Breast cancer is the most frequently diagnosed cancer in women under 60, and the second most diagnosed cancer in women over 60. While significant </span><span style="font-family:Verdana;">progres...Breast cancer is the most frequently diagnosed cancer in women under 60, and the second most diagnosed cancer in women over 60. While significant </span><span style="font-family:Verdana;">progress has been made in developing targeted therapies for breast cancer,</span> <span style="font-family:Verdana;">advanced breast cancer continues to have high mortality, with poor 5-year</span> <span style="font-family:Verdana;">survival rates. Thus, current therapies are insufficient in treating advanced</span><span style="font-family:Verdana;"> stages of breast cancer;new treatments are sorely needed to address the complexity of advanced-stage breast cancer. Oncolytic virotherapy has been explored as a therapeutic approach capable of systemic administration, targeting cancer cells, and sparing normal tissue. In particular, oncolytic adenoviruses have been exploited as viral vectors due to their ease of manipulation, production, and demonstrated clinical safety profile. In this study, we engineered an oncolytic adenovirus to target the chemokine receptors CXCR4 and CXCR7. The overexpression of CXCR4 and CXCR7 is implicated in the initiation, survival, progress, and metastasis of breast cancer. Both receptors bind to the ligand, CXCL12 (SDF-1), which has been identified to play a crucial role in the metastasis of breast cancer cells. This study incorporated a T4 fibritin protein fused to CXCL12 into the tail domain of an adenovirus fiber </span><span style="font-family:Verdana;">to retarget the vector to the CXCR4 and CXCR7 chemokine receptors. We</span> <span style="font-family:Verdana;">showed that the modified virus targets and infects CXCR4- and CXCR7-</span><span style="font-family:Verdana;">overexpressing breast cancer cells more efficiently than a wild-type control</span><span style="font-family:Verdana;"> vector. In addition, the substitution of the wild-type fiber and knob with the modified chimeric fiber did not interfere with oncolytic capability. Overall, the results of this study demonstrate the feasibility of retargeting adenovirus vectors to chemokine receptor-positive tumors.展开更多
OBJECTIVE To investigate whether CXCL12 and its receptor, CXCR7, play a role in lung cancer invasion and metastasis. METHODS Western blot and immunocytochemistry were used to detect CXCR7 protein expression in 8 lung ...OBJECTIVE To investigate whether CXCL12 and its receptor, CXCR7, play a role in lung cancer invasion and metastasis. METHODS Western blot and immunocytochemistry were used to detect CXCR7 protein expression in 8 lung cancer cell lines, EKVX, HOP62, HOP92, NCI-H23, NCI-H226, NCI- H322M, NCI-H446, and A549, and cell migration experiment was conducted to observe mobility of the lung cancer cells. The concentration of intracellular calcium in cytoplasm was measured under the fluorescence microscopy. RESULTS CXCR7 protein was positively expressed in the 8 lung cancer cell lines EKVX, HOP62, HOP92, NCI-H23, NCI-H226, NCI- H322M, NCI-H446, and A549. Following CXCL12 stimulation, obvious pseudopodia of lung cancer cells was observed under the microscope. The cell migration experiment showed that after incubation with CXCL12, the number of EKVX cells, which passed through the polycarbonate microporous filter membranes increased to a great extent. This phenomenon can be reversed by CXCR7-siRNA. After CXCL12 incubation, the intracellular Ca2＋ level in the EKVX cells was increased to a great extent. CONCLUSION Chemokine CXCL12 facilitates the migration of lung cancer cells by changing the concentration of intracellular Ca2＋. The CXCL12-CXCR7 axis may play an important role in lung cancer invasion and metastasis. It could be a potential target for lung cancer therapy and an effective way to prevent recurrence and metastasis of lung cancer.展开更多
Background: Recent studies indicate that C-X-C motif chemokine receptor 4(CXCR4) and its ligand, C-X-C motif chemokine ligand 12(CXCL12), stimulate expression of the cell cycle regulatory protein Cyclin D1 in neurofib...Background: Recent studies indicate that C-X-C motif chemokine receptor 4(CXCR4) and its ligand, C-X-C motif chemokine ligand 12(CXCL12), stimulate expression of the cell cycle regulatory protein Cyclin D1 in neurofibromatosis 1-associated malignant peripheral nerve sheath tumor(MPNST) cells and promote their proliferation. In this study, we measured the expression of CXCR4, CXCL12, and Cyclin D1 proteins in sporadic MPNST tissues from Chinese patients and investigated their prognostic values.Methods: CXCR4, CXCL12, and Cyclin D1 protein expression in samples from 58 Chinese patients with sporadic MPNST was assessed with immunohistochemical staining.Their prognostic values were evaluated with Kaplan-Meier analysis and a log-rank test. Multivariate Cox regression analysis was used to identify independent prognostic factors.Results: High expression of CXCR4, CXCL12, and Cyclin D1 was observed in 19(32.8%), 32(55.2%), and 16(27.6%)samples, respectively. CXCR4 expression was positively correlated with CXCL12 expression(r = 0.334, P = 0.010) and Cyclin D1 expression(r = 0.309, P = 0.018). Patients with high CXCR4 expression showed longer overall survival than those with low CXCR4 expression(χ~2 = 4.642, P = 0.031).Conclusion: High CXCR4 expression may define a specific subtype of sporadic MPNST with favorable prognosis.展开更多
