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  Table of Contents    
ORIGINAL ARTICLE  
Year : 2013  |  Volume : 56  |  Issue : 3  |  Page : 204-210
Molecular and phenotypic expression of decorin as modulator of angiogenesis in human potentially malignant oral lesions and oral squamous cell carcinomas


1 Department of Pathology, King George's Medical University, Lucknow, Uttar Pradesh, India
2 Department of Pathology, All India Institute of Medical Sciences, Bhopal, Madhya Pradesh, India
3 Department of Otolaryngology, King George's Medical University, Lucknow, Uttar Pradesh, India
4 Department of Oral and Maxillofacial Surgery, King George's Medical University, Lucknow, Uttar Pradesh, India
5 Toxicology Division, Central Drug Research Institute, Chattar Manzil Palace, Lucknow, Uttar Pradesh, India

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Date of Web Publication24-Oct-2013
 

   Abstract 

Background: Decorin is an extracellular matrix, multifunctional small proteoglycan molecule in tumor stroma that has been shown to be modulator of angiogenesis. No clinical data is available so far on decorin expression and survival outcome of oral cancer. Aim: The aim of the present study was to examine molecular and phenotypic expression of two angiogenesis modulators viz. decorin and vascular endothelial growth factor-A (VEGF-A) in human potentially malignant oral lesions (PMOLs) and oral squamous cell carcinomas (OSCC) in relation to clinico-pathological variables and survival outcome. Materials and Methods: Tissue biopsies were obtained from 72 PMOLs, 108 OSCC and 52 healthy controls. The PMOLs included cases of leukoplakias and oral submucous fibrosis. Immunohistochemistry was performed using antibodies against decorin, VEGF-A and CD-31. Messenger-ribonucleic acid (mRNA) expression was analyzed by using real-time polymerase chain reaction. Results: Cytoplasmic staining of decorin was observed in the basal layer of epithelium in 53 (73.61%) cases of PMOLs and in peritumoral stroma in 55 (50.92%) cases of OSCC. None of the cases showed nuclear expression of decorin. Decorin expression both at phenotypic and molecular level was found to be down-regulated from PMOLs to OSCC. Lymph node metastasis and reduced decorin expression independently correlated with overall survival in OSCC. VEGF-A expression had no significant impact on survival outcome. Conclusion: Micro vessel density and VEGF-A expression were significantly associated with reduced decorin expression in tumor stroma suggesting, decorin as angiogenic modulator in OSCC. Down-regulation of decorin expression and the presence of lymph node metastasis were adverse factor independently affecting overall survival in OSCC.

Keywords: Angiogenesis, decorin, potentially malignant oral lesions, squamous cell carcinoma, vascular endothelial growth factor-A

How to cite this article:
Nayak S, Goel MM, Bhatia V, Chandra S, Makker A, Kumar S, Agrawal SP, Mehrotra D, Rath SK. Molecular and phenotypic expression of decorin as modulator of angiogenesis in human potentially malignant oral lesions and oral squamous cell carcinomas . Indian J Pathol Microbiol 2013;56:204-10

How to cite this URL:
Nayak S, Goel MM, Bhatia V, Chandra S, Makker A, Kumar S, Agrawal SP, Mehrotra D, Rath SK. Molecular and phenotypic expression of decorin as modulator of angiogenesis in human potentially malignant oral lesions and oral squamous cell carcinomas . Indian J Pathol Microbiol [serial online] 2013 [cited 2019 Aug 24];56:204-10. Available from: http://www.ijpmonline.org/text.asp?2013/56/3/204/120366



   Introduction Top


Oral squamous cell carcinoma (OSCC) is the sixth most common malignancy and is a major cause of cancer morbidity and mortality world-wide due to the popularity of addictive habits, cultural, ethnic and geographic factors. [1] Tumor microenvironment and angiogenesis are essential components for tumor growth, progression and outcome. Decorin is a small proteoglycan molecule of 38 KDa core protein of extracellular matrix (ECM), found in tumor stroma and synthesized by fibroblasts and myofibroblasts. It plays a major role in ECM assembly and regulation of cell behavior. [2] Decorin prevents cell proliferation and metastasis of various tumor cells by down-regulating epidermal growth factor receptor tyrosine kinase and has also been shown to be a positive or negative modulator of angiogenesis. [3],[4],[5] Although, decorin is expressed predominantly in tumor stroma, it is sometimes expressed in the cytoplasm of cancer cells in a variety of tumors; down-regulated in some and up-regulated in others. [6],[7],[8],[9],[10],[11],[12],[13] Therefore, it has been proposed as a possible prognostic marker in these cancer patients. Aberrant nuclear expression of decorin has also been reported by some workers in pre-cancer and OSCC. [14]

