Deletion of Wild-type p53 Facilitates Bone Metastatic Function by Blocking the AIP4 Mediated Ligand-Induced Degradation of CXCR4
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Background: Management of patients with prostate cancer and bone metastatic disease remains a major clinical challenge. Loss or mutation of p53 has been identified to be involved in the tumor progression and metastasis. Nevertheless, direct evidence of a specific role for wild-type p53 (wt-p53) in bone metastasis and the mechanism by which this function is mediated in prostate cancer remain obscure. Methods: The expression and protein levels of wt-53, AIP4, and CXCR4 in prostate cancer cells and clinical specimens were assessed by real-time PCR, immunohistochemistry and western blot analysis. The role of wt-p53 in suppressing aggressive and metastatic tumor phenotypes was assessed using in vitro transwell chemotaxis, wound healing, and competitive colocalization assays. Furthermore, whether p53 deletion facilitates prostate cancer bone-metastatic capacity was explored using an in vivo bone-metastatic model. The mechanistic model of wt-p53 in regulating gene expression was further explored by a luciferase reporter assay and chromatin immunoprecipitation (ChIP) assay. Results: Our findings revealed that wt-p53 suppressed the prostate cancer cell migration rate, chemotaxis and attachment toward the osteoblasts in vitro. The bone-metastatic model showed that deletion of wt-p53 remarkably increased prostate cancer bone-metastatic capacity in vivo. Mechanistically, wt-p53 could induce the ligand-induced degradation of the chemokine receptor CXCR4 by transcriptionally upregulating the expression of ubiquitin ligase AIP4. Treatment with the CXCR4 inhibitor AMD3100 or transduction of the AIP4 plasmid abrogated the pro-bone metastasis effects of TP53 deletion. Conclusion: Wt-p53 suppresses the metastasis of prostate cancer cells to bones by regulating the CXCR4/CXCL12 activity in the tumor cells/bone marrow microenvironment interactions. Our findings suggest that targeting the wt-p53/AIP4/CXCR4 axis might be a promising therapeutic strategy to manage prostate cancer bone metastasis.Chemokine receptor CCR5
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The CXCR4/CXCL12 pathway has recently been reported to be involved in stimulating the metastasis of many different neoplasms, in which CXCR4 activates various phenomena such as chemotaxis, invasion, angiogenesis and proliferation. The purpose of this study was to analyze a possible association between the expression of chemokine receptors CXCR4, CCR6 and CCR7 with the clinicopathological features of cutaneous malignant melanoma, and to assess the usefulness of these chemokine receptors for diagnosis and prognosis. In our study, a percentage of immunoexpression of both CXCR4 and its ligands CXCL12 was associated with high clinical risk. In contrast, the patients with a low immunoexpression of CXCR4 and CXCL12 had low clinical risk. CCR6 and CCR7 immunoexpressions were also correlated with some clinical parameters, but seemed no more useful than CXCR4. These data suggest that the assessment of CXCR4 immunoexpression is a novel tool for predicting tumor aggressiveness in malignant melanomas, and in particular, a high immunoexpression percentage of CXCR4 and CXCL12 might be a sign of a poor prognosis.
