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 Table of Contents  
Year : 2016  |  Volume : 14  |  Issue : 4  |  Page : 182-189

Immunohistochemical expression of β-catenin in osteoblastoma and osteosarcoma

Department of Pathology, Sohag University, Sohag, Egypt

Date of Submission12-Dec-2016
Date of Acceptance06-Mar-2017
Date of Web Publication23-Jun-2017

Correspondence Address:
Afaf T El-Nashar
Department of Pathology, Sohag University, Sohag
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/AZMJ.AZMJ_59_16

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Introduction Osteosarcoma (OS) is the most prevalent primary malignant tumor of bone in adolescents. Osteoblastoma (OB) is a rare benign bone tumor with a few aggressive variants. The differentiation between OS (low-grade types) OB (especially aggressive variant) by microscopic examination alone can be difficult, especially when using small biopsy specimens. Recently, the Wnt/β-catenin pathway has emerged as an essential pathway in bone development.
Aim The aim of this study was to evaluate the immunohistochemical expression of β-catenin in OS and OB and its possible role in tumor diagnosis and prognosis.
Materials and methods In total, 28 biopsies of OS (18 male and 10 female) and 12 cases of OB (10 male and two female) were examined for β-catenin immunostaining.
Results β-Catenin showed cytoplasmic expression in 5/28 (17.9%) OS samples and in 8/12 (66.7%) OB samples, with a statistically significant relationship (P>0.008).
Conclusion β-Catenin is a valuable tumor marker to differentiate between OS and OB, especially the aggressive variant.

Keywords: β-catenin, osteoblastoma, osteosarcoma

How to cite this article:
Hassab El-Naby NE, El-Nashar AT. Immunohistochemical expression of β-catenin in osteoblastoma and osteosarcoma. Al-Azhar Assiut Med J 2016;14:182-9

How to cite this URL:
Hassab El-Naby NE, El-Nashar AT. Immunohistochemical expression of β-catenin in osteoblastoma and osteosarcoma. Al-Azhar Assiut Med J [serial online] 2016 [cited 2021 Mar 5];14:182-9. Available from: http://www.azmj.eg.net/text.asp?2016/14/4/182/208935

  Introduction Top

Osteosarcoma (OS) is an aggressive malignant primary bone tumor that most often occurs in adolescents and young adults in the long bones with a 5-year survival ranging from 65 to 75% for localized disease and less than 30% for patients with metastases [1].

The current WHO classification 2013 recognized major subtypes of conventional OS: osteoblastic, chondroblastic, and fibroblastic, reflecting the predominant type of matrix within the tumor. In addition to classical OS, the WHO classification recognizes additional histological variants including telangiectatic OS, small-cell OS, parosteal and periosteal OSs, as well as low-grade central and high-grade surface OSs. The classical central subtypes are nearly always WHO high-grade III malignant tumors, whereas surface OSs are mostly low-grade I or intermediate-grade II tumors [2].

Osteoblastoma (OB) is a rare, benign tumor that accounts for less than 1% of all bone tumors and most commonly involves the spine and sacrum of young individuals [3]. Conventional OBs are biologically benign with limited growth potential and typically do not exceed 4 cm in diameter. However, there is a small subgroup of borderline OBs that possesses a locally aggressive growth pattern, usually exceeding 4 cm. These tumors cannot easily be classified as conventional OBs or OSs, and have thus been separated from the classic lesion and designated as OB-like OS and malignant OBs or aggressive OBs [4]. These aggressive OBs occur in the older age group compared with benign OB. On the clinical side, this tumor shows aggressive behavior. It is able to extend into adjacent tissues and to recur in 10–21%, but it does not metastasize. The histological findings in aggressive OB are those that suggest the possibility of OS rather than an obviously benign lesion [5].

Therefore, the differentiation between OB (especially aggressive variant) and OS (low-grade types) by microscopic histological examination alone can be very difficult, especially with small biopsy specimens.