Vascular endothelial growth factor (VEGF) is a known modulator of angiogenesis. [15] Increased expression of VEGF-A has been demonstrated in many solid tumors including head and neck squamous cell carcinoma [16] and correlates with poor clinical outcome in most of the studies. In a recent study, we have reported that circulating VEGF estimation may be a reliable, convenient and noninvasive surrogate marker of tissue VEGF. [17]

Extensive review of the literature based on experimental evidence suggests that decorin molecule may play a potential role in adjuvant therapy in modulation of tumor response. No published clinical data is however available on decorin expression and survival outcome of oral cancer. The present study was carried out to examine decorin and VEGF-A expression in potentially malignant oral lesions (PMOLs) and OSCC in relation to clinico-pathological variables, angiogenesis and survival outcome.


   Materials and Methods Top


Patients and sample collection

Tissue biopsies from cases of 72 PMOLs (which includes 29 oral submucous fibrosis [OSMF] and 43 Leukoplakia [LKP]), 108 OSCCs and 52 healthy controls were collected from the Departments of Oral and Maxillofacial Surgery, General Surgery and Otolaryngology after obtaining the Institutional Ethical approval and informed written consent from patients. Healthy oral tissues were obtained from patients undergoing cosmetic surgery, who otherwise did not have any infective or inflammatory oral lesion. A small part of the tissue was snapped frozen for molecular work and was stored at –80°C. The relevant clinical and demographic details were recorded.

Histopathological examination

All oral tissues were fixed in 10% neutral buffered formalin and processed for histopathological examination according to the method described earlier. [17]

Follow-up

The patients were diagnosed histologically and followed-up every 2 months in the 1 st year, every 3 months in the 2 nd year and every 4-6 months thereafter. Overall survival was measured from the date of histological diagnosis to death or last follow-up to a maximum of 5 years.

Immunohistochemistry (IHC) for decorin and VEGF-A

Sections were deparaffinized in xylene followed by hydration in descending ethanol grades. Endogenous peroxidase was blocked in 3% H 2 O 2 in methanol for 30 min. Antigen retrieval was performed by heating specimens for 15 min at 95°C in citrate buffer (pH 6.0) for decorin and 10 mM Trisaminomethane-Ethylenediaminetetraacetic (Tris-EDTA) buffer (pH 9.0) for VEGF-A using an EZ antigen retriever system (BioGenex, USA). Sections were then incubated with power block (BioGenex, USA) for 10 min to reduce the non-specific antibody binding followed by overnight incubation at 4°C with primary antibodies. Mouse monoclonal antibody against human decorin (Santa Cruz Biotechnology Inc., Santa Cruz, CA, 1:50 dilution) and rabbit polyclonal antibody (A-20; 1:50 dilution) raised against a 20 amino acid synthetic peptide of human VEGF-A (Santa Cruz Biotechnology, Inc., Santa Cruz, CA) were used. Primary antibodies were detected using super sensitive polymer-HRP IHC detection system (BioGenex, USA). After thorough washing with Tris buffered saline (TBS; pH 7.4) sections were treated with super enhancer for 20 min at room temperature followed by incubation with poly-HRP reagent for 30 min at room temperature. After three washes with TBS, 3,3'-diaminobenzidine substrate (DAB tetrahydrochloride) was applied to the sections for 5-10 min in the dark. Sections were counterstained with hematoxylin, dehydrated with ethanol and xylene and mounted permanently with DPX. Negative control sections were processed by omitting primary antibody. Positive controls were: (1) internal stromal fibroblast cells for decorin and (2) previously known positive case for VEGF-A.

Evaluation of staining

The level of expression was assessed by semi-quantitative scoring including the overall percentage area of the lesion stained positive and intensity of immunostaining. In all cases, the expression of decorin and VEGF-A was analyzed in the epithelium, endothelial cells and stroma. Grading for percentage area positivity was categorized as <10% = 0, 10-25% = 1, 25-50% = 2, 50-75% = 3, >75 = 4. Intensity of staining was categorized as none = 0, mild = 1, moderate = 2, strong = 3 staining. The percentage score (0-4) was multiplied by the intensity score (0-3) to generate a final score. A final score of 0-4 was considered as negative staining, whereas a score of 5-12 was positive staining. [18]

Microvessel staining and counting

Microvessel staining and counting was performed using rabbit monoclonal antibody CD-31 (Santa Cruz Biotechnology, Inc., Santa Cruz, CA) by the method described by Guttman et al., [19] with slight modifications as reported earlier. [17]

