast growth factor, especially in glandular epithelium, with progression from the normal to the hyperplastic state may indicate dysregulated growth control, which may contribute to the development of endometrial carcinoma.

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