β-Catenin is an intracellular protein with two important cellular functions: cell–cell adhesion and transmission of extracellular-initiated Wnt signals to the nucleus [6]. The Wnt signaling pathway is an ancient and evolutionarily conserved pathway that regulates the crucial aspects of cellular processes such as cell migration, cell polarity, cell fate determination, neural patterning, and organogenesis during embryonic development and tissue homeostasis [7]. The Wnts are secreted glycoproteins and comprise a large family of 19 proteins that pass signals from the outside of a cell through cell surface receptors to the inside of a cell [8]. The best characterized Wnt signaling pathways are the canonical or beta catenin-dependent pathway (Wnt/β-catenin) and the noncanonical or β-catenin-independent pathway, which can be again divided into the planar cell polarity pathway and the Wnt/Ca2+ pathway [9]. Among the two pathways, the canonical Wnt signaling pathway is thought to be critical and is the most studied Wnt pathway, as it functions by regulating the amount of the transcriptional co-activator β-catenin (a subunit of the cadherin protein complex), which controls the expressions of key developmental genes, and acts as an intracellular signal transducer in the Wnt signaling pathway [7].

The hallmark of the Wnt/β-catenin pathway is the accumulation and translocation of β-catenin into the nucleus to act as a transcriptional co-activator of transcription factors that belong to the DNA-bound T-cell factor/lymphoid enhancer factor (TCF/LEF) family of proteins. Without Wnt signaling, β-catenin cannot accumulate in the cytoplasm, as it is degraded by a β-catenin destruction complex, which includes the following proteins: axin, adenomatosis polyposis coli, protein phosphatase-2A, glycogen synthase kinase-3, and casein kinase-1α. Within this complex, casein kinase-1α and glycogen synthase kinase-3 sequentially phosphorylate the amino terminal region of β-catenin, resulting in β-catenin recognition by β-Trcp (an E3 ubiquitin ligase subunit for ubiquitination and proteasomal degradation). Binding of Wnt to a seven-pass, transmembrane, Frizzled (Fz) receptor and its co-receptor (low-density lipoprotein receptor related protein 5 or 6) (LRP5/6) triggers a series of events that induces the translocation of both a negative regulator of axin and a destruction complex to the plasma membrane. The formation of a Wnt/Fz/LRP5/6 complex, together with the recruitment of the scaffolding protein disheveled (Dsh/Dvl), results in LRP5/6 phosphorylation and axin recruitment to the receptors. These events induce stabilization of β-catenin by disrupting axin-mediated phosphorylation/degradation of β-catenin, allowing β-catenin to accumulate in the nucleus to form complexes with TCF/LEF to mediate transcriptional induction of target genes [10],[11],[12].

The Wnt/β-catenin signaling pathway is reported to be closely associated with OS. Many studies have indicated that the aberrant activation of this pathway plays a crucial role in the development and progression of OS [13],[14],[15]. Recently, targeting Wnt/β-catenin pathway has gained significant interest as the potential therapeutic application for the treatment of bone cancer. Blocking the Wnt/β-catenin pathway by small-RNA technology has been shown to be effective. In one study, Zhang et al. [16] transfected siRNA against β-catenin into the human OS cell line MG-63 and investigated the effect of β-catenin-siRNA on the survival, invasion, and chemosensitivity of MG-63. They reported that knockdown of the β-catenin gene by siRNA decreases the invasion and motility of MG-63 cells through the downregulation of membrane-type matrix metalloproteinase-1 expression and enhances chemoresistance to doxorubicin through the nuclear factor-κB pathway. Combination therapies incorporating nuclear factor-κB inhibitor together with β-catenin inhibitor have been indicated as a promising approach for the treatment of OS [16]. The Wnt signaling pathway has been identified as an essential pathway in mammalian skeletal development [17]. Activation of the Wnt signaling pathway is necessary for the commitment of mesenchymal stem cells to the osteoblast lineage [18].

Two studies have investigated the proliferation and the invasion-inhibitory effects of dihydroartemisinin and artemisinin − a natural product originally isolated from the plant Artemisia annua L. that has been used in traditional Chinese medicine for centuries − on human OS cells, and demonstrated that dihydroartemisinin can inhibit proliferation, decrease migration, reduce invasion, and induce apoptosis in human OS cells by inactivating the Wnt/β-catenin signaling [19],[20].

  Aim Top

To aims of the present study were to evaluate the immunohistochemical (IHC) expression of β-catenin in OS and OB cases and to evaluate its possible diagnostic and prognostic role.

