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 Table of Contents  
Year : 2017  |  Volume : 14  |  Issue : 4  |  Page : 187-192

Immunohistochemical expression of osteonectin/SPARC in oral epithelial dysplasia, carcinoma in situ and squamous cell carcinoma

Department of Oral Pathology, Tanta University, Tanta, Egypt

Date of Submission21-Mar-2017
Date of Acceptance15-Jun-2017
Date of Web Publication21-Dec-2017

Correspondence Address:
Ahmed A Essa
Department of Oral Pathology, Tanta University, Medical and Dental Campus, Al-Geish Street, Tanta 31111
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/tdj.tdj_15_17

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This study demonstrated the immunohistochemical expression of secreted protein acidic and rich in cysteine (SPARC) in oral epithelial dysplasia, carcinoma in situ and different grades of oral squamous cell carcinoma (OSCC).
Materials and methods
This study used 28 OSCC; 11 well differentiated OSCC, 10 moderate differentiated OSCC and seven poorly differentiated OSCC that simultaneously contained dysplastic epithelium and carcinoma in situ were subjected to immunohistochemical staining for SPARC.
All cases of OSCC showed positivity to SPARC. There was a significant correlation between SPARC expression and grades of OSCC (P < 0.01). The high expression was noted in poorly differentiated OSCC in addition to the expression of some stromal cells. No SPARC expression was noted in normal oral epithelium.
The results of this study showed that SPARC may be useful in early stages of cancerization and may be used as a marker for predicting the progression of OSCC. In addition, stromal SPARC expression is an effective indicator for targeted stromal therapy.

Keywords: oral epithelial dysplasia, oral squamous cell carcinoma, osteonectin, secreted protein acidic and rich in cysteine, stroma

How to cite this article:
Essa AA, Wahba OM. Immunohistochemical expression of osteonectin/SPARC in oral epithelial dysplasia, carcinoma in situ and squamous cell carcinoma. Tanta Dent J 2017;14:187-92

How to cite this URL:
Essa AA, Wahba OM. Immunohistochemical expression of osteonectin/SPARC in oral epithelial dysplasia, carcinoma in situ and squamous cell carcinoma. Tanta Dent J [serial online] 2017 [cited 2018 Dec 9];14:187-92. Available from: http://www.tmj.eg.net/text.asp?2017/14/4/187/221376

  Introduction Top

Oral squamous cell carcinoma (OSCC) accounts about 90% of all malignant tumors of the oral cavity. It is characterized by high mortality rate, if not early diagnosed. So, it is necessary to well understand the molecular mechanisms related to the pathogenesis of this tumor in order to designate new and more effective diagnostic and prognostic strategies. Recently, the main target is to identify novel molecular markers that can be used in rapid and economic tests, which should be not invasive for OSCC patients [1].

Tumor microenvironmental events, including relation between cells and the extracellular matrix (ECM), can affect cellular survival and resistance to apoptosis. Cancers can display alterations of the normal cell–matrix interactions linked to increased proliferation, angiogenesis and invasion [2]. Matricellular proteins are a specific group of ECM molecules that can serve as cell regulators and modulators of cellular behavior and signalling during embryonic development, cell differentiation, physiological and pathological conditions [3],[4],[5].

One of the components of the ECM is secreted protein acidic and rich in cysteine (SPARC) which is known as osteonectin. It is a glycoprotein (glycosylated 43-kDa secreted protein) whose main function is to modulate cell–cell and cell–matrix interaction [6]. SPARC acts as an important regulator of some critical cellular functions such as tissue differentiation, embryonic growth, cell proliferation, survival and migration and also in cell cycle regulation [7]. SPARC was originally discovered as a component of bone [8] but is also expressed in epithelial tissue exhibiting high rates of turnover [9] and in tissues undergoing development, remodelling and repair [10].

SPARC can bind some soluble and structural ECM proteins in a Ca 2+-dependent manner, including collagens, vitronectin, fragments of fibrinogen, thrombospondin-1, vascular endothelial growth factor and platelet-derived growth factor [9],[11].

In addition to its important physiological role, SPARC has been also linked to cancer progression as many cancers can express SPARC which is also increased during invasion or metastasis. The mechanisms through which SPARC functions in cancer progression still complex and depend on tumor cell type and the microenvironment [12].

SPARC can be secreted by both cancer cells and the reactive stromal cells and is found to be highly expressed in the tumor ECM interface of the invading tumors and induced by hypoxia. Overexpression of SPARC is associated with increased tumor invasion and metastasis associated with poor prognosis in multiple tumor types, including lung, breast, prostate and colorectal cancers [13]. In addition to parenchymal cancer cells, strong SPARC expression has been detected predominantly in the stroma especially adjacent to the neoplastic cells [14].