Quantitative real-time polymerase chain reaction (PCR) for decorin and VEGF-A

Ribonucleic acid (RNA) was extracted from frozen tissue samples with Trizol reagent (Invitrogen, Carlsbad, CA). RNA purification and complementary deoxyribonucleic acid synthesis was carried out as described earlier. [17] Quantitative real-time PCR was performed using a StepOne Real-Time PCR system (Applied Biosystems, USA using SYBR Green fluorescent dye according to the manufacturer's instructions. Briefly, the 2X SYBR Green master mix containing deoxynucleotide Triphosphates, ROX dye and 10 μM of forward and reverse primers was dispensed into a fast optical 48 - well real time PCR reaction plate (Applied Biosystems, USA). Specific primers for decorin [14] and VEGF-A [20] genes were selected from published articles and synthesized by Imperial Life Sciences, India. These were rechecked using Primer Express Software 3.0 (Applied Biosystems, USA) and checked for homology by Blast sequence analysis. The forward and reverse primer sequences are as follows: (1) beta-actin (internal control): Forward 5'-GAGACCTTCAACACCCCAGCC-3'; reverse 5'-AGACGCAGGATGGCATGGG-3' (Amplicon size 140 bp, Tm = 55°C); (2) Decorin: Forward 5'-CGAGTGGTCCAGTGTTCTGA-3'; reverse: 5'-AAAGCCCCATTTTCAATTCC-3'(Amplicon size 69 bp, Tm = 58°C); (3) VEGF-A: Forward 5'-GCTGTCTTGGGTGCATTGG-3'; reverse 5'-GCAGCCTGGGACCACTTG-3' (Amplicon size 69 bp, Tm = 58°C). The amplification cycles for decorin consisted of initial denaturation at 95°C for 14 min followed by 35 cycles of 94°C for 1 min, 58°C for 1 min, 10°C for 75 s and final extension at 72°C for 5 min. For VEGF-A, the thermal cycle conditions were: initial denaturation at 94°C for 5 min, followed by 35 cycles of 94°C for 45 s, 58°C for 30 s and 72°C for 30 s. Fluorescence was detected after a final extension at 72°C for 10 min followed by a dissociation cycle. Quantification was based on cycle number required to reach the threshold level of SYBR Green fluorescence in the linear phase of amplification. Gene expression level was determined using the 2-ΔΔCt method using beta-actin as an endogenous control. [21] A negative control without a template was run in parallel to assess the overall specificity of the reaction. All reactions were run in duplicate.

Statistical analysis

Statistical analysis was performed by using the version 17.0 SPSS software for windows (SPSS, INC, Chicago, IL). For assessing proportional data, Chi-square test was carried out. Micro vessel density (MVD) was expressed as mean ± standard deviation. Pearson's correlation coefficient was used to evaluate the correlation between decorin, VEGF-A and MVD. Survival curve was plotted by the Kaplan-Meier method and compared using the log-rank test. Univariate analysis of overall survival was performed by Kaplan-Meier method. Multivariate analyses of overall survival were measured by Cox proportional hazards model in a stepwise manner. For all the tests, a P < 0.05 was considered as statistically significant.


   Results Top


Immunohistochemical expression of decorin and VEGF-A in PMOLS and OSCC

IHC showed that decorin expression was detected in the cytoplasm of the basal layer of epithelium and stromal cells [Figure 1]a-f. Decorin immunoexpression was observed in 73.61% cases of PMOLs and 50.92% cases of OSCC and 55.77% cases of healthy controls. Expression of decorin in the epithelium was found in 68.97% cases of OSMF, 97.67% cases of LKP and 5.56% cases of cancer. Underlying connective tissue beneath dysplastic epithelium showed decorin expression in 65.52% cases of OSMF, 72.09% cases of LKP and stromal decorin expression was observed in 56.48% cases of cancer [Table 1]. VEGF-A immunostaining was observed in the lining epithelium of OSMF and LKP and cytoplasm of tumor cells. Tumor stroma seldom showed VEGF-A expression. VEGF-A immunoexpression was observed in 52.78% cases of PMOLs and 72.22% cases of OSCC [Table 2]. No VEGF-A expression was observed in healthy controls except for focal staining in 8 cases.
Figure 1: Immunohistochemical staining of decorin. (a) Histological section of leukoplakia (LKP) with dysplasia (H and E, ×100) (b) Decorin positivity in LKP with dysplasia Immunohistochemistry (IHC ×100) (c) Histological secti on of oral submucous fi brosis (OSMF) (H and E, ×100) (d) Decorin positi vity in the area of fi brosis in OSMF (IHC ×100) (e) Histological secti on of oral squamous cell carcinomas (OSCC) (H and E, ×100) (f) Decorin positi vity in peritumoral stroma in OSCC (IHC ×100)