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Abstract Prostate cancer metastasis to bone occurs in 50-90% of men with advanced disease for which there is no cure. Bone metastasis leads to debilitating fractures and severe bone pain. It is associated with disease progression, therapy resistance, poor prognosis, and rapid decline. Androgen ablation therapy is standard of care for advanced prostate cancer, however, the role of androgens in bone metastatic prostate cancer is not understood. The effects of anti-androgens as seen on bone scans can also be inconsistent with the biochemical PSA response. There are few pre-clinical models to understand the interaction between the bone microenvironment and prostate cancer. It is essential to understand the unique interaction of prostate cancer with the bone environment and to develop novel therapies that target these pathways. Here we report the development of novel patient-derived intra-femoral xenograft models of prostate bone metastatic cancer. METHODS: Surgical prostate cancer bone metastasis specimens were transplanted by direct injection into the femurs of Rag2-/-γc-/- mice or sub-cutaneously into the right flank. Patient-derived xenograft (PDX) tumors that grew out were analyzed for prostate cancer biomarker expression using quantitative RT-PCR and immunohistochemistry. Bone lesion formation was measured using micro-computed tomography (μCT). RESULTS: Prostate cancer surgical bone metastasis specimens have been collected from which we have established new serially transplantable, prostate cancer bone metastasis xenograft models – PCSD1, PCSD4 and PCSD5. PCSD1 (Prostate Cancer San Diego 1) was molecularly characterized as advanced, luminal epithelial-type prostate cancer. PCSD1 intra-femoral xenografts formed mixed osteoblastic/osteolytic lesions that closely mimicked those of the patient. Treatment with the anti-androgen, bicalutamide, did not inhibit intra-femoral PCSD1 xenograft growth although there was a decrease in PSA as seen in some patients treated with anti-androgen who had discordant PSA and bone scan tests. CONCLUSION: PCSD1, PCSD4 and PCSD5 are new patient-derived prostate cancer bone metastasis-derived xenograft models. PCSD1 xenograft model closely recapitulates the mixed osteolytic/osteoblastic bone metastatic lesions seen in patients, and we are using it to develop novel therapies for inhibiting prostate cancer growth in the bone-niche. Citation Format: Christina Jamieson, Christina Wu, Amy Strasner, Jason R. Woo, Michelle Muldong, Young B. Jeong, Michael A. Liss, Omer Raheem, Tomonori Yamaguchi, Heather Leu, Deborah Marshall, Sheldon Morris, Nicholas A. Cacalano, Koichi Masuda, Catriona H.M. Jamieson, Anna A. Kulidjian, Christopher J. Kane. Novel prostate cancer patient-derived xenograft models of bone metastatic castrate-resistant prostate cancer. [abstract]. In: Proceedings of the AACR Special Conference: The Translational Impact of Model Organisms in Cancer; Nov 5-8, 2013; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Res 2014;12(11 Suppl):Abstract nr A43.
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OBJECTIVE To investigate the application value of MRI combined PSA in prostate cancer bone metastasis. METHODS 74 prostate cancer patients were selected in our hospital, patients were tested for the serum PSA level and MRI after admission to detect the expression of prostate cancer bone metastasis. RESULTS All 74 patients in our group, the positive cases of prostate cancer bone metastasis were 43 cases (58.1%), positive cases in prostate cancer bone metastasis with PSA≥ 20 μg / L group was 69.6%, significantly higher than PSA (μg / L) ﹤20 μg / L groups 22.2%, the difference had a statistical significance, P﹤0.05. CONCLUSION PSA has a good prediction effect on prostate cancer bone metastasis. When PSA≥20 μg, the probability of prostate cancer bone metastasis increases significantly. PSA≥20 μg/L combined MRI can significantly improve the detection rate in prostate cancer bone metastasis.
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Radiotherapy plays an important role in the treatment of malignant head and neck tumors. Chemokines are chemotactic cytokines, which can induce tumor proliferation as well as metastasis, although the influence of chemokines and their signaling pathways via chemokine receptors is not fully understood. Moreover, the radiation-induced expression of chemokines and chemokine receptors is poorly studied. Therefore, the purpose of this work was to analyze the expression of the chemokines of the CC-and CXC-class and their receptors in untreated and in irradiated squamous cell carcinoma of the head and neck (SCCHN). The expression of chemokines and chemokine receptors in 15 head and neck carcinoma cell lines and two normal tissue cell lines was analyzed. The spontaneous expression and the expression 6 hours after irradiation with 2 Gy was determined. To validate the results, certain chemokines and chemokine receptors were re-analyzed in selected cell lines. In this second independent analysis the expression was detected for 48 hours after irradiation. Gene expression of chemokines and their receptors was detected by real-time PCR. In addition, the protein expression of two chemokines was analyzed by ELISA. The results of the first analysis showed, that the chemokine receptors were less widely expressed in the investigated cell lines than the chemokines. Irradiation with 2 Gy caused an altered expression of the chemokines and chemokine receptors in all investigated cell lines. Radiation caused up- and downregulation in the expression of the chemokines, whereas the expression of the investigated receptors was predominantly downregulated after irradiation. The results of the chemokine expression were validated in the second, independent analysis. Radiation caused again up- and downregulation in the expression of the chemokines, but also showed that the expression of the chemokines and its receptors varies over the entire period of 48 hours after irradiation. The protein expression of the chemokines CXCL1 and CXCL12 corresponded well with the mRNA expression. In summary, irradiation of squamous cell carcinoma of the head and neck (SCCHN) and normal tissue cells caused a radiation-induced change of gene expression of the chemokine and its receptors. The results of this analysis show the complexity of the topic, so further studies will be needed to fully understand the influence of chemokines and chemokine receptors and their effect under a treatment of squamous cell carcinoma of the head and neck.