In cancerization of oral mucosa, the concept of field cancerization is accepted, in which an accumulation of mutations by various carcinogens cause multiple precancerous lesions resulting in cancer of the oropharyngeal, upper digestive tract field [15],[16]. The phenomena that mutant cells were extruded by surrounding more adapted cells, were observed and called 'cell competition'. Furthermore, failure of cell competition can be associated with carcinogenesis [17]. SPARC is expressed in 'loser cells' and performs a self-protecting function in cell competition [18]. The role of SPARC in cancer is being increasingly recognized. SPARC plays multifaceted roles depending on the cancer type and whether it is produced by cancer cells or surrounding stromal cells [19].

Although plenty of studies were done in different cancer types, few were established on OSCC. So this study was designed to clarify the role of SPARC in OSCC.

  Materials and Methods Top

Clinical samples

This study included 28 archival OSCC cases that were collected from Oral Pathology Department, Faculty of Dentistry, Tanta University during the last 6 years from January 2010 to January 2016. These cases were histologically graded as well differentiated SCC (11 cases), moderately differentiated SCC (10 cases) and poorly differentiated SCC (seven cases) that simultaneously contained dysplastic epithelium and carcinoma in situ(CIS) foci. Normal oral epithelium is supplied from five gingivectomy cases after obtaining a written consent. The experimental protocol for analyzing surgical materials was reviewed and approved by the Ethical Board of Faculty of Dentistry, Tanta University.

Conventional hematoxylin and eosin staining

The surgical specimens were fixed in 10% formalin and routinely processed and embedded in paraffin. Serial sections cut at 5 mm, one set of sections was stained with hematoxylin and eosin to confirm their original diagnosis, while the other sets were used for immunohistochemical staining.


Mouse monoclonal antibody against human osteonectin/SPARC (AON-5031) was obtained from Haematologic TI. A mouse monoclonal antibody against pan-keratin (AE1/AE3, IgG1) was purchased from Dako (Glostrup, Denmark).


Deparaffinized tissue sections were rehydrated through graded alcohols, and then were immersed in 0.3% hydrogen peroxide in methanol for 30 min at room temperature to block endogenous peroxidase activities. For osteonectin/SPARC, sections were pretreated with 0.2% trypsin (type II, Sigma-Aldrich Co., St Louis, Missouri, USA) in 0.01 mmol Tris-HCl (pH 7.6) containing 0.1% CaCl2 for 30 min at 37°C according to the manufacturer's instruction. Sections then were incubated with 2% normal goat serum (Dako) in 0.01 mmol phosphate-buffered saline (PBS, pH 7.4) for 30 min at room temperature to block nonspecific protein-binding sites. They were then incubated overnight at 4°C with the primary antibodies diluted at 1: 1000 (antiosteonectin) in PBS. For pan-keratin, dilution was 1: 100 and sections were autoclaved in citrate buffer (pH 6.0) for 10 min at 121°C. After overnight incubation, the sections were washed with PBS then reacted with the Envision reagents for 1 h at room temperature and treated with 0.02% 3,3′-diaminobenzidine in 0.05 mmol tris-HCl buffer (pH 7.6) containing 0.005% hydrogen peroxide to visualize the reaction products. Finally, the sections were counterstained with hematoxylin. For control studies, the primary antibodies were replaced with mouse or rabbit preimmune IgGs (Dako).

Evaluation of secreted protein acidic and rich in cysteine expression levels

Representative sections of OSCC cases were selected then SPARC expression levels were evaluated. The normal, dysplastic, CIS and OSCC epithelia were given a score according to the intensity of cytoplasmic staining (no staining = 0, weak staining = 1, moderate staining = 2, strong staining = 3) and the extent of stained cells (0% = 0, 1–10% = 1, 11–50% = 2, 51–80% = 3, 81–100% = 4) [20].

Statistical analysis

All data obtained in the current study were collected, tabulated and statistically analyzed. The data were analyzed using version 20 of the SPSS (SPSS Inc., Chicago, Illinois, USA). Qualitative data were compared using χ2 statistics. Quantitative data were summarized using mean, SD, and confidence interval and compared using Student's t-test and/or one way analysis of variance test. A P value less than or equal to 0.01 was required to assess the level of significance.