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Table 1: Immunohistochemical expression of decorin in healthy controls, PMOLs and OSCC

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Table 2: Overall immunohistochemical expression of decorin and VEGF-A in PMOLs and OSCC as compared to controls

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Association of decorin and VEGF-A with ­ clinico-pathological features in PMOLS and OSCC

Association of decorin and VEGF-A with clinico-pathological factors in PMOLs and OSCC was analyzed using Chi-square test [Table 3] and [Table 4]. Significant association of decorin (P < 0.010) with age was observed in patients with OSCC ≥42 years. There was no significant association between decorin and lymph node metastasis, tumor stage and tumor differentiation. VEGF-A expression was significantly associated with dysplasia (P < 0.042) in PMOLs and lymph node involvement (P < 0.017) in OSCC.
Table 3: Relation of decorin and VEGF-A expression with clinico-pathological parameters in PMOLs

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Table 4: Relation of decorin and VEGF-A expression with clinico-pathological parameters in OSCC

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Quantitative real-time PCR for decorin and VEGF-A in PMOLS and OSCC

Relative gene expression for decorin was found to be significantly higher in PMOLs (6 fold, P < 0.0000) and OSCC (3 fold, P < 0.0001) patients as compared with healthy controls. Unlike decorin, gene expression for VEGF-A with respect to healthy controls was much higher in OSCC patients than in PMOLS patients. Relative gene expression for VEGF-A was 52 fold higher in OSCC (P < 0.0001) and 39 fold higher in PMOLs (P < 0.0001) patients as compared with healthy controls [Figure 2]a.
Figure 2: Real time polymerase chain reaction (PCR) results of decorin and vascular endothelial growth factor-A (VEGF-A) and overall survival curves. (a) Bar diagram showing fold change expression of decorin and VEGF-A by real time PCR in oral submucous fibrosis, LKP, oral squamous cell carcinomas and healthy controls. (b) Scatter diagram for correlati on of relative decorin Messenger-ribonucleic acid expression with micro vessel density (c) Kaplan-Meier overall survival curve in correlati on with lymph node status. (d) Kaplan-Meier overall survival curve in correlation with decorin expression

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Correlation of decorin with angiogenic factors VEGF-A and MVD in PMOLS and OSCC

Pearson's correlation coefficients were calculated to analyze the association of decorin with VEGF-A and MVD in PMOLs and OSCC. Immunohistochemical and molecular expression of decorin showed a significant correlation with VEGF-A (r = 0.207, P < 0.032 and r = 0.320 P < 0.027) and MVD (r = 0.200, P < 0.038 and r = 0.259 P < 0.044) in OSCC patients [Figure 2]b; [Table 5].
Table 5: Correlation of immunohistochemical and gene expression of decorin with VEGF-A and MVD in PMOLs and OSCC

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Survival analysis

Overall survival was measured from the date of histological diagnosis to death or last follow-up to a maximum of 5 years. In the present follow-up study, we observed that 73.01% of cancer patients survived. The presence of lymph node (P < 0.016) and reduced decorin expression (P < 0.043) correlated significantly with overall survival in cancer patients independently [Figure 2]c and d. Other variables viz. tumor stage, tumor differentiation and VEGF-A expression did not achieve statistical significance. The result of univariate and multivariate analysis with Cox proportional-hazards model is shown in [Table 6]. The presence of lymph node metastasis and reduced decorin expression correlated with a worse prognosis. The multivariate analysis showed that lymph node and reduced expression of decorin had an independent prognostic effect on overall survival.
Table 6: Univariate (log rank test) and multivariate analysis (cox proportional hazard model) of overall survival in OSCC

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   Discussion Top


In the present study, we examined the expression of two angiogenesis modulators viz. decorin and VEGF-A at phenotypic and molecular level in biopsy tissues obtained from patients of OSMF, LKP and OSCC as well as from healthy controls. The findings were further correlated with clinico-pathological variables in both PMOLs and OSCC patients and overall survival in cancer patients.

The involvement of decorin in angiogenesis and particularly tumor angiogenesis is still open to investigation and far from being resolved. In some experimental settings, decorin has been shown to be proangiogenic. [4],[22] Decorin is expressed during endothelial cell sprouting in vitro, that occurs when endothelial cells become post-confluent mimicking angiogenesis and is produced by capillary endothelial cells during inflammation-associated angiogenesis. [23]

Decorin is normally present in extracellular stromal component. However, decorin expression can be altered by transcriptional, posttranscriptional and post-translational modifications [24] in cancer cells. In the present study, immunoexpression of decorin was observed in the epithelial lining of PMOLs. Further, its expression at phenotypic and molecular level was found to be down-regulated from pre-cancer to cancer.

