Osteosarcoma is a life-threatening bone malignancy that often occurs in teenagers. It is the second leading cause of cancer-related death in pediatric age group and young adults . Current treatments for osteosarcoma include surgical resection of both primary and pulmonary lesions, chemotherapy, and radiotherapy. Disease-free survival escalated from <20% prior to the introduction of effective chemotherapy to around 60% and overall survival to 60–70% . At present, the ability to predict the prognosis of osteosarcomas is limited. Therefore, identifying prognostic markers of survival in osteosarcomas could be informative for selecting proper management. Traditional prognostic markers, such as gender, age, tumor location, disease-free interval, tumor doubling time, representation, and number of detectable pulmonary metastases, have had limited success in identifying those patients that need aggressive chemotherapy and those that do not . In recent years, a number of cell surface markers were found to indicate a small group of cancer cells, referred as cancer stem cells, which are responsible for tumor initiation, progression, metastasis and drug resistance . Many researchers have reported that high expression of these markers indicates bad clinical features and poor prognosis [29, 30], and CD44 was one of the most reported cancer stem cells markers.
CD44 was previously thought to be a transmembrane adhesion molecule, which also played a role in the metabolism of its principal ligand hyaluronan. It may exist in three distinct physical phases, as a transmembrane cell surface receptor, an integral component of the matrix and in a fluid phase, each with the potential for being functionally significant. CD44 is known to be a major hyaluronic acid receptor in vitro, although it is not known how often CD44 is expressed or what role it plays in normal bone tissues. CD44 proteins have been observed in osteoclasts and osteocytes by means of immunohistochemical analysis on bone tissue, but there have been some controversial reports that CD44 proteins were found in osteoblasts . As CD44 reacts with the extracellular matrix, several published reports have suggested that CD44 expression is related to metastatic potential, prognosis, and the biologic properties of human malignancies. Investigations of CD44 over the past 20 years have established additional functions for CD44, including its capacity to mediate inflammatory cell function, tumor growth, adhesion, migration and metastasis. It has also become evident that intricate post-translational modifications of CD44 regulate the affinity of the receptor for its ligands . Whether CD44 is a prognostic marker in osteosarcoma patients has been studied extensively, but the conclusions are inconsistent. This meta-analysis was carried out by critically reviewing six studies on the association of CD44 with prognosis in osteosarcoma.
The present meta-analysis showed that high CD44 expression did not indeed predict poor survival and metastasis in patients with osteosarcoma. However, it should be circumspect to make a verdict of the association with CD44 and osteosarcoma, because there are still several issues should be considered. First, since the number of included studies in this meta-analysis was only six, it might weaken the reliability of our results. More well-designed clinical studies with large cases of osteosarcoma should be performed in the future to validate the relationship between CD44 expression level and prognosis of osteosarcoma patients. Second, lack of abundant CD44 expression data in global population makes it difficult to set a standard value for the measurement of CD44. Third, the methods used for the evaluation of the levels of markers in osteosarcoma patients and the use of standard threshold, are both likely to impact on our results. Although immunohistochemistry was the most commonly applied method, the cut-off value was defined differently in inclusion studies. Therefore, we strongly suggest conducting more prognostic studies for high CD44 expression in osteosarcoma.
Moreover, recently studies have demonstrated that microRNAs might influence chemoresistance of osteosarcomas with different pathways including CD44, resistance to chemotherapeutic agents is still one of the major reasons for the failure of osteosarcoma treatment, while we did not excluded the role of CD44 in chemoresistance of osteosarcoma. The identification of cancer-specific miRNAs and their targets is pivotal for understanding their role in tumorigenesis and metastasis, and may be important for the discovery of novel therapeutic targets. CD44 which contained the corresponding binding site of microRNAs’ 3′UTR, was regulated by some microRNAs, such as miR-34a, miR-140 and miR-215 [33–35]. The results of these published studies showed that the CD44 level inversely correlated with the microRNAs level. So in the future research, we will discuss the role of CD44 in chemoresistance of osteosarcoma.
On the other hand, many researchers have reported that high expression of some markers indicates bad clinical features. Such as clinical stage, positive distant metastasis and poor response to chemotherapy [36, 37]. In this present study, we also discussed the relationship between overexpression of CD44 and clinicopathological parameters in osteosarcoma patients. Nonetheless, the result showed that no significant difference was observed between the expression of CD44 and patients’ age, gender, tumor size, clinical stage, positive distant metastasis and poor response to chemotherapy (data not shown).
Despite the inherent limitations of meta-analysis on prognostic literature, this meta-analysis, representing a quantified synthesis of all published studies of CD44, has shown that the high expressed CD44 is not significantly associated with poor survival and metastasis in patients with osteosarcoma. For better analysis the relationship between CD44 expression and prognostic with the osteosarcoma, it is necessary to improve the experimental methods and detection methods, and to clear a unified quantitative standard. Future adequately multi-center designed prospective with larger sample size were of great value to confirm these findings and more clinical studies should be carried out before the application of CD44 in prognosis of osteosarcoma.