  Results Top

Osteonectin/secreted protein acidic and rich in cysteine expression in normal, dysplastic epithelia and carcinoma in situ

In normal oral epithelia [Figure 1]a obtained from gingivectomy cases, osteonectin/SPARC was not expressed in any cell layer [Figure 1]b. In dysplastic epithelia [Figure 1]c where there are dysplastic changes are seen including nuclear hyperchromatism and pleomorphism, osteonectin/SPARC was strongly expressed in the cytoplasm of upper prickle cell layer in a homogenous pattern [Figure 1]d. In CIS [Figure 1]e where the dysplastic changes extend throughout the entire thickness of epithelium but the basement membrane still intact, osteonectin/SPARC was in almost all layers in a cytoplasmic fashion as well as in some stromal cells beneath the CIS foci [Figure 1]f. The expression of SPARC was highly significant between epithelial dysplasia and CIS with P value of 0.001 [Figure 2].
Figure 1: Osteonectin/ SPARC expression in normal, dysplastic epithelia and CIS. Hematoxylin and eosin (HE) (a, c and e) and immunoperoxidase stains for SPARC (b, d and f), hematoxylin counterstain. (a and b) × 10; (c and d) × 20; (e and f) × 40.

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Figure 2: Immunohistochemical profiles for Osteonectin/ SPARC in different grades of oral squamous cell carcinoma. HE (a, c and e) and immunoperoxidase stains for SPARC (b, d and f), hematoxylin counterstain. (a-e) × 20; (f) × 40.

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Osteonectin/secreted protein acidic and rich in cysteine expression in oral squamous cell carcinoma

In well differentiated OSCC [Figure 2]a, osteonectin/SPARCwas strongly expressed in outer cells but not expressed in central keratinized cancer cells [Figure 2]b. In moderately differentiated squamous cell carcinoma [Figure 2]c, osteonectin/SPARC was strongly expressed in almost all malignant cells in a homogenous cytoplasmic pattern [Figure 2]d. In poorly differentiated squamous cell carcinoma [Figure 2]e where there are scattered malignant cells, osteonectin/SPARC expression was markedly seen in malignant cells as well as adjacent stromal cells [Figure 2]f.

The expression of SPARC in all grades of OSCC was highly significant between each two grades with P value less than or equal to 0.05 [Figure 3].
Figure 3: Diagram showing enhanced the expression of SPARC in poorly differentiated OSCC.

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Osteonectin/secreted protein acidic and rich in cysteine expression in oral squamous cell carcinoma stroma

In poorly differentiated squamous cell carcinoma, the stroma was less cellular and composed of angular-shaped fibroblasts, sparsely scattered in myxoid basophilic background and scanty inflammatory cells, [Figure 4]a, the OSCC cells were positive for pan cytokeratin while the stromal cells were not positive [Figure 4]b, osteonectin/SPARC expression was markedly seen in malignant cells as well as adjacent stromal cells [Figure 4]c and [Figure 4]d. More higher magnification reveals angular-shaped stromal fibroblasts and inflammatory cells exhibit cytoplasmic staining for Osteonectin/SPARC.
Figure 4: Immunohistochemical expression of Osteonectin/ SPARC in oral squamous cell carcinoma stromal cells. HE (a) and immunoperoxidase stains for pan CK (b) and for SPARC (c and d), hematoxylin counterstain. (a-c) × 20; (d) × 40.

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  Discussion Top

In the present study, we have demonstrated the immunohistochemical expression profile of SPARC in OSCC was enhanced during progression from oral epithelial dysplasia to OSCC. We also showed SPARC expression in stromal cells beneath CIS foci and in-between cancer cells in OSCC cases.

SPARC expression was not detected in normal oral epithelium but noted in epithelial dysplasia and enhanced in CIS. This was in accordance with the results of Jing et al. [21] who found that no SPARC expression in normal tongue epithelium, suggesting that SPARC might be related to tumorigenesis. The same results were detected by Neil et al. [22] who showed that there was no expression of SPARC in normal tissue but overexpression was noted in head and neck cancers.

In addition, epithelial dysplasia, CIS, and OSCC had more SPARC-positive cells than normal epithelial cells. This may suggest that some transformation of cells provoke SPARC expression. SPARC localized mainly in the stratum spinosum layer, but little in the suprabasal and basal layer. The localization was consistent with that of cytokeratin-17 [23].

The function of SPARC in the behavior and pathogenesis of human cancer is complex. SPARC increases the production of collagenase, stromelysin, gelatinase, fibronectin and laminin in fibroblasts. SPARC produced by melanoma cells can modulate the antitumor activity of polymorphonuclear leukocytes. It functions as a counter adhesive protein, modifying the cell shape through the dissociation of focal adhesion, and modulates cell–matrix interactions by binding to the ECM [24]. Increased synthesis of SPARC in stromal fibroblasts has been reported in experimental studies during the early steps of chemical carcinogenesis [25].

