Summary
Periostin (PN), originally named as osteoblast‐specific factor‐2 (OSF‐2), has been involved in regulating adhesion and differentiation of osteoblasts. Recently many studies have shown that high‐level expression of PN is correlated significantly with tumour angiogenesis and prognosis in many kinds of human cancer. However, whether and how periostin expression influences prognosis in osteosarcoma remains unknown. This study aimed to examine the expression of PN in patients with osteosarcoma and explore the relationship of PN expression with clinicopathologic factors, tumour angiogenesis and prognosis. Immunohistochemistry was performed to determine the expression of PN in osteosarcoma and osteochondroma respectively. Vascular endothelial growth factor (VEGF) and CD34 were also examined in tissues from the osteosarcoma patients mentioned above. The results showed that PN expression was significantly (P < 0.05) higher in osteosarcoma (80.9%) than in osteochondroma (14.7%). Increased PN protein expression was associated with histological subtype (P = 0.000), Enneking stage (P = 0.027) and tumour size (P = 0.009). The result also showed that high expression of PN correlated with VEGF expression (r = 0.285; P = 0.019) and that tumours with PN‐positive expression significantly had higher microvessal density (44.6 ± 13.7 vs. 20.6 ± 6.5; P = 0.000) compared to those in normal bone tissues. Additionally, the expression of PN was found to be an independent prognostic factor in osteosarcoma patients. In conclusion, our findings suggest that PN may have an important role in tumour progression and may be used as a prognostic biomarker for patients with osteosarcoma.
Keywords: angiogenesis, biomarker, osteosarcoma, periostin, prognosis
Osteosarcoma is the most common primary malignancy in orthopaedic surgery, which accounts for approximately 20% of primary malignancies of bone (Arndt & Crist 1999). Osteosarcomas tends to develop distant metastases frequently and ultimately this results in death, especially in cases where there is lung metastasis. About 20% of patients have visible metastases on imaging at diagnosis and a quarter of the patients have metastases during the course of treatment (Théoleyre et al. 2005). Despite recent advances in multimodality treatments consisting of aggressive neoadjuvant chemotherapy and wide tumour resection, metastatic or recurrent disease still occurs in 30–40% of these patients and the majority of those succumb to the disease (Yang et al. 2014). Therefore, developing a novel biomarker to identify the invasive potential and prognosis of osteosarcoma is significantly crucial.
Periostin (PN), also named osteoblast‐specific factor‐2 (OSF‐2), was originally identified in 1993 as an 90 kDa protein acids, which was secreted from the mouse osteoblastic cell line MC3T3‐E1 (Takeshita et al. 1993). This protein shows homologous with an insect cell adhesion protein named fasciclin I (FAS I) protein family, members of which are involved in many biologic processes, such as cell motility, adhesion, metastatic growth and angiogenesis (Gillan et al. 2002; Bao et al. 2004; Shao et al. 2004). Initially, periostin has been shown to be expressed preferentially in the periosteum and periodontal ligaments, which act as a critical regulator for bone and tooth formation and maintenance (Litvin et al. 2004). Recently, accumulating evidence has revealed that high‐level expression of PN is correlated significantly with various human cancers including liver, head and neck, neuroblastoma, breast, colon, oesophageal, ovary etc (Gillan et al. 2002; Bao et al. 2004; Shao et al. 2004; Kudo et al. 2006; Sasaki et al. 2002; Lv et al. 2013a; Wang et al. 2014). Furthermore, emerging evidence suggests that high expression of PN protein is closely correlated with tumour angiogenesis in some types of human cancer (Shao et al. 2004; Wang et al. 2014). Whether and how PN expression influences prognosis in osteosarcoma, however, remains unknown.
In the present study, we used the immunohistochemistry to examine the expression of PN, vascular endothelial growth factor (VEGF) and microvessel density (MVD) in osteosarcoma tissues. Further, the survival analysis was observed by Kaplan–Meier method. A multivariate survival analysis was performed for all parameters that were significant in the univariate analysis using the Cox regression model. The objectives of this were to elucidate the expression of PN in osteosarcoma and to examine its correlation with clinicopathological characteristics and prognosis.
