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ORIGINAL ARTICLE
Year : 2020  |  Volume : 16  |  Issue : 2  |  Page : 335-342

Correlation between the changes of serum COX 2, APE1, VEGF, TGF-β and TSGF levels and prognosis in patients with osteosarcoma before and after treatment


1 Department of Spine Surgery, The Third Hospital of Hebei Medical University, Shijiazhuang, China
2 Department of Anesthesiology, Xingtai People's Hospital, Xingtai, China
3 Department of Orthopedics, Xingtai People's Hospital, Xingtai, China

Date of Submission03-Jan-2020
Date of Decision18-Mar-2020
Date of Acceptance22-Apr-2020
Date of Web Publication28-May-2020

Correspondence Address:
Wenyuan Ding
Department of Spine Surgery, The Third Hospital of Hebei Medical University, No. 139, Ziqiang Road, Shijiazhuang 050051, Hebei Province
China
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jcrt.JCRT_11_20

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 > Abstract 


Context: Osteosarcoma (OS) is a progressive primary bone tumor that originates from immature stromal spindle cells. After chemotherapy, the serum-related indexes which are related to the prognosis.
Aims: The aim of this study is to investigate the correlation between changes in serum cyclooxygenase-2 (COX-2), basic fibroblast growth factor (bFGF), vascular endothelial growth factor (VEGF), transforming growth factor-beta (TGF-β), and tumor-specific growth factor (TSGF) levels and prognosis of patients with osteosarcoma (OS) before and after treatment.
Settings and Design: Data of 75 patients with OS (observation group) and 55 healthy controls (control group) were retrospectively analyzed.
Materials and Methods: Chemotherapy was administered to the observation group. Serum lactate dehydrogenase, alkaline phosphatase, and TSGF levels were measured before and after treatment. The observation group patients were classified as normal or abnormal according to the changes in serum COX-2, bFGF, VEGF, TGF-β, and TSGF levels after chemotherapy. Patients were followed up for 7.5 years, and the survival rate was determined.
Statistical Analysis Used: Single-factor influencing prognosis was included in the Cox model, and independent factors influencing prognosis were analyzed.
Results: After chemotherapy, the mean serum COX-2, bFGF, VEGF, and TSGF levels decreased significantly in the observation group but were still higher than those in the control group. Furthermore, serum TGF-β levels increased in the observation group but were still lower than those in the control group. The 5-year survival rate of patients with normal serum COX-2, bFGF, VEGF, and TSGF levels was significantly higher in the normal subgroup than in the abnormal subgroup. Cox analysis showed that the Enneking stage and COX-2 level after chemotherapy were independent prognostic factors.
Conclusions: The serum COX-2, bFGF, VEGF, and TSGF levels of patients with OS significantly changed after chemotherapy, and the short-term survival rate of patients with normal levels of these biomarkers after chemotherapy was high.

Keywords: Basic fibroblast growth factor, cyclooxygenase-2, osteosarcoma, transforming growth factor-beta, tumor-specific growth factor, vascular endothelial growth factor


How to cite this article:
Zhang Q, Dong G, Wang F, Ding W. Correlation between the changes of serum COX 2, APE1, VEGF, TGF-β and TSGF levels and prognosis in patients with osteosarcoma before and after treatment. J Can Res Ther 2020;16:335-42

How to cite this URL:
Zhang Q, Dong G, Wang F, Ding W. Correlation between the changes of serum COX 2, APE1, VEGF, TGF-β and TSGF levels and prognosis in patients with osteosarcoma before and after treatment. J Can Res Ther [serial online] 2020 [cited 2020 Jul 5];16:335-42. Available from: http://www.cancerjournal.net/text.asp?2020/16/2/335/285179