  Materials and methods Top

Forty specimens were retrospectively and randomly obtained from the Pathology Laboratories of both Sohag University and Assuit University Hospitals. The research protocol of the study was approved by the local medical ethics committee. The studied specimens included 28 OSs (four low grade and 24 high grade) and 12 OBs (four of them were aggressive OBs). Clinical data included age, sex of the patient, clinical presentation, the method of sample collection, and the site of the lesion. Biopsies were obtained by bone curettage and incisional and excisional biopsy. All the specimens were formalin-fixed and paraffin-embedded tissue blocks.

For IHC staining, precleaned (Superfrost/Plus-Fisherbrand, USA; EDTA catalog #(TA xxx-PM 4x) DAKO) slides were used. Formalin-fixed, paraffin-embedded sections were immunostained using peroxidase-labeled streptavidin-biotin to detect β-catenin expression. Rabbit monoclonal antibody (catalog #RM-2101-S0/S, 0.1 ml; Lab Vision Corporation) and antipolyvalent horseradish peroxidase-DAB Detection System (catalog #TPD-015, 15 ml) were used. Tissue sections were deparaffinized in twice with xylene, rehydrated through descending grades of alcohol, and washed in distilled water. Endogenous peroxidase activity was blocked with hydrogen peroxide (catalog # DHP-xxx) (catalog #RM 2101-R7 (7 ml) RTU Thermo Scientific, USA) using peroxidase blocking reagent, and then washed in 20% diluted PBS. Slides were immersed in antigen retrieval solution (10-mmol sodium citrate buffer solution, pH 6.0), microwaved at 100°c for 20 min, and then washed in distilled water and PBS. Tissue sections were incubated in 1/25 β-catenin in 1/100 normal goat serum overnight at room temperature to block nonspecific interactions. After rinsing in PBS, tissue sections were treated with biotinylated goat serum for 10 min at room temperature. The slides were rinsed, and peroxidase-labeled streptavidin was applied for 10 min at room temperature, rinsed again with PBS, and blotted. The slides were incubated with DAB (14-diaminobenzidine) and 0.06% H2O2 for 20 min, washed in distilled water, and counter-stained using Myer’s hematoxylin. Tissue sections were washed with tap water, dehydrated in ascending grades of alcohol, cleared in xylol, left to dry, mounted with dibutyl phthalate in xylene, and then cover slipped. Sections from normal skin were used as positive controls.

Evaluation of immunostaining of β-catenin

Immunostained sections were evaluated for nuclear or cytoplasmic/membranous immunostaining with a 12-point weighted score system [21]. First, the percentage of positive cells (PP) was scored with a five-point scale: 0 for less than 5%, 1 for 5–25%, 2 for 25–50%, 3 for 50–75%, and 4 for over 75%. Second, the staining intensity was scored with a three-point scale: 0 for negative, 1 for weak, 2 for medium, and 3 for intense staining [22]. The average weighted score (AWS) for each area was calculated by multiplying the percentage of positive cells by the intensity of staining score. The results were scored as negative (AWS=0–1), weak (AWS=2–3), moderate (AWS=4–6), and strong (AWS=8–12) [21]. Nuclear staining was considered positive if any of the nuclei of the tumor cells were positively stained [23].

Data were analyzed using statistical package for the social sciences version 22.0 (SPSS; SPSS Inc., Chicago, Illinois, USA). Qualitative data are presented as numbers and percentages. Quantitative data are expressed as mean±SD, medians, and ranges. The data were tested for normality using the Kolmogorov–Smirnov test and the Shapiro–Wilk test, which were significant, indicating the use of nonparametric tests, as data regarding age were not normally distributed. The χ2-test was used for comparing qualitative variables. The nonparametric Mann–Whitney test was used for comparing two quantitative variables. The level of significance was set at 0.005 for all the statistical tests used in the present study.

  Results Top

This study included 40 specimens − 28 OSs and 12 OBs. OS specimens included four low-grade and 24 high-grade tumors, and two of the low-grade tumors were chondroblastic OS. The OS specimens were obtained from 18 males and 10 females (mean: 16.05±7.35 and median: 14.5 years). Five (17.9%) out of 28 OS specimens showed mild focal cytoplasmic positivity for β-catenin − four (three male and one female) were low-grade, and the remaining positive case was a high-grade tumor of a male patient. Moreover, β-catenin was expressed in malignant osteoids in 10/28 OS cases ([Table 1] and [Table 2], [Figure 1], [Graph 1 [Additional file 1]]).
Table 1 Clinical profiles and β-catenin expression in osteosarcoma cases