Materials and methods
Patients and specimens
Sixty‐eight patients with osteosarcoma were selected at the Department of Orthopedics in Anhui Provincial Hospital and the First Hospital Affiliated to Anhui Medicine University between 2001 and 2011. The selection criteria were as follows: (i) a diagnosis of malignant osteosarcoma based on pathology; (ii) complete records of the cases and the follow‐up information had been preserved; and (iii) no anti‐angiogenesis drugs had been used. These patients with osteosarcoma were treated according to the standardized protocol consisting of neoadjuvant chemotherapy (four cycles of methotrexate and cisplatin were administered with a minimum of a 21‐day interval between consecutive cycles), followed by appropriate surgical management and postoperative adjuvant chemotherapy. Follow‐up was terminated on 6 May 2014. Sixty‐eight osteochondroma tissue specimens were obtained from the same hospital as the controls. Two pathologists (Hang‐Cheng Zhou, Jiang Zhu) who were blinded to the clinical information confirmed all of histological diagnoses and judged the degree of staining independently. This study was approved by the Institutional Review Board of the Anhui Provincial Hospital affiliated to Anhui Medical University. All patients involved in this study had signed the informed consent. The study protocol conformed to the ethical guide lines of the Declaration of Helsinki.
Ethical approval
Ethical approval for the use of human subjects was obtained from the research ethics committee of Anhui Medical University
Histopathological and immunohistochemical analyses
The histopathological and immunohistochemical analyses were performed on biopsies prior to neoadjuvant chemotherapy. The expressions of PN, VEGF and CD34 were detected by immunohistochemistry using a two‐step method according to the manufacturer's instructions. Semiquantitative estimation was made to interpret the results of immunohistochemistry according to the percentage of staining cells per 100 cells in 10 microscopic fields with high‐power (400×) microscope, as follows: 0–10%, negative (−); 10–30%, weak positive (+); >30%, strong positive (++). MVD was quantified in five fields in which there was high expression using high‐power lens (400 ×) and values were expressed by average measurements.
Statistical analysis
All statistical analyses were performed using spss 19.0 for Windows (SPSS, Inc., Chicago, IL, USA). The corrections between PN expression and clinicopathological parameters were assessed by χ2 test or Fisher's exact test. The Kaplan–Meier method was used for survival analysis, and differences in survival were estimated using the log‐rank test. Cox proportional hazards regression model was used for multivariate survival analysis to assess the prognostic factors that were significant in the univariate analysis. P < 0.05 was considered statistically significant.
Results
Expression of PN in osteosarcoma and osteochondroma tissues
Sixty‐eight patients with osteosarcoma were comprised of 37 males and 31 females, with the mean age of 25 ± 13 years old. Detailed histologic subtype included 63 cases of conventional osteosarcoma and five cases of special osteosarcoma (including four cases of low‐grade central osteosarcoma and one case of parosteal osteosarcoma). As shown in Table 1, the positive rate of PN expression was 80.9% (55/68) in osteosarcoma and 14.7% (10/68) in osteochondroma samples. The protein expression level of PN was significantly higher in osteosarcoma tissues than the level in osteochondroma tissues (P < 0.05). The distribution of positive expression area of PN was mainly localized in the cytoplasm, some tumour cells stained strongly, while others exhibited slightly or no staining at all (Figure 1). To elucidate its clinical significance, we also assessed the correlation between PN expression and clinicopathological parameters available for the patients (Table 2). Positive expression of PN in osteosarcoma was significantly correlated with histological subtype (P = 0.000), Enneking stage (P = 0.027) and tumour size (P = 0.009). However, there are no significant correlation with age, gender, location and alkaline phosphatase.
Table 1.
Differential expression of periostin between osteosarcoma tissues and osteochondroma tissues (cases)
| Tissues | Case number | Periostin | Positive rate (%) | |
|---|---|---|---|---|
| Positive | Negative | |||
| Osteosarcoma | 68 | 55 | 13 | 80.9% |
| Osteochondroma | 68 | 10 | 58 | 14.7% |
Figure 1.
Representative immunohistochemical staining of periostin in osteosarcoma and osteochondroma tissues. Periostin (PN) mainly expressed in the cytoplasm of osteosarcoma tissues. (a) HE staining of osteosarcoma, ×100; (b) ++ for PN staining in osteosarcoma, ×100; (c) ++ for PN staining in osteosarcoma, ×400; (d) + for PN staining in osteosarcoma, ×100; (e) negative for PN staining in osteosarcoma, ×40; (f) negative for PN staining in osteochondroma, ×100.