 > Introduction Top


Osteosarcoma (OS) is a progressive primary bone tumor that originates from immature stromal spindle cells.[1] Although rare, OS is the most common primary bone tumor in children and adolescents. It usually occurs in the long bone, the metaphysis being the most common site, accounting for approximately 75% of cases, with a high degree of lung metastasis. When OS was clinically diagnosed approximately 30 years ago for thefirst time, most patients would die within 1 year and the overall 5-year survival rate was approximately 10%. With the emergence of new adjuvant chemotherapy (the four most effective drugs, 4–6 cycles before surgery and 9–13 cycles after the surgery), the 10-year disease-free survival rate of patients with OS with and without metastasis increased to approximately 30% and 60%, respectively.[2],[3],[4],[5],[6] At present, approximately three new cases of OS per 1 million individuals are reported every year. Among the newly diagnosed cancer cases every year, OS accounts for <1% of cases in adults and 3%–5% in children. After leukemia and lymphoid cancer, OS represents the most common tumor in teenagers.[7] The distribution of OS incidence by age shows the double-peak characteristics. Thefirst peak appears in the period of rapid growth and development between 10 and 16 years of age (average peak age, 16 years), and the second peak appears after 60 years of age.[8],[9] Compared with women, men are more likely to develop OS, and the ratio of men to women is approximately 1.6:1. In addition, because women develop and mature earlier, the average time to increase in hormone levels is slightly lesser in women than in men; therefore, compared with men, women have an earlier peak age of OS incidence.[10],[11],[12] Thus, the occurrence and development of OS are associated with changes in hormone levels and bone physiological characteristics in adolescence.[10],[13],[14],[15] Although the long bone of the limb remains the most common site of OS in patients aged >60 years, it is no longer the primary site of OS because of the increasing diversity of primary tumor sites. The incidence of the craniomaxillofacial OS is increasing with age. Indeed, craniomaxillofacial OS accounts for approximately 40% of OS cases in patients aged ≥60 years and <12% in those aged <24 years.[16]

At present, cisplatin, doxorubicin, ifosfamide, and methotrexate are commonly used asfirst-line chemotherapy drugs. If patients have lung metastasis, etoposide, ifosfamide, sorafenib, docetaxel, topotecan, gemcitabine, and rapamycin can prolong the life of patients.[17],[18]

This study was aimed to determine the correlation between the changes in serum-related indexes (i.e., cyclooxygenase-2 [COX-2], basic fibroblast growth factor [bFGF], vascular endothelial growth factor [VEGF], transforming growth factor beta [TGF-β], and tumor-specific growth factor [TSGF] levels) and the prognosis of 75 patients with OS before and after chemotherapy and to provide treatment directions to further improve the survival rate of these patients.


 > Materials and Methods Top


Ethics

The patients provided informed consent before participating in this study. This study was approved by the ethics committee of the Xingtai people's Hospital. The study obeyed the Declaration of Helsinki.

Study design

Selection and description of participants:

The data of 75 patients with OS (observation group) and 55 healthy controls (control group) admitted to our hospital for physical examination from January 2010 to June 2018 were retrospectively analyzed.

The inclusion criteria were as follows. Control group: those who were admitted to the hospital for physical examination at the same time as the patients in the observation group. Observation group: (1) patients with complete medical records; (2) those diagnosed with OS by computed tomography, magnetic resonance imaging, and pathological examination; (3) those with no previous history of a tumor; (4) those with no distant metastasis on systemic examination; (5) those who were not operated previously and could tolerate chemotherapy; and (6) those who understand and agree to participate and provide data and sign the informed consent.

The exclusion criteria were as follows. Control group: those who did not pass the physical examination. Observation group: (1) Patients with a bone tumor caused by other tumor metastasis; (2) those who cannot tolerate chemotherapy; (3) those with an extremely short estimated survival time to accept chemotherapy; (4) those who did not receive chemotherapy according to the guidelines and were lost to follow-up; and (5) those with incomplete case data.

The control group comprised 55 healthy controls (36 men and 19 women) with an average age of 15.45 ± 5.26 years, whereas the observation group comprised 75 patients with OS (52 men and 23 women) with an average age of 16.75 ± 6.45 years (age range: 9–26 years). With regard to the Enneking stage, 20 patients had stage I cancer, 41 had stage II cancer, and 14 had stage III cancer. In terms of pathological classification, there were eight cases of chondroblastic type, five cases of vasodilation type, and 62 cases of osteoblast type. The course of the disease was 1–12 months, with an average duration of 5.55 ± 1.52 months. There were no significant differences in age and sex among all the participants (P > 0.05).

Treatment

All the patients in the observation group were treated with neoadjuvant chemotherapy, and the treatment was performed as follows:

First course of treatment

On the 1st day, doxorubicin hydrochloride 420 mg/m2 was intravenously administered for 3 days. Simultaneously, cisplatin 600 mg/m2 was intravenously administered on the 1st day for 2 weeks.

Second course of treatment

After thefirst course, there was a 2-week rest period before thefirst course was repeated.

Third course of treatment

After the second course of treatment, there was a 2-week rest period. Then, doxorubicin hydrochloride 420 mg/m2 static push was administered for 3 days. Simultaneously, cisplatin 600 mg/m2 was intravenously administered for 2 weeks.