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Table 2 β-Catenin expression in osteosarcoma and osteoblastoma cases

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Figure 1 (a) Low-grade osteosarcoma with osteoid and moderate cellularity, hematoxylin and eosin stains (×40). (b) High-grade osteosarcoma with hypercellularity (double arrow) and immature osteoid (arrow), hematoxylin and eosin (×100). (c) β-Catenin staining in the osteoid matrix of low-grade osteosarcoma (arrows) (×100)

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OB specimens included 12 cases (10 male and two female) (mean: 16.83±2.62 and median: 17 years) − four of them were aggressive OBs, and eight (66.7%) (six male and two female) OBs showed mild cytoplasmic positivity for β-catenin. All aggressive tumors were negative for β-catenin ([Table 2] and [Table 3], [Figure 2], [Graph 2 [Additional file 2]]).
Table 3 Clinical profiles and β-catenin expression in osteoblastoma cases

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Figure 2 (a) Aggressive osteobastoma with hypercellularity and atypical cells (arrows), hematoxylin and eosin stain (×100). (b) Mild cytoplasmic β-catenin immunostaining in osteoblastoma (arrows), (average weighted score 2+) (×100)

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The relationship between β-catenin expression in OS and OB was statistically significant (P=0.008) ([Graph 3 [Additional file 3]]) as well as between OS and aggressive OB (P=0.000). The differences in expression between low-grade and high-grade OSs were statistically significant (P=0.000) as well as between aggressive and nonaggressive OBs (P=0.002) ([Graph 1] and [Graph 2]). No nuclear positivity for β-catenin was detected in all the examined tumors (both OSs and OBs). There was no statistically significant correlation between the clinical data (age, sex, or clinical presentations) and the immunoexpression of β-catenin.

  Discussion Top

The Wnt/β-catenin pathway is a highly complex and unique signaling pathway, which has the ability to regulate gene expression, cell invasion, migration, proliferation, and differentiation for the initiation and progression of bone cancers, especially OS [24]. The Wnt pathway is clearly important in many types of human cancers, particularly in epithelial cancer types where gain-of-function or loss-of-function events appear to contribute to both inherited cancer risk and somatic carcinogenesis [25]. Knowledge of the Wnt pathway in OS is limited. The Wnt signaling pathway has been identified as a key component of normal skeletal development and disease [26],[27]. Previous studies have suggested that active Wnt signaling contributes to OS development based on cytoplasmic and/or membranous β-catenin staining or detection of a Wnt pathway component [28],[29],[30]. However, this is not proof of active Wnt signaling. β-Catenin has been shown to play a dual role: membranous β-catenin functions in a complex with cadherin in cell–cell contact, whereas nuclear β-catenin acts as a transcriptional co-regulator to transduce Wnt signaling [31].

The antibody in our study and others is against the C-terminal of β-catenin and can detect all β-catenin proteins, whether they are unphosphorylated or phosphorylated forms. Therefore, it is of importance to distinguish the location of β-catenin when interpreting its expression. Only nuclear staining, but not membranous/cytoplasmic staining, of β-catenin can be interpreted as active Wnt signaling because β-catenin in the cytoplasm cannot initiate target gene expression [32].

In the present study, membranous and/or cytoplasmic β-catenin staining was found in 17.9% (5/24) of OS cases − 4/24 were low-grade tumors and 1/24 was a high-grade tumor. None of the positive cases showed nuclear positivity for β-catenin. Our findings support that Wnt signaling is inactive in OS. The Wnt pathway may play a tumor suppressive role as its stimulation inhibits proliferation or promotes differentiation, which is in contrast with its oncogenic role in colorectal cancer and other tumors [33]. In agreement with our findings, Piperdi et al. [34] reported that activation of the Wnt/β-catenin pathway through stabilization of β-catenin does not induce malignant features or tumorigenesis in mesenchymal stem cells.

