| Oral squamous cell carcinoma (OSCC) is the most common oral cancer, accounting for more than 80% of oral cancer and for 3% -5% of systemic cancer. Oral leukoplakia (OLK) is the most common precancerous lesions .It turns to cancer in the rate from 9% to 19%, with an average duration of 8.2 years. From normal mucosa to OLK then to OSCC is a long process of development. The use of natural or synthetic chemicals in the treatment of oral precancerous lesions to block or even reverse the development of cancer is one of the means to reduce the incidence of cancer. In recent years much attention has been paid to the development and the use of Chinese medicine. Many of these traditional medicines are used for cancer treatment.VEGF is widely considered as the most effective growth factor in tumor's angiogenesis.Uncontrolled angiogenesis plays a dominant role in tumor's growth and metastasis. The degree of tumor proliferation, angiogenesis and tumor metastatic potential are closely related to angiopoiesis. Angiopoiesis is an important condition for the occurrence of cancer. In the various stages of carcinogenesis, angiogenesis become higher and the proliferation and the extent of the malignancy also continues to grow in tumor tissue through the effection of autocrine and paracrine secretion of the vascular growth factor (VEGF). As a precancerous lesion, there is angiogenesis in OLK following the increasing degree of epithelial dysplasia.Apoptosis is an initiative of cell death process. It plays an important role in the development of tumor. This is a hot spot of today's oncology research. It provides a new idea for people particularly in the selection and mechanism of antineoplastic agents. The serious imbalance of apoptosis is destructive to the body. It has been demonstrated that the incidence of many diseases, particularly in the development of cancer, is related to the imbalance of apoptosis. The growth of tumor is due to the imbalance of proliferation and apoptosis. Caspase (cystiny1 aspartate specific protease) family,'aspartate - specific cysteine protease',is the key enzymes in mammalian cells apoptosis including human. caspase-3 is the key to execute apoptosis in the downstream. Most factors triggering apoptosis is mediated by caspase-3 through the signal transduction pathways leading to apoptosis in the end. Triterpenes are bitter compounds extracted from the traditional Chinese medicinal herb Ganoderma. They have a variety of pharmacological effects such as protect the liver, anti-tumor; anti-HIV-1 and HIV-1 protease activity, hypoglycemic, inhibit histamine release, inhibit of angiotensin-converting enzyme (ACE), inhibit cholesterol synthesis, analgesia, inhibit platelet aggregation, inhibit farnesyl protein transferase (FPT), anti-oxidation, inhibit eukaryotic DNA polymerase activity and so on.Study of the purification and biological activity of triterpenes is a focal point of Ganoderma lucidum's research. Among triterpenes pharmacological activity the anti-tumor effect is concerned much. The study of its anti-tumor effect is the focus of attention. Ganoderma triterpene compounds has a certain therapeutic effect for lung cancer, liver cancer, breast cancer and so on. Its cytotoxic effect, FPT inhibition, anti-oxidation and the analgesic effect have something to do with the anti-tumor effect.The mechanism of anti-tumor research of Ganoderma triterpenes is not very clear currently. The studies from the molecular level are fewer and most of them are related to the cancer in the other part of body. Most research are about the clinical or the molecule level of Ganoderma polysaccharide. Whether prevention or treatment effections of triterpenes in OSCC and OLK is not clear now. In order to find out these questions, we established the animal models of canceration induced by DMBA in the hamster. We observed the pathological changes between the group given the drug and not given the drug on 6th week, 9th week and 12th week and measured VEGF and caspase-3 Expression from the normal buccal mucosa, epithelial hyperplasia, dysplasia, eventually to squamous cell carcinoma between the two groups.In organization samples HE staining, we found the normal epithelial cases of group A were more than group B and the epithelial dysplasia rate was significantly lower than group B (P<0.01) on 6th week.On 9th week groups the moderate and severe epithelial dysplasia and carcinoma rate was lower in group A than in group B (P<0.05). On 12th week groups the cancer rate was significantly lower in group A than in group B (P<0.01). In the whole dynamic carcinogenesis observation period, the occurrence of two groups'histological difference was significant (P<0.01). The severity in group A was still lower than group B and the grade of cancer induced was lower. These results confirmed that the Ganoderma triterpenes inhibited OSCC. Immunohistochemical study of VEGF showed that its expression with the development of squamous cell carcinoma from normal mucosa gradually strengthened. In the normal mucosa VEGF was not or only weak expressed. In OSCC positive stainings were prevalent.There were significant differences on the three grades the simple hyperplasia, dysplasia and carcinoma information of group A and B by rank sum test (P <0.05). This showed that there were lower grades in group A than in group B and also proved triterpenes can inhibit angiogenesis with its anti-tumor activity. Immunohistochemical study of caspase-3 indicated that caspase-3 positive staining mainly distributed in the cytoplasm, a few nucleus could be seen. It's brown or yellow brown. Caspase-3 was not expressed in normal tissue or was weakly positive.It scattered mainly in endochylema in the bottom of the acanthocyte layer or in a very small number of the surface cells and could be scarcely observed in the nuclei. With the worsing of epithelial lesions, caspase-3 expression was gradually increased. In severe abnormal epithelial hyperplasia the positive cells were found all over the epithelial layer. Caspase-3 expression in squamous cell carcinoma is extensive. With the process of organizations from the normal, simple hyperplasia, dysplasia to carcinoma, the expression of caspase-3 showed a gradual upward trend. We believed that caspase expression was strengthened in order to promote apoptosis and antagonism cell proliferation. So it could maintain the number of cells stable. However, proliferation appeared to overwhelm the apoptotic defence.So the absolute cell apoptosis rate was lowered. The dysplasia cells accumulated until turning to cancer. The positive staining of caspase-3 in OSCC suggested a higher degree of tumor differentiation, lighter extent disturbance of apoptosis regulation mechanisms, weaker cell proliferation and better prognosis. In different lesions from normal, simple hyperplasia, dysplasia to carcinoma, the positive staining in group A were slightly lower than in group B. This might be due to lower malignant grade and active cell proliferation and relatively weaker apoptosis in group A. There was no significant difference in the normal and simple hyperplasia between group A and B. However, there was a significant difference in dysplasia and carcinoma between group A and B(P <0.05). Molecular events of apoptosis including degradation of chromosomal DNA, decrease in the level of Bcl-xL, the disruption of mitochondrial membrane, cytosolic release of cytochrome c and activation of caspase-3 were elucidated. The current main arguments about the mechanism of Ganoderma triterpenes is between whether it has the direct cytotoxic effect on tumor cells and whether it enhance the anti-tumor immunity and indirectly through inhibition of tumor cell growth or induce tumor cell apoptosis. In this study, we did not see the expression of caspase-3 in group A stronger than in group B. It noted that Ganoderma triterpenes might not play a role in apoptosis. Conversely it confirmed Ganoderma triterpenes might have a direct cytotoxic effect.These results suggest that Ganoderma triterpenes has prevention and treatment effect in oral premalignant lesions. This provide us a new way of thinking the treatment for oral squamous cell carcinoma. It has broad application prospects used as a preventative and auxiliary treatment of cancer. Ganoderma triterpenes has complex mechanism and need further study. |
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