Observation index

  1. Before chemotherapy, 5 ml of fasting venous blood was collected from both the groups in the early morning, and the supernatant was centrifuged for cryopreservation. After chemotherapy, 5 ml of venous blood was collected from the patients in the observation group separately, and the same method was used for treatment. The serum COX-2, bFGF, VEGF, TGF-β, and TSGF levels were measured by immunocolorimetry
  2. The patients were classified as normal or abnormal according to the ratio of the serum COX-2, bFGF, VEGF, and TGF-β levels in the observation group to those in the control group, and the change in survival rate over a 7.5-year follow-up was statistically analyzed
  3. Tumor-free survival within 3 years of chemotherapy was considered a good prognosis.


Statistics

All statistical analyses were performed using the SPSS 25.0 statistical software (International Business Machines Corporation, New York, NY, USA). The single factors affecting the prognosis were analyzed, and statistically significant items were incorporated into the Cox risk model to analyze the independent factors affecting the prognosis. Count data were expressed as percentage (%), and the survival rate between the groups was compared and expressed based on the Chi-square test. The measurement data were expressed as mean ± standard deviation (x ± s). The comparison of serum levels between the groups was expressed based on the independent sample t-test, and the comparison of these levels before and after treatment between the groups was expressed based on paired t-test. Values of P < 0.05 were considered statistically significant.


 > Results Top


Comparison of serum levels between the two groups

Before chemotherapy, the COX-2, bFGF, VEGF, TGF-β, and TSGF levels in the observation group were significantly higher than those in the control group (all P < 0.05); after chemotherapy, the water levels of lactate dehydrogenase, alkaline phosphatase, and TSGF in the observation group were significantly lower (all P < 0.05) but significantly higher than those in the control group (all P < 0.05) [Table 1].
Table 1: Comparison of serum levels in observation Group (before and after chemotherapy) and Control Group

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The observation group was divided into normal or abnormal subgroups according to the serum COX-2, bFGF, VEGF, TGF-β, and TSGF levels after chemotherapy, and the 5-year survival rate was determined. All the patients completed follow-up and none were lost to follow-up. The 5-year survival rates of patients with normal and abnormal serum COX-2, bFGF, VEGF, TGF-β, and TSGF levels are shown in [Figure 1]. The survival rate was lower in patients with abnormal serum COX-2, bFGF, VEGF, TGF-β, and TSGF levels than in those with normal levels.
Figure 1: Relationship between cyclooxygenase-2, basic fibroblast growth factor, vascular endothelial growth factor, transforming growth factor beta and tumor specific growth factor and survival rate (Kaplan–Meier, P < 0.05)

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Univariate analysis of prognosis showed that course of the disease; Enneking stage; and COX-2, bFGF, VEGF, TGF-β, and TSGF levels were related to prognosis (P < 0.05), whereas sex, age, and pathological type were not (P > 0.05) [Table 2].
Table 2: Single factor analysis of prognosis

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Multivariate Cox analysis incorporated course of disease; Enneking stage; and COX-2, bFGF, VEGF, TGF-β, and TSGF levels after chemotherapy into a Cox proportional risk analysis model. The results showed that the Enneking stage and COX-2 level after chemotherapy were independent factors affecting prognosis [Table 3].
Table 3: Multivariate cyclooxygenase analysis of prognosis

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Correlation among cyclooxygenase-2, basic fibroblast growth factor, vascular endothelial growth factor, transforming growth factor-beta, and tumor-specific growth factor after treatment

TSGF is a relatively specific serum marker for OS, and we found that the serum COX-2, bFGF, and VEGF levels were positively correlated with TSGF, whereas serum TGF-β level was negatively correlated with TSGF. The correlation coefficients of COX-2 and TSGF were 0.275, whereas those of bFGF, TSGF, VEGF, and TSGF were 0.230, 0.495, and − 0.238, respectively (all P < 0.05) [Table 4] and [Figure 2], [Figure 3], [Figure 4], [Figure 5].
Table 4: Correlation among cyclooxygenase-2, basic fibroblast growth factor, vascular endothelial growth factor, transforming growth factor beta and tumor specific growth factor after treatment

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Figure 2: Relationship between cyclooxygenase-2 and tumor specific growth factor (Pearson, P < 0.05)

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Figure 3: Relationship between basic fibroblast growth factor and tumor specific growth factor (Pearson, P < 0.05)

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Figure 4: Relationship between vascular endothelial growth factor and tumor specific growth factor (Pearson, P < 0.05)