Ng et al. [35] found no nuclear immunostaining of β-catenin in any of the 19 cases of OS in their study. In the study by Lu et al. [36], cytoplasmic immunostaining was observed in the majority of OS cases (66/96). Furthermore, it was observed that cytoplasmic β-catenin expression was upregulated and membrane-associated β-catenin expression was downregulated in advanced-stage tumors [36]. Stein et al. [37] characterized the expression of β-catenin in 37 cases of primary canine OS and three cases of pulmonary metastases from canine OS. β-Catenin was detected by IHC in the majority of canine OS samples, and its intracellular location was most frequently cytoplasmic [37]. These results are similar to human OS, as shown in a similar study that detected cytoplasmic and/or nuclear β-catenin expression by IHC in 33/47 (70%) cases [28]. In a study by Du et al. [38], Wnt1 protein expression was detected in 69.6% (32/46) of OSs; however, no β-catenin protein expression was observed in the nucleus, and β-catenin protein expression was detected only in the membrane and cytoplasm. They concluded that the Wnt signaling pathway genes are frequently deleted in patients with OS [38]. Cai et al. [39], reported in their study no nuclear staining of Wnt/β-catenin in 90% (47/52) cases of OS, and most of the positively studied cases (5/52) showed membranous/and or cytoplasmic staining. They concluded that the Wnt pathway is inactivated in OSs [39].

In our study, we detected positivity for β-catenin in the osteoid matrix of 10/28 OS cases, whereas the tumor cells in these cases were negative. Moreover, the two cases of chondroblastic OS were negative for β-catenin, which can be explained by the theory that β-catenin activation promotes osteoblastogenesis and inhibits chondrogenesis during osteochondrocyte fate commitment [40].

A recent study reported that the major components in the Wnt/β-catenin pathway, such as Wnt3a, β-catenin, and Lef1, were consistently upregulated in human OS cell lines, which might be responsible for the invasiveness and chemoresistance. High β-catenin levels in OS samples seem to be positively correlated with lung metastasis. Consistently, the expressions of Wnt-β-catenin inhibitors are often suppressed in OS [41]. This finding was different from our study, as we found that 4/5 β-catenin-positive cases were low-grade OSs, whereas in OB all (8/12) β-catenin-positive cases were conventional benign tumors, and none of the four aggressive OB cases showed immunostaining. Contradictory to these findings, a recent report indicated that the Wnt-β-catenin pathway is inactivated in OS and that the loss of Wnt-β-catenin activity induces OS development.

In agreement with our findings, a recent study observed β-catenin staining in the cytoplasm or membrane but not in the nucleus in all 37/37 cases of osteoblastic and fibroblastic OS and the classic component of chondroblastic OS, but they observed positive nuclear β-catenin staining within chondroblastic OS cells (5/5). They explained this by the fact that Wnt/β-catenin signaling promotes chondrocyte maturation and survival once cartilage is formed [42].

In the last decade, numerous in-vitro and in-vivo studies have demonstrated that active Wnt/β-catenin signaling promotes osteoblast differentiation [43].

In the present study, β-catenin was expressed in the cytoplasm of 8/12 (66.7%) OB specimens and no nuclear staining could be observed in any of the cases. All the positive cases were conventional osteobastomas, and the four negative cases were aggressive OBs. Differentiated osteoblasts with more mature osteoids are present, suggesting that activation of the Wnt pathway promotes osteoblast lineage differentiation [39]. Wan et al. [42] reported in their study that cytoplasmic and/or membranous β/catenin immunostaining suggests OS, whereas nuclear staining strongly suggests OBs. Dao et al. [44] also observed moderate-to-strong nuclear staining of β-catenin in all 17 cases of OB. These results suggest that activation of the Wnt/β-catenin pathway may be the factor driving maturational changes in osteoblasts in OB. They mentioned that the cellular distribution of β-catenin may be used as a valuable marker in the differential diagnosis of OB and OS [44]. In contrast to our findings, Cai et al. [39] observed strong membranous and nuclear β-catenin staining in all 15 OB cases in their study, suggesting that Wnt signaling is active in benign bone tumors. The difference between our findings and others’ may be due to the small number of OB specimens.

  Conclusion Top

The Wnt/β-catenin pathway is a key component for normal skeletal development, and alteration in this signaling pathway plays vital roles in OS and OB. At present, debate exists as to whether or not alterations in this pathway contribute to human OS development and progression. These conflicting reports indicate that additional studies are necessary to clarify the role of the Wnt signaling pathway in OS development and progression. Targeting the Wnt/β-catenin pathway might be an innovative approach for the treatment of bone cancer, especially OS.

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Conflicts of interest

There are no conflicts of interest.

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  [Figure 1], [Figure 2]

  [Table 1], [Table 2], [Table 3]


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