文摘Breast cancer is the most frequently diagnosed cancer in women under 60, and the second most diagnosed cancer in women over 60. While significant </span><span style="font-family:Verdana;">progress has been made in developing targeted therapies for breast cancer,</span> <span style="font-family:Verdana;">advanced breast cancer continues to have high mortality, with poor 5-year</span> <span style="font-family:Verdana;">survival rates. Thus, current therapies are insufficient in treating advanced</span><span style="font-family:Verdana;"> stages of breast cancer;new treatments are sorely needed to address the complexity of advanced-stage breast cancer. Oncolytic virotherapy has been explored as a therapeutic approach capable of systemic administration, targeting cancer cells, and sparing normal tissue. In particular, oncolytic adenoviruses have been exploited as viral vectors due to their ease of manipulation, production, and demonstrated clinical safety profile. In this study, we engineered an oncolytic adenovirus to target the chemokine receptors CXCR4 and CXCR7. The overexpression of CXCR4 and CXCR7 is implicated in the initiation, survival, progress, and metastasis of breast cancer. Both receptors bind to the ligand, CXCL12 (SDF-1), which has been identified to play a crucial role in the metastasis of breast cancer cells. This study incorporated a T4 fibritin protein fused to CXCL12 into the tail domain of an adenovirus fiber </span><span style="font-family:Verdana;">to retarget the vector to the CXCR4 and CXCR7 chemokine receptors. We</span> <span style="font-family:Verdana;">showed that the modified virus targets and infects CXCR4- and CXCR7-</span><span style="font-family:Verdana;">overexpressing breast cancer cells more efficiently than a wild-type control</span><span style="font-family:Verdana;"> vector. In addition, the substitution of the wild-type fiber and knob with the modified chimeric fiber did not interfere with oncolytic capability. Overall, the results of this study demonstrate the feasibility of retargeting adenovirus vectors to chemokine receptor-positive tumors.
文摘OBJECTIVE To investigate whether CXCL12 and its receptor, CXCR7, play a role in lung cancer invasion and metastasis. METHODS Western blot and immunocytochemistry were used to detect CXCR7 protein expression in 8 lung cancer cell lines, EKVX, HOP62, HOP92, NCI-H23, NCI-H226, NCI- H322M, NCI-H446, and A549, and cell migration experiment was conducted to observe mobility of the lung cancer cells. The concentration of intracellular calcium in cytoplasm was measured under the fluorescence microscopy. RESULTS CXCR7 protein was positively expressed in the 8 lung cancer cell lines EKVX, HOP62, HOP92, NCI-H23, NCI-H226, NCI- H322M, NCI-H446, and A549. Following CXCL12 stimulation, obvious pseudopodia of lung cancer cells was observed under the microscope. The cell migration experiment showed that after incubation with CXCL12, the number of EKVX cells, which passed through the polycarbonate microporous filter membranes increased to a great extent. This phenomenon can be reversed by CXCR7-siRNA. After CXCL12 incubation, the intracellular Ca2＋ level in the EKVX cells was increased to a great extent. CONCLUSION Chemokine CXCL12 facilitates the migration of lung cancer cells by changing the concentration of intracellular Ca2＋. The CXCL12-CXCR7 axis may play an important role in lung cancer invasion and metastasis. It could be a potential target for lung cancer therapy and an effective way to prevent recurrence and metastasis of lung cancer.
基金supported by the National Nature Science Foundation of China(81372872 to Jilong Yang,81672650 to Ze Zhu,and 81402215 to Xiaoling Du)funds from the University Cancer Foundation via the Sister Institution Network Fund(to Jilong Yang)
文摘Background: Recent studies indicate that C-X-C motif chemokine receptor 4(CXCR4) and its ligand, C-X-C motif chemokine ligand 12(CXCL12), stimulate expression of the cell cycle regulatory protein Cyclin D1 in neurofibromatosis 1-associated malignant peripheral nerve sheath tumor(MPNST) cells and promote their proliferation. In this study, we measured the expression of CXCR4, CXCL12, and Cyclin D1 proteins in sporadic MPNST tissues from Chinese patients and investigated their prognostic values.Methods: CXCR4, CXCL12, and Cyclin D1 protein expression in samples from 58 Chinese patients with sporadic MPNST was assessed with immunohistochemical staining.Their prognostic values were evaluated with Kaplan-Meier analysis and a log-rank test. Multivariate Cox regression analysis was used to identify independent prognostic factors.Results: High expression of CXCR4, CXCL12, and Cyclin D1 was observed in 19(32.8%), 32(55.2%), and 16(27.6%)samples, respectively. CXCR4 expression was positively correlated with CXCL12 expression(r = 0.334, P = 0.010) and Cyclin D1 expression(r = 0.309, P = 0.018). Patients with high CXCR4 expression showed longer overall survival than those with low CXCR4 expression(χ~2 = 4.642, P = 0.031).Conclusion: High CXCR4 expression may define a specific subtype of sporadic MPNST with favorable prognosis.