Table 2.
Periostin expression status in relation to selected clinicopathologic features in 68 osteosarcoma patients (cases)
| Clinicopathologic data | Case number | Periostin | χ2 | P value | |
|---|---|---|---|---|---|
| Positive | Negative | ||||
| Sex | |||||
| Male | 37 | 29 | 8 | 0.329 | 0.566 |
| Female | 31 | 26 | 5 | ||
| Age at diagnosis (year) | |||||
| <30 | 48 | 39 | 9 | 0.014 | 0.905 |
| ≥30 | 20 | 16 | 4 | ||
| Site of primary disease | |||||
| Tibia | 29 | 24 | 5 | 0.614 | 0.893 |
| Femur | 18 | 15 | 3 | ||
| Humerus | 11 | 8 | 3 | ||
| Other | 10 | 8 | 2 | ||
| Histologic subtype | |||||
| Conventional | 62 | 54 | 8 | 17.549 | 0.000 |
| Special | 6 | 1 | 5 | ||
| Enneking stage | |||||
| III | 21 | 20 | 1 | 4.049 | 0.027 |
| I, II | 47 | 35 | 12 | ||
| Size (at diagnosis) (cm) | |||||
| ≥5 | 27 | 26 | 1 | 6.881 | 0.009 |
| <5 | 41 | 29 | 12 | ||
| Alkaline phosphatase (μ/l) | |||||
| <500 | 38 | 31 | 7 | 0.027 | 0.869 |
| ≥500 | 30 | 24 | 6 | ||
Expression of VEGF and MVD in osteosarcoma tissues and its correlation with PN
The positive rate of VEGF expression was 66.18% (45/68), and the distribution of positive expression area was mainly localized in the cytoplasm (Figure 2b). The relationships between expression of PN and VEGF were calculated and have been outlined in Table 3. The result also showed that high expression of PN correlated with VEGF expression (r = 0.285; P = 0.019; Table 3).
Figure 2.
Immunohistochemical staining of periostin, vascular endothelial growth factor (VEGF) and CD34 in osteosarcoma tissues. (a) Positive for periostin staining (×100); (b) positive for VEGF staining (×100); (c) positive for CD34 staining (×100); (d) partial enlargement of CD34 staining with the magnifying power of 400x.
Table 3.
The expression correlation between vascular endothelial growth factor (VEGF) and periostin (cases)
| Stain | Periostin | r | P value | |
|---|---|---|---|---|
| Positive | Negative | |||
| VEGF | ||||
| Positive | 40 | 5 | 0.285 | 0.019 |
| Negative | 15 | 8 | ||
To further evaluate the association between PN and angiogenesis, we detected the expression of MVD in the osteosarcoma and the normal bone tissue using an antibody against CD34 (Figures 2c,d and 3b). The results indicated that tumours with PN‐positive expression had significantly higher MVD (44.6 ± 13.7 vs. 20.6 ± 6.5; P = 0.000) compared to those in normal bone tissues.
Figure 3.
Immunohistochemical staining of periostin and CD34 in normal bone tissues. (a) negative for periostin staining in normal bone tissues, ×100; (b) negative for CD34 staining in normal bone tissues, ×400.
Relationship between PN expression and prognosis
Kaplan–Meier survival analysis was used to assess the relationship between PN expression and patients' survival. Patients with PN‐positive expression showed a poorer prognosis than those with PN‐negative expression. The log‐rank test revealed that the overall survival time of osteosarcoma patients with PN‐positive expression (30.14 ± 3.15 months) was markedly shorter than that with PN‐negative expression (60.27 ± 5.18 months; P = 0.014; Figure 4a; Table 4). Furthermore, similar results were also observed in the disease‐free survival analysis (24.78± 4.10 months vs. 50.98 ± 4.86 months; P = 0.016; Figure 4b). To further analyse the relationship between the PN‐positive expression and prognosis, two different levels of positive expression were analysed by using the Kaplan–Meier method (Figure 5).
Figure 4.
Kaplan–Meier analysis of overall survival (OS) and disease‐free survival (DFS) curves of patients with osteosarcoma based on periostin expression as positive or negative. (a) OS curve of patients with osteosarcoma based on periostin expression; (b) DFS curve of patients with osteosarcoma based on periostin expression. The osteosarcoma patients with periostin‐positive expression showed notably worse OS and DFS rates than those with periostin‐negative expression.