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Figure 5: Relationship between transforming growth factor beta and tumor specific growth factor (Pearson, P < 0.05)

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 > Discussion Top


OS is a type of systemic cancer, and patients often have blood metastasis when they visit the hospital, with lung metastasis being the most common metastasis.[19],[20],[21] In recent years, with improvement in chemotherapy methods, the survival rate of patients with OS has greatly improved and an increasing number of patients now choose chemotherapy. At present, the most commonly used chemotherapy drugs include methotrexate, cisplatin, and doxorubicin. Doxorubicin, also known as adriamycin, can be used as a template for DNA replication and RNA reverse transcription. When the DNA chain is opened, it binds to the exposed base pairs and functions to inhibit tumor cell division and proliferation, ultimately leading to tumor cell death.[22],[23],[24],[25],[26],[27] Cancer cells proliferate faster than other cells, making them more sensitive to drugs (e.g., cisplatin) that interfere with the cell cycle. Cisplatin can combine with purines and cytosines on the DNA chains of tumor cells to form a cross-linked complex; this complex destroys the structure and function of DNA from within and eventually leads to tumor cell death.[28]

In the present study, the serum COX-2, bFGF, VEGF, TGF-β, and TSGF levels were significantly decreased after chemotherapy, but they were still higher than the normal values, indicating that chemotherapy can inhibit the growth and proliferation of OS cells to some extent. We measured the serum levels of these biomarkers in 75 patients after chemotherapy and analyzed the relationship between these biomarkers and the survival rate. All single factors associated with diseases were included in the Cox risk proportion model, and the results showed that the Enneking stage and COX-2 levels after chemotherapy were independent factors affecting prognosis.

Previous studies have demonstrated that COX-2 is highly expressed in several tumor cells.[29],[30] Apoptosis refers to programmed cell degeneration and death caused by a series of stimulation signals controlled by genes to maintain the stability of the internal environment. Apoptosis plays an important role in the process of maintaining growth, development, and reproductive aging. It involves the activation, expression, and regulation of a series of genes;[31] it is not a self-injury process under pathological conditions but a death process that actively strives for adaptation to the living environment. The body can remove damaged and precancerous cells in time through apoptosis. During the process of tumor occurrence and development, cells proliferate and accumulate without limitation, and apoptosis is inhibited in this process. Therefore, the inhibition of apoptosis is an important mechanism of tumorigenesis and development. Both caspase 3 and caspase 9 are apoptotic regulators; it is generally believed that apoptosis is the result of a series of highly regulated caspase cascade events. There are two classic apoptotic pathways: the extracellular pathway and the intracellular pathway. In the extracellular pathway, the conduction of the death signal depends on the binding of the death receptor and ligand (such as the binding of Fas and FasL). This is followed by binding of the death domain of the death receptor to the signaling molecule (such as the Fas-related death domain protein). In the context of Fas–FasL binding, the Fas-related death domain protein can bind to the death effect domain of the caspase 8 zymogen to form the death induction signal complex. Subsequently, caspase 8 becomes activated, leading to cytochrome C release from mitochondria by cleavage of the death receptor agonists in the cross-domain of the apoptosis promoting member BH3 or directly through caspase 3 and the downstream caspase cascade.[31],[32]

In the intracellular pathway, intracellular death signals such as DNA damage and toxins can induce the release of cytochrome c from mitochondria. Cytochrome c and the caspase 9 zymogen combine to form the apoptosis complex. Caspase 9 is released and activated, followed by apoptosis through downstream Caspase 3, caspase 7, and other activated degradation substrates. Kim et al.[29] found that a COX-2 inhibitor can inhibit cell growth by regulating the expression of caspase 3 and caspase 9, leading to cell apoptosis. Moreover, Lin et al.[32] found that when the expression levels of COX-2 were decreased, the growth of ovarian cancer cells was significantly inhibited, indicating the involvement of COX-2 in the growth of ovarian cancer cells. This study also confirmed that COX-2 may promote the growth of ovarian cancer cells by inhibiting the apoptosis of tumor cells. At present, the specific mechanism by which COX-2 inhibits apoptosis is unclear, but the involvement of the expression of several apoptotic genes and regulatory factors has been suggested. Bcl-2 is one such apoptosis-related gene and is the main protooncogene involved in cell apoptosis. Bcl-2 can prolong the cell cycle and inhibit cell apoptosis. The protein product of Bcl-2 is an important antiapoptotic protein that is mainly distributed in the inner membrane, including the mitochondria and nuclear membrane, which mainly plays an antiapoptotic role through the intracellular pathway. Overexpression of Bcl-2 may lead to cell proliferation and tumor development. Therefore, it has been speculated that COX-2 inhibits the apoptosis of tumor cells by upregulating the expression of Bcl-2.

