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Objective To investigate the expression of substance P ( SP) and neurokinin-1 recep-tor (NK1R) in patients with breast cancer and to further understand the correlations of them with the clinico-pathological features and the prognosis of breast cancer.Methods SP levels in serum samples and superna-tants of breast cell culture were measured by ELISA.The expression of total NK1R, full-length NK1R (NK1R-FL) and truncted NK1R (NK1R-Tr) in 82 patients with breast cancer and 30 patients with breast hyperplasia were detected by using immunohistochemistry and Western blot.Results The levels of SP in patients with breast cancer were higher than those in patients with breast hyperplasia and healthy subjects ( P0.05).Conclusion The invasion and metastasis of breast cancer showed a negative cor-relation with the expression of NK1R-FL, but a positive correlation with the expression of NK1R-Tr and SP.
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Objective To investigate the significance of abnormal gene in histologically normal mammary epithelial tissue for the early diagnosis of breast cancer. Methods Microarray technology was used to identify abnormal gene expres-sion and analyzed bioinformatics of normal mammary epithelial tissue in breast cancer patients and healthy normal control to establish a model for early diagnosis of breast cancer. The differentially expressed genes were screened by using signal path-way enrichment analysis. The accuracy (Ac), sensitivity (Sn) and specificity (Sp) were used to measure the prediction accura-cy of the different methods. Results The best prediction model was derived from the combination of differential genes en-riched from KEGG and BioCarta database. The number of differential expressed genes in three random created prediction models was reduced from 22 to 7, 14 to 3 and 18 to 4. However, the prediction accuracy was consistent with the model estab-lished from all of the differentially expressed genes, and the average accuracy of all models was 96.3%. Conclusion The prediction model can be simplified with the prediction accuracy unchanged, and thus facilitate the model apply to early diag-nosis and prevention of breast cancer.
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Objective: This study aimed to examine the number of activated circulating endothelial cells (aCECs) in the peripheral blood of patients with non-small cell lung cancer (NSCLC), and investigate the relationship among aCECs, anti-angiogenic therapy, and prognosis of NSCLC patients. This study also aimed to identify novel predictive markers for anti-angiogenic therapy, and provide basic data and experimental basis for establishing an evaluation system for this therapy. Methods: A total of 142 NSCLC patients were randomly divided into the chemotherapy group (Group 1) and combined therapy group (i.e., chemotherapy plus endostatin, Group 2). The number of aCECs was measured using flow cytometry by detecting the expression status of CD105 and CD146 in the peripheral blood. The correlation between the changes in aCECs and efficacy of drug treatment was statistically analyzed using SPSS software. Results:The number of aCECs in Group 2 increased significantly at 8 and 29 d, two cycles, 50 and 71 d, and four cycles after treatment, respectively (P<0.05). In particular, aCECs amount in cases of progressive disease increased more significantly after combined therapy (P<0.05). A negative correlation was found between the treatment cycle and difference in aCECs amount before and after therapy (r=-0.970, P=0.001). A negative correlation was also observed between the difference in aCECs amount and time to tumor progression (TTP) (r=-0.351, P=0.039). Therefore, the difference in aCECs amount before and after therapy could serve as an important predictor for TTP in NSCLC patients. Conclusion:CD105 and CD146 reflected the activation status of endothelial cells, and responded to the drug treatment. Thus, CD105 and CD146 could act as ideal markers for aCECs. The number of aCECs increased during cancer progression, but significantly decreased after long-term treatment. Therefore, the change in aCECs amount may be a useful marker in predicting the efficacy of anti-angiogenic therapy.
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Tissue factor pathway inhibitor-2 (TFPI-2), a member of the Kunitz-type family, is a broad-spectrum serine proteinase inhibitor. The expression of TFPI-2 is inversely related to increasing degree of malignancy, suggesting a role of TFPI-2 in the mainte-nance of tumor stability and inhibition of the growth of neoplasma. Aberrant methylation of TFPI-2 promoter cytosine-phosphorothio-ate-guanine (CpG) islands has been widely documented to be responsible for diminished expression of TFPI-2 mRNA and protein dur-ing cancer progression. TFPI-2 expression is significantly up-regulated by the ERK1/2 and JNK signaling pathways and modestly in-creased by VEGF, TNF-alpha, and fibroblast growth factor in time-and dose-dependent manners. TFPI-2 can maintain the stability of the tumor environment and inhibit invasiveness and growth of neoplasms. TFPI-2 has also been shown to regulate proliferation, apopto-sis, and vasculogenic mimicry of tumor cells, which may contribute significantly to tumor growth inhibition. Restoration of TFPI-2 ex-pression in tumor tissue inhibits tumor growth and metastasis, which creates a novel possibility of cancer patient treatment. This review focuses on the expression and the molecular regulation mechanisms of TFPI-2 in malignant tumors that control the functions of TFPI-2 in proliferation, apoptosis, and angiogenesis. Insight into these processes will improve our understanding of TFPI-2 and provide new ap-proaches for rational treatment strategies.