Table 4.
Univariate analysis of factors associated with OS and DFS
| Variable | OS | DFS | ||
|---|---|---|---|---|
| 95% CI | P value | 95% CI | P value | |
| Periostin | ||||
| Negative | 52.36–65.46 | 0.014 | 46.45–54.39 | 0.016 |
| Positive | 26.32–35.44 | 21.48–27.33 | ||
| Sex | ||||
| Male | 42.34–51.76 | 0.102 | 34.87–42.66 | 0.163 |
| Female | 40.01–47.76 | 34.67–40.12 | ||
| Age at diagnosis (year) | ||||
| <30 | 39.87–46.29 | 0.673 | 32.43–38.76 | 0.684 |
| ≥30 | 41.56–49.86 | 36.44–43.56 | ||
| Site of primary disease | ||||
| Tibia | 38.21–45.76 | 0.582 | 32.14–36.54 | 0.643 |
| Femur | 42.12–48.76 | 36.56–43.22 | ||
| Humerus | 42.34–48.98 | 36.87–43.42 | ||
| Other | 43.32–48.65 | 34.66–40.21 | ||
| Histologic subtype (n) | ||||
| Special | 54.98–63.22 | 0.033 | 49.08–56.98 | 0.031 |
| Conventional | 29.76–35.63 | 20.34–24.87 | ||
| Enneking stage | ||||
| I, II | 70.64–78.33 | 0.012 | 62.67–70.32 | 0.016 |
| III | 12.33–18.64 | 7.90–13.34 | ||
| Size (at diagnosis) (cm) | ||||
| <5 | 65.83–74.43 | 0.018 | 56.78–65.56 | 0.012 |
| ≥5 | 17.22–23.12 | 12.54–18.65 | ||
| Alkaline phosphatase (μ/l) | ||||
| <500 | 44.86–51.32 | 0.467 | 36.53–43.32 | 0.498 |
| ≥500 | 40.12–46.87 | 33.58–39.87 | ||
Figure 5.
Kaplan–Meier analysis of overall survival (OS) and disease‐free survival (DFS) curves of patients with osteosarcoma based on periostin expression as strongly positive, weakly positive or negative. (a) OS curve of patients with osteosarcoma based on periostin expression; (b) DFS curve of patients with osteosarcoma based on periostin expression. The osteosarcoma patients with periostin positive showed significantly poorer OS and DFS rates than those with periostin negative. The survival of patients in the strongly positive periostin expression was poorest.
Univariate analysis showed that variables including PN expression, histological subtype, Enneking stage and tumour size had significantly prognostic influences on overall survival (OS) and disease‐free survival (DFS) (Table 4). Moreover, multivariate survival analysis using Cox proportional hazard analyses of factors that were appeared significant in the univariate analyses revealed that PN expression as an independent prognostic factor for OS [hazard ratio (HR) 3.36; 95% CI 1.58–6.98; P = 0.001] and DFS [HR 3.04; 95% CI 1.50–6.36; P = 0.002], along with histological subtype, Enneking stage and tumour size (P < 0.05, Table 5).
Table 5.
