Expression And Clinical Significance Of CXCR4 And HPA In Non-small Cell Lung Cancer Cells

Objective: Lung cancer is an aggressive and rapidly fatal malignancy worldwide. Approximately 80% of lung cancers can be histologically classified as non-small cell lung cancers (NSCLCs). The migration of tumor cells to a secondary site from their primary location is a crucial issue in cancer metastasis, which is a important factor of leading to patient's death. However, the precise mechanisms for the directional migration of malignant cells into different organs is unknown. Studies have indicated that dissemination of cancer metastasis occurs in a discrete orientation to specific organs rather than a random process. More than one hundred years ago Paget advocated the"seed and soil"hypothesis and tried to explain how malignant cells move to distant sites from their primary location. Recently, a novel"homing"signaling mechanism has been proposed, in which target organs produce and release specific chemokines that attract cancer cells bearing corresponding receptors. Since Muller et al. initially reported in Nature in 2001 that chemokines and their receptors play an important role in the organ-specific metastasis of breast cancer, numerous studies support this"homing"theory by demonstrating that malignant cells can target specific organs or tissues using select chemokine receptors. CXchemokine receptor-4( CXCR4),which belong to a member of a super family of 7-transmembrane-domain, G-protein-coupled receptors, is the only chemokine receptor that interacts with and activates its ligand stromal cell-derived factor-1(SDF-1 also known as CXCL12), which contributes to a variety of physiological and pathological processes . Recent studies found that CXCR4 was closely related with tumor invasion, tumor growth and metastasis. During metastasis formation malignant cells must penetrate barriers, such as basement membranes and extracellular matrixs composed of collagens, glycoproteins and proteoglycans. Thus, it is necessary that specific enzymes produced by cancer cells are activated to degrade the cell basement membrane and extracellular matrixs. Heparanase is an endo-β-glucuronidase that specifically cleaves carbohydrate chains of heparan sulphate proteoglycans (HSPG), which are important components of both extracellular matrix and basement membrane. Heparan sulfate chains bind a large number of bioactive molecules and regulate their availability and function. These include growth factors, chemokines, cytokines, and enzymes, thus influencing many physiological and pathological cellular and matrix processes. When heparan sulfate chains are degraded, the bound bioactive molecules from extracellular matrix depots are released and become available, At the same time, it facilitates disassembly of the extracellular matrix and enhances cell invasion. Since mammalian heparanase(heparanase-1) was first cloned by the groups of Vlodavsky and Parish in 1999, a large number of studies have been reported that heparanase is involved in invasion and metastasis of most malignant tumors.It has been shown that SDF-1/ CXCR4 may play a role in the metastasis of non-small cell lung cancer. However, no data are presently available on the expressions of CXCR4 and HPA in non-small cell lung cancer, and its impact on disease progression and prognosis. Therefore, In this study, we used immunohistochemical methods to examine the expression of HPA and CXCR4 in non-small cell lung cancer and normal lung tissues, and examine the correlation between their expressions and the clinicopathologic features to explore their role in the process of tumorigenesis, progression, invasion and metastasis of non-small cell lung cancer to provide new theory and experiment evidence for pathogenesy, and immunotherapy, clinical prognosis of non-small cell lung cancer.Methods: 50 specimens obtained from individuals with Surgically resected and histologically confirmed NSCLC were collected in this study, None of the patients had received preoperative chemocherapy or radiotherapy . Information about clinicopathological characteristics, such as age and sex of the patients, lung cancer cell differentiation and histological type, lymph node metastasis, (TNM) stage were obtained from surgical and pathological records. Immunohistochemistry was preformd to detect the expressions of CXCR4 and HPA in 52 tumor specimens and in 20 normal lung tissues. SPSS for windows 13.0 was applied to analyze the results of experiment.Results:1. Expression of CXCR4 protein and relation with clinical parameterImmunohistochemistry was employed to measure the expression of CXCR4 protein in 52 specimens of non-small cell lung cancer tissue and 20 specimens of normal lung tissue. The positive expression rate of CXCR4 protein in non-small cell lung cancer tissues was63.46% (33/52), while that in the normal lung tissues was 15%(3/20). There was significant difference in the positive rates of CXCR4 protein between non-small cell lung cancer tissues and the normal lung tissues (P<0.01). Expression of CXCR4 wasn't correlated with patients gender, age, lung cancer histological type and lung cancer cell differentiation (P>0.05), but that was correlated with lymph node metastasis and TNM stage (P<0.05).2. Expression of HPA protein and relation with clinical parameterImmunohistochemistry was employed to measure the expression of HPA protein in 52 specimens of non-small cell lung cancer tissue and 20 specimens of normal lung tissue. The positive expression rate of HPA protein in non-small cell lung cancer tissues was 55.77% (29/52), while that in the normal lung tissues was 10% (2/20). There was significant difference in the positive rates of HPA protein between non-small cell lung cancer tissues and the normal lung tissues (P<0.05). Expression of CXCR4 wasn't correlated with patients'gender, age, lung cancer histological type and lung cancer cell differentiation (P>0.05), but that was correlated with lymph node metastasis, TNM stage (P<0.05).3. There was a positive correlation between CXCR4 and HPA in non-small cell lung cancer tissues (r=0.289, P=0.038<0.05).Conclusion: There was over-expression of CXCR4, HPA in NSCLC.The expression of HPA had positive correlation with CXCR4 in NSCLC. The interactions of CXCR4, HPA may co-regulate the progress of NSCLC. The joint detection may serve as a judge of metastatic potential and prognostic indicator for NSCLC. It suggest that CXCR4, HPA might be promising molecular targets for treatment of NSCLC.