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Objective
To explore the clinical value of combined application of bone imaging and prostate specific antigen(t-PSA), free prostate specific antigen(f-PSA) and alkaline phosphatase(ALP) in the diagnosis and treatment of prostate cancer bone metastasis.
Methods
The data of 372 patients diagnosed of prostate cancer were reviewed, and the results of the whole body bone scan and t-PSA, f-PSA, ALP were analyzed retrospectively.
Results
282 cases in 372 cases of prostate cancer were diagnosed as bone metastasis.The t-PSA, f-PSA and ALP of prostate cancer patients with metastasis were significantly higher than those of prostate cancer patients without metastasis, the difference was statistically significant (P<0.05). The sensitivity of bone imaging in the diagnosis of bone metastases was 91.84%, the specificity was 76.67%, the accuracy was 88.17%, the positive predictive value was 92.50%, the negative predictive value was 75.00%.The combined application of bone scan and serum t-PSA, f-PSA, ALP detection, the sensitivity of the diagnosis of bone metastasis of prostate cancer was 95.71%, specificity was 87.69%, accuracy was 94.36%, the positive predictive value was 87.56%, the negative predictive value was 92.22%.
Conclusion
Combined application of whole body bone scan and serum t-PSA, f-PSA, ALP detection has high sensitivity and accuracy in diagnosis of bone metastasis of prostate cancer, and it can provide reliable basis for early diagnosis, treatment and prognosis of prostate cancer.
Key words:
Prostate neoplasm; Prostate specific antigen; Free prostate specific antigen; Alkaline phosphatase; Bone metastasis
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In different tumour entities, expression of the chemokine receptor 4 (CXCR4) has been linked to tumour dissemination and poor prognosis. Therefore, we evaluated, if the expression of CXCR4 exerts similar effects in human hepatocellular carcinoma (HCC). Expression analysis and functional assays were performed in vitro to elucidate the impact of CXCL12 on human hepatoma cells lines. In addition, expression of CXCR4 was evaluated in 39 patients with HCC semiquantitatively and correlated with both, tumour and patients characteristics. Human HCC and hepatoma cell lines displayed variable intensities of CXCR4 expression. Loss of p53 function did not impact on CXCR4 expression. Exposure to CXCL12 mediated a perinuclear translocation of CXCR4 in Huh7/Hep3B cells and increased the invasive potential of Huh7 cells. In HCC patients, CXCR4 expression significantly correlated with progressed local tumours (T-status; P=0.006), lymphatic metastasis (N-status; P=0.005) and distant dissemination (M-status; P=0.009), as well as with a decreased 3-year-survival rate (P=0.01). In summary, strong expression of CXCR4 is significantly associated with progressed hepatocellular cancer.
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The chemokine receptors CCR5 and CXCR4 are the main coreceptors of the macrophage-tropic and T-cell- tropic HIV-1 strains, respectively. CCR5 antagonists (such as TAK-779 and SCH-C) and CXCR4 antagonists (such as AMD3100 and T22) can block HIV-1 entering their target cells by binding to CCR5 and CXCR4, respectively. The mechan- isms of HIV-1 binding to these two coreceptors and progress of research and development of the coreceptor antagonists are reviewed.
CCR5 receptor antagonist
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