Multivariate analysis of prognostic parameters associated with OS and DFS
| Variable | OS | DFS | ||||
|---|---|---|---|---|---|---|
| Hazard ratio | 95% CI | P value | Hazard ratio | 95% CI | P value | |
| Periostin (Negative vs. Positive) | 3.36 | 1.58–6.98 | 0.001 | 3.04 | 1.50–6.36 | 0.002 |
| Pathologic subtype (conventional vs. Special) | 2.64 | 1.56–4.63 | 0.001 | 2.30 | 1.31–4.09 | 0.002 |
| Enneking stage (I–II vs. III) | 1.72 | 1.36–2.31 | 0.000 | 1.70 | 1.33–2.29 | 0.000 |
| Tumour size, cm (≤5 vs. >5) | 1.77 | 1.31–2.42 | 0.000 | 1.63 | 1.21–2.18 | 0.001 |
Discussion
PN, a stroma‐associated protein, has been previously found to regulate adhesion and differentiation of osteoblasts and stimulate myocardial regeneration (Litvin et al. 2004). Recently, it has been frequently reported that PN is overexpressed in various types of human malignant tumours. What is more, accumulating evidence revealed that PN was correlated significantly with tumour invasiveness and progression in nasopharyngeal carcinoma and can regulate epithelial‐to‐mesenchymal transition (EMT) and cell invasiveness in prostate and bladder cancer cells and mediate pro‐angiogenic activity in gastric cancer and melanoma (Li et al. 2012; Kim et al. 2011; Qiu et al. 2013). Some authors have reported that the serum levels of PN, as well as tissue expression, can be used for prognostication in invasive breast carcinoma and hepatocellular carcinoma (Contié et al. 2011; Lv et al. 2013b). However, the influence of PN on osteosarcoma prognosis is still uncertain. In this study, we found that the levels of PN were significantly higher in osteosarcoma tissues compared with osteochondroma tissues. Overexpression of PN was detected in 55 of 68 (80.9%) tumour tissues. Furthermore, we found that osteosarcoma with PN‐positive expression were more frequently Enneking stage III, a tumour size >5 cm and a conventional pathologic subtype than osteosarcoma with PN‐negative expression. Accumulated findings indicated that OS and DFS were better in patients without PN expression than those in patients with PN‐positive expression. Both Kaplan–Meier and multivariate analysis showed that the expression of PN was an independent predictor of poor prognosis for both OS and DFS. The relationship between PN staining intensity and patient survival was also analysed, and a general inverse trend between a decline in patient survival and an increase in PN staining intensity was observed.
Osteosarcoma frequently tends to develop distant metastasis especially in lung and results in ultimate death. There is a plentiful of evidence to support significance of angiogenesis in the initiation, development and aggressiveness of osteosarcoma (Kaya et al. 2000; Rastogi et al. 2012; Chen et al. 2012). VEGF is considered as a prime mediator for both physiological and pathological angiogenesis and has been implicated in carcinogenesis and metastasis. Kaya et al. (2000) have reported that VEGF expression in untreated osteosarcoma is predictive of pulmonary metastasis and poor prognosis. Rastogi et al. (2012) have demonstrated that serum VEGF levels might prove to be of diagnostic, predictive and prognostic value in patients with primary osteosarcoma. Additionally, Chen et al. (2012) showed that pre‐operative high expression of VEGF and MVD has great predictive value with regard to relapse of osteosarcoma patients. Thus, to explore the relationship between PN and tumour angiogenesis, we quantified the levels of VEGF and MVD in this study, which were the most widely accepted markers of tumour angiogenesis. Our results showed that tumours with PN‐positive group expressed higher VEGF and had higher MVD than those in PN‐negative group. We analysed the relation between VEGF and PN by spearman's rank‐correlation test and found that there was a significant positive correlation between PN and VEGF. Taken together, these findings suggested that PN plays a crucial role in osteosarcoma tumorigenesis by inducing and/or promoting tumour angiogenesis.
PN plays a major role in stromal invasion and tumour adhesion. However, its exact mechanism of action remains unclear. Histopathological analyse of PN expression indicates that the niche component PN is produced by cancer‐associated fibroblasts (Kikuchi et al. 2014). Here, PN can act as an adhesion protein by facilitating interaction between the cancer stem cells and the niche. This protects tumour stem cells from detection and destruction by the immune system and so maintains them in an undifferentiated state. As mentioned above, PN can also promote angiogenesis in tumour metastases and facilitate survival and proliferation of tumour cells following their colonization of distant tissues. Recently, Wong et al. (2013) have reported that PN cooperates with mutant p53 to mediate invasion through the induction of STAT1 signalling in the oesophageal tumour microenvironment. Additionally, Utispan et al. (2012) have showed that PN activates integrin alpha5 and beta1 through a PI3K/AKTdependent pathway in invasion of cholangiocarcinoma. To demonstrate these hypotheses, further investigations are needed to explore possible molecular mechanisms.
However, there are several inherent limitations to this study, including the small sample size and the possible selection bias of the cohort. Thus the current findings should be verified in a prospective, randomized and multicenter study.
In conclusion, our study found that PN is overexpressed in human osteosarcoma compared with osteochondroma tissues. The overexpression of PN has a close correlation with tumour metastasis and angiogenesis and may be used as a prognostic biomarker and therapeutic target in patients with osteosarcoma.
Conflict of interest
The authors declare that they have no conflict of interests.
Funding source
This work was not supported by funds from any organization.
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