In the present study the expression of SPARC in OSCC cells was more than CIS and normal oral epithelium. This was in accordance with Yiqun et al. [26] who used SPARC antibody, to investigate the expression of SPARC in normal esophagus and esophageal squamous cell carcinoma. In normal esophagus, SPARC exhibited weak expression, but a strong reactivity was noted in the esophageal squamous cell carcinoma. The findings were also in accordance with other studies showing a lack of SPARC expression in normal liver, stomach, colon and kidneys [13],[27],[28],[29].

Progressive increase in SPARC expression from normal and premalignant to malignant lesions in esophageal cancer was demonstrated [30] suggesting the utility of SPARC screening for diagnosis of malignancies. Several investigators have shown that SPARC levels may have prognostic significance in esophageal cancer indicating that patients with low SPARC level had a significant improvement in outcome [31].

SPARC expression was correlated with the grade of malignancy of OSCC. It was increased in moderately differentiated OSCC than well differentiated OSCC. The intense staining was detected in poorly differentiated OSCC. This is in accordance with studies of Parker et al. [32] on breast cancer who indicated that SPARC expression was correlated to the degree of malignancy and invasiveness of the cancer. Furthermore, St Croix et al. [33] studies on colon cancer, showed that the expression level of SPARC in tumor epithelial cells was two times as high as that in normal colonic epithelial cells.

SPARC was more expressed highly in poorly differentiated squamous cell carcinomas of tongue or those with lymph node metastases, suggesting that the expression level of SPARC is correlated to the degree of malignancy of tongue squamous cell carcinoma [21].

SPARC expression is associated with promotion of tumor growth, metastasis, more aggressive tumor types and worse prognosis [34]. In cancers of the head and neck including oral cancer, there are some reports that SPARC expression correlates with poor prognosis [35]. In invasive OSCC, immunohistochemical expression of SPARC was not correlated with survival rate and clinicopathological features such as T stage, clinical type, differentiation, and lymph node metastasis. Therefore, SPARC may be expressed at an early stage and is consistent with some signals as a result of competition with surrounding normal cells [36].

In contrary, Yiqun et al. [26] found that SPARC expression was not associated with the histological differentiation of esophageal squamous cell carcinoma. Also, Gary et al. [37] revealed strong cytoplasmic immunoreactivity in the surface epithelial cells of human normal ovaries and benign epithelial tumors, which is progressively decreased in borderline epithelial tumors, and is absent or significantly reduced in invasive ovarian epithelial cancers. This strong direct correlation indicates that repression of SPARC expression is important in ovarian cancer development. In addition, SPARC was less expressed in tumors localized at the lip, which appear to be the least aggressive.

The biological functions of SPARC may be variable in human cancers. Different tumors exhibit different patterns of SPARC expression. High levels of SPARC have been detected in several human cancers as melanoma [38], breast cancer [39] and colorectal cancer [40]. Moreover, it has been reported that SPARC promotes cell migration and invasion in prostate cancer and glioblastoma [41],[42]. Suppression of SPARC expression by antisense RNA results in a significant decrease in the tumorigenicity of melanoma cells [43].

In this study, SPARC was expressed in some stromal cells around the tumor cells. The expression was high in poorly differentiated OSCC. This is in accordance with Gabriella et al. [44] who found a correlation between deep invasion and the overexpression of SPARC in stromal cells.

The data associated with the expression of SPARC in the stroma was particularly interesting for several reasons; its expression significantly correlated with the presence of metastases, its expression in the deep margin very significantly correlated with patients' survival rate and its expression significantly correlated with tumor grade [44].

SPARC plays an important role in tumor– host interactions between pancreatic cancer cells and stromal fibroblasts. This was observed by Norihiro et al. [14] who detected SPARC expression in stromal fibroblasts. As SPARC is a multifunctional protein involved in cell proliferation, cell spreading, adhesion, motility, and invasion, the fibroblast-derived SPARC may have diverse effects on the biology of pancreatic cancer cells [24].

Although SPARC was found expressed abundantly by stroma cells in advanced phases of human ovarian cancer, evidence points to SPARC as a protein that tries to normalize the microenvironment to counter tumor growth [45].

From the results of this study, SPARC may be useful maker for predicting the prognosis of OSCC. Therefore, for SPARC-positive patients, more thorough cervical lymph node clearance and intensive postoperative follow-up are needed.

In conclusion, SPARC might have potential diagnostic, prognostic and biological value in tumor assessment. However, the mechanism of its regulation remains unknown, further investigations is still needed to verify the involvement and the molecular mechanism of SPARC in OSCC development. In addition, in cancers with high stromal SPARC, SPARC can be exploited as biomarker for targeted stromal therapy and delivery of chemotherapeutics or immunotherapeutics.

Financial support and sponsorship


Conflicts of interest

There are no conflicts of interest.

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