Tumor occurrence, development, and metastasis depend on the formation of blood vessels. Only after the formation of new blood vessels can the tumor grow rapidly, further infiltrate into the surrounding tissues, and enter the blood circulation. There are many factors involved in tumor angiogenesis, including VEGF, bFGF, platelet-derived growth factor, hepatocyte growth factor, and matrix metalloproteinases belonging to the fibroblast growth factors family. bFGF is closely related to tumor angiogenesis and can promote the angiogenesis of solid tumors. bFGF is an indirect finger plate reflecting tumor angiogenesis and is closely related to tumor growth, invasion, metastasis, and prognosis. However, there are few studies on bFGF in patients with Al.[33],[34] Previous studies have demonstrated that the microvessel density in the bone marrow is significantly higher in patients with leukemia than in normal healthy controls and that the bFGF content in the urine of children increases before treatment but decreases after complete remission.[35],[36] Furthermore, high levels of bFGF have been detected in the serum and bone marrow of patients with hairy cell leukemia.

VEGF can promote the proliferation, migration, and chemotaxis of vascular endothelial cells in the bone, lung, kidney, brain, and tumor. Under pathological conditions, hypoxia is the most important factor that promotes the synthesis of VEGF.[37] Research has shown that the synthesis of VEGF in cells under hypoxic conditions is approximately 12-fold greater than that under normoxic conditions. Hypoxia of cells can cause the release of hypoxia-inducible factor-1 and subsequently promote VEGF gene transcription. Greenberg and Jin[38] found that VEGF can significantly promote the neovascularization of ischemic focus after stroke as a result of the combination of injury and hypoxia; this leads to VEGF-mediated proliferation and migration of residual capillary endothelial cells in the ischemic penumbra and subsequent neovascularization.[39],[40] I In addition, the stimulation of inflammation and tumor growth is also the main factor that promotes the release of VEGF under pathological conditions.

TGF-β is thefirst growth factor that can induce the epithelial-mesenchymal transition process in normal mammary epithelial cells[3],[4] as well as tumor cells. TGF-β has multifunctional biological activity,[7] and in addition to regulating development, proliferation, and immune responses, it has dual roles in the process of tumorigenesis. In the early stage of tumorigenesis, TGF-β can play a role in tumor inhibition by inducing apoptosis and cell cycle arrest, whereas it can promote the transfer of tumor cells in the later stage.[8] Furthermore, TGF-β can promote the migration and invasion of tumor cells.

TSGF was discovered in 1989 by scholars from the University of Toronto, Canada,[41],[42] as a tumor marker secreted by tumor cells in the process of cell formation and growth. TSGF is a general term for many internationally recognized carbohydrates and metabolites related to the growth of malignant tumors, also known as the “tumor-related substances group.” Its relative molecular weight is small, and its mechanism of action is mainly through the synthesis and secretion of TSGF by different cells, which is accepted by receptors on the target cells. The receptor of TSGF is transmembrane distributed, and its structure can be divided into three parts: the region that can recognize the specific growth factor outside the cell, the region that can connect with it, and the region that has tyrosine-protein kinase activity facing the cell interior. TSGF can be significantly increased in the early stages of malignant tumor formation,[43],[44],[45] and can induce dominant expression related to malignant transformation. It can affect the differentiation of some cloned T lymphocytes by inhibiting the production of IgG and IgM,[46] increase the resistance of tumor cells to NK cells, and promote tumor angiogenesis. Through the above mechanisms, TSGF can promote tumor formation, growth, and even metastasis.[47],[48],[49]


 > Conclusions Top


The results of this study showed that the serum COX-2, bFGF, VEGF, TGF-β, and TSGF levels decreased significantly in patients with OS after chemotherapy, but the short-term survival rate of patients with normal serum levels was higher than that of patients without recovery. Cox model analysis showed that the Enneking stage and COX-2 after chemotherapy were independent factors affecting prognosis. Thus, clinical treatment methods could be formulated accordingly to predict prognosis.

Financial support and sponsorship

Xingtai Science and Technology Project: 2018ZC152.

Conflicts of interest

There are no conflicts of interest.



 
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    Figures

  [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5]
 
 
    Tables

  [Table 1], [Table 2], [Table 3], [Table 4]



 

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