TGF-β signaling is disrupted in endometrioid-type endometrial carcinomas
Introduction
Transforming growth factor β (TGF-β) is a member of the large family of structurally related cytokines that play an important role in controlling cell proliferation, differentiation, migration, and apoptosis [1], [2]. TGF-β signaling is initiated by ligand binding to specific transmembrane serine/threonine kinase TGF-β receptors such as type II (TGFβRII), which in turn transphosphorylates type I receptor (TGFβRI). Receptors convey signals across the plasma membrane through intracellular effectors such as SMAD proteins, which are translocated to the nucleus where they act as transcription factors [3], [4], [5], [6]. SMAD proteins have been divided into three functional classes: receptor-regulated (R-SMADs), common mediator (Co-SMAD), and inhibitory (I-SMADs) [5], [6]. Representatives of the first class are directly phosphorylated by TGFβRI and are involved in the various signaling pathways. SMAD2 and SMAD3 are effectors of TGF-β/activin signaling, while SMAD1, SMAD5, and SMAD8 are involved in BMP (bone morphogenetic protein) signaling. Common mediator SMAD4 is critical for TGF-β/activin and BMP signaling cascades. Representatives of the third class of SMADs (SMAD6 and SMAD7) have the ability to inhibit the TGF-β signaling pathway [7], [8].
TGF-β signaling through SMADs may integrate information from distinct signaling pathways, thus introducing the possibility that SMADs play important roles in the intracellular network and in the complexity of the responses to TGF-β and related growth factors [9], [10]. Although regulation of the TGF-β signaling pathway has been extensively studied, many aspects are still unclear and should be further elucidated. TGF-β can play multiple roles in human tumorigenesis, behaving as a tumor suppressor at early stages and a tumor promoter at late stages of carcinogenesis [11], [12], [13]. It has been well documented that deregulation and/or inhibition of the TGF-β signaling through SMADs may be very important for neoplastic transformation and as well as tumor progression [2], [12], [13].
Our laboratory is focused on determining the role of the TGF-β signaling cascade in the development and progression of endometrial cancer. In our first study, although no significant differences in the TGF-β receptor mRNA level between normal and carcinomatous endometrium was observed, we did see significantly lower TGFβRI (P = 0.028) and significantly higher TGFβRII (P = 0.007) protein levels in cancerous endometrium compared with normal endometrial tissue [14]. Moreover, differences in SMAD protein expression and intracellular localization between neoplastic and normal endometrium were noted [15]. To expand this research, this study sought to analyze the relationship, if it exists, between changes in the TGF-β signaling cascade and clinicopathological features of cancer of the uterine corpus. The expression of TGF-β receptor type I and type II as well as SMAD2, SMAD3, and SMAD4 was analyzed both at the mRNA and protein level in relation to the patient's age, tumor grade, FIGO classification, and depth of myometrial invasion using RT-PCR and ELISA techniques, respectively. Simultaneously, intracellular distribution of SMAD with regard to the clinicopathological features of endometrial cancers was examined.
Section snippets
Materials
The study group is comprised of endometrial cancer specimens (n = 39) collected from women who underwent TAH/BSO (total abdominal hysterectomy/bilateral salpingo-oophorectomy) surgery from 1999 to 2000 at the Department of Gynecology, Lublin University School of Medicine in Poland. The Independent Ethics Committee of the Lublin University School of Medicine approved the tissue collection and subsequent experiments, and informed consent was obtained from all patients enrolled in the study.
Expression of TGF-β receptors and clinicopathological parameters of ECs
The expression of TGF-β type I and type II receptor in endometrial cancers was estimated at the mRNA level by RT-PCR (Fig. 1A) while protein levels were measured using ELISA techniques.
This study found no statistically significant differences in the level of TGFβRI and TGFβRII mRNA in relation to the clinical and histopathological features of ECs such as patient's age, tumor grade, clinical stage, or depth of myometrial invasion (P > 0.05, data not shown). However, tumors infiltrating less than
Discussion
Endometrial cancer in one of the most common gynecologic malignancy in Poland with approximately 3500 new cases diagnosed annually [22]. Based on clinical, histopathological, and molecular features, a dualistic model of endometrial carcinogenesis has been proposed by Bokhman [23], and recently by Sherman [24]. There are two main types of endometrial carcinomas: endometrioid (type I) and nonendometrioid (type II). In general, type I tumors are associated with signs of hyperestrogenism (ovarian
Acknowledgments
The authors would like to express their gratitude to the staff at the Department of Pathology, Lublin University School of Medicine, Poland, for their scrupulous histological assessment of the material. This study was funded in the part by the State Committee for Scientific Research, Poland. (No. P405A00119).
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Loss of CD73 shifts transforming growth factor-β1 (TGF-β1) from tumor suppressor to promoter in endometrial cancer
2021, Cancer LettersCitation Excerpt :Deeply invasive stage I EC cells have higher expression of TGFβR2 protein compared to non-invasive tumors [36]. Higher Smad4 expression occurs in EC cells of stage I tumors with significant myometrial invasion and poor tumor differentiation [36]. Additionally, plasma levels of TGF-β1 are higher in patients with deeply invasive than non-invasive tumors [35].
TGFβ1 induces endometrial cancer cell adhesion and migration by up-regulating integrin αvβ3 via SMAD-independent MEK-ERK1/2 signaling
2017, Cellular SignallingCitation Excerpt :As well, plasma levels of TGFβ1 are greater in Stage-Ib/Ic patients than in Stage-Ia patients [13]. Endometrial cancers have been shown to have higher TGFΒR2 protein levels compared to normal endometrial tissues, and TGFBR2 levels are higher in tumors with myometrial invasion compared to non-infiltrating tumors [14,15]. SMAD proteins are generally considered to be tumor suppressors, however deregulated SMAD signaling is frequently associated with tumor progression [10].
TGFβ-pathway is down-regulated in a uterine carcinosarcoma: A case study
2013, Pathology Research and PracticeCitation Excerpt :This suggests impaired TGFβ signaling exclusively mediated by TGFβ2 isoform and its accessory receptor TGFβR3. Deregulation of TGFβ signaling initiation via TGFβ isoforms and their canonical receptor in uterine CS seems to resemble data previously presented in primary human endometrial carcinomas (ECs) [24,27,28]. Presented data are also in line with those concerning TGFβ co-receptors [12,35,36].
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Present address (until October 5, 2004): Women's Reproductive Health Research Center, Vanderbilt University Medical Center, B-1100 Medical Center North, Nashville, TN 37232-2519, USA. Fax: +1 615 343 7913.