Banerjee et al., [14] have reported up-regulation and abnormal retention of decorin molecule inside the cells obtained from dysplastic oral mucosa. The authors attributed this to production of longer decorin transcripts. However, in the present study, we did not find decorin expression in tumor cells. The mechanism by which decorin expression in tumor cells is switched off is not clear. It is expected that in tumor cells, epigenetic control including hypermethylation of the promoter region might play a role in silencing decorin gene. In the tumor stroma, hypomethylation of the decorin promoter has been reported. [25]

Aberrant decorin expression, i.e., both nuclear and cytoplasmic has been reported in dysplastic oral epithelial cells. Role of aberrantly expressed nuclear decorin in migration and invasion of dysplastic and malignant oral epithelial cells has been shown by the same group in their recent study. [26] Contrary to the findings of Banerjee et al., [14] we did not find aberrant nuclear expression in any of our PMOL and OSCC cases. Only cytoplasmic expression of decorin was seen in epithelial cells and peritumoral areas. The cytoplasmic localization of decorin has a negative regulatory role in cell proliferation and angiogenesis. It has been hypothesized that if native decorin (cytoplasmic) could be released and diffusely spreads through the stroma, it could inhibit growing tumor cells by suppressing the production of powerful angiogenic stimulus. The aberrantly localized nuclear form of decorin molecule in oral epithelial cell is however unable to function as a natural inhibitor of angiogenesis. Its clinical implication is probably the development of anti-angiogenic therapy, targeting tumor vessels instead of cancer cells.

Our study demonstrated a significant correlation of decorin expression with VEGF-A and MVD in OSCCs. Association between decorin expression and MVD was significant in peritumoral stroma of OSCC, whereas, it was non-significant in LKP and OSMF. Decorin has been reported to inhibit angiogenesis in tumor xenograft in vivo in nude mice. De novo expression of decorin, derived from either stably-expressing cells or as an exogenous recombinant proteoglycan resulted in a reduced expression of endogenous VEGF mRNA and protein. [27]

We did not find any clinical study in the literature showing correlation of MVD and decorin. Pathological lymph node metastases (pN+) are an established prognostic factor in OSCC. [28] We found the presence of lymph node metastasis was associated with poor overall survival.

In the current study, prognostic significance of decorin expression in terms of patient survival was calculated in OSCCs. Univariate and multivariate analysis showed that reduced decorin expression correlated with worse prognosis, suggesting that the decorin is likely to function as a tumor suppressor in OSCC. A few studies in the literature have described reduced amount of decorin to be associated with poor prognosis in node negative invasive breast cancer. [8] Especially, lower decorin levels have been shown to correlate with larger primary breast tumor burden, high-risk of early recurrence and overall poor prognosis. In advanced ovarian cancer, high expression of decorin was associated with poor response to treatment and greater incidence of relapse for patients that initially responded. [29]

To conclude, the down-regulation of decorin expression and positive lymph node status are adverse factors affecting independently to overall survival in OSCC. As there is lack of sufficient data on oral cancer and also since the reports in literature present contradictory results, this area needs further investigation in order to explore the possibility of decorin as a future angiogenic modulator or adjuvant anticancer agent.


   Acknowledgments Top


Authors gratefully acknowledge the financial support from Indian Council of Medical Research (ICMR), New Delhi and Council of Science and Technology, UP, India.

 
   References Top

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3.Schönherr E, Sunderkötter C, Iozzo RV, Schaefer L. Decorin, a novel player in the insulin-like growth factor system. J Biol Chem 2005;280:15767-72.  Back to cited text no. 3
    
4.Schönherr E, Levkau B, Schaefer L, Kresse H, Walsh K. Decorin-mediated signal transduction in endothelial cells. Involvement of Akt/protein kinase B in up-regulation of p21 (WAF1/CIP1) but not p27(KIP1). J Biol Chem 2001;276:40687-92.  Back to cited text no. 4
    
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8.Troup S, Njue C, Kliewer EV, Parisien M, Roskelley C, Chakravarti S, et al. Reduced expression of the small leucine-rich proteoglycans, lumican, and decorin is associated with poor outcome in node-negative invasive breast cancer. Clin Cancer Res 2003;9:207-14.  Back to cited text no. 8
    
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Correspondence Address:
Seema Nayak
Research Scholar, Department of Pathology, King George's Medical University, Lucknow - 226 003, Uttar Pradesh
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0377-4929.120366

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