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<p><b>OBJECTIVE</b>To investigate the expression of apoptotic regulator c-FLIP(L) in invasive breast carcinoma tissues, and to evaluate its correlation with molecular subtyping and clinical prognosis.</p><p><b>METHODS</b>Immunohistochemistry using EnVision staining for c-FLIP(L) was performed in 264 cases of invasive breast carcinomas and matched adjacent normal breast tissue samples from January 1996 to December 1999. ER, PR, HER2, Ki-67, CK5/6 and EGFR were evaluated by immunohistochemistry in order to classify the tumors into five molecular subtypes and the difference of c-FLIP(L) expression in these molecular subtypes was also analyzed. The influence of c-FLIP(L) expression on prognosis was evaluated by Kaplan-Meier curves and multi-factor Cox proportional risk model.</p><p><b>RESULTS</b>High expression of c-FLIP(L) was observed in 84.5% (223/264) of cases of invasive breast carcinomas which were significantly higher than the 45.1% (119/264) of cases in adjacent normal epithelium of breast (χ² = 89.78, P = 0.000). The expression of c-FLIP(L) in luminal B (HER2 positive) and basal-like breast cancers was 78.1% (25/32) and 46.2% (18/39), respectively, with significant difference (P < 0.05). Moreover, the expression of c-FLIP(L) in luminal B (HER2 positive) was higher than in luminal A cancers (P < 0.05), and the expression of c-FLIP(L) in HER2 positive cancers was higher than in basal-like cancers (P < 0.01). C-FLIP(L) showed deep yellow staining in node positive breast cancer with a high-expression rate of 93.1% (134/144); whereas the expression was sporadic and light yellow in node negative breast cancer with a lower high-expressed rate of 72.5% (87/120, P < 0.01). C-FLIP(L) expression had significant influence on disease-free survival time, with c-FLIP(L)-positive patients showing poor prognosis (P < 0.01). Multi-factor Cox proportional risk model analysis showed that expression of c-FLIP(L), lymph nodes status and molecular subtypes were independent prognostic factors for invasive breast carcinomas (P < 0.05).</p><p><b>CONCLUSIONS</b>C-FLIP(L) is highly expressed in invasive breast carcinomas, and its expression level is closely related to the molecular subtypes and clinical prognosis of breast cancer patients. Thus, c-FLIP(L) could be used as an important tumor marker for personalized cancer therapy and prognostic prediction.</p>
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Aged , Female , Humans , Biomarkers, Tumor , Metabolism , Breast , Metabolism , Breast Neoplasms , Classification , Metabolism , Mortality , CASP8 and FADD-Like Apoptosis Regulating Protein , Metabolism , Disease-Free Survival , Immunohistochemistry , Prognosis , Receptor, ErbB-2 , MetabolismABSTRACT
Cellular Fas-associated death domain-like interleukin-1β-converting enzyme inhibitory protein (c-FLIP) belongs to the death effector domain superfamily, which is important in regulating apoptosis and proliferation. c-FLIP inhibits the extrinsic recep-tor-mediated apoptotic pathways and intrinsic mitochondrial apoptotic pathways through competition with caspase-8 for recruitment to Fas-associated death domain protein. Moreover, the cleavage products (i.e., p43-FLIP fragment and p22-FLIP fragment) directly acti-vate NF-κΒ, Erk survival signaling, and other non-apoptotic signaling pathways. The c-FLIP (L) can function either as an anti-apoptotic molecule, in a way analogous to c-FLIP (S) and c-FLIP (R), or as a pro-apoptotic molecule to facilitate the activation of caspase-8 at the death-induced signaling complex. The identified dual functionality of c-FLIP depends on various factors, including its expression level, interaction with caspase-8, and its subcellular localization. c-FLIP is frequently over-expressed in many different tumor types, and con-tributes to tumor cell immune surveillance, chemotherapy resistance, and apoptosis-resistance induced by TNFα, TRAIL, and FasL. Fur-thermore, c-FLIP is essential in obtaining aggressive biological behaviors, and is useful in predicting the prognosis of patients with vari-ous malignant tumors. This review focuses on the molecular mechanisms that control the dual regulation of c-FLIP in life/death deci-sion at death-induced signaling complex. Increasing evidence supports the function of c-FLIP as a tumor therapeutic marker to restore an apoptotic response for TRAIL therapy in cancers. Insight into these processes will improve our understanding of apoptosis, and pro-vide new approaches for rational treatment strategies.
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Objective To evaluate a therapeutic strategy using aromatase inhibitors and TAM in postmenopausal Luminal B breast cancer patients. Methods The clinical data of 733 primary breast cancer cases receiving postoperative endocrine thempy from July 2002 to Mar 2005 in Tianjin Cancer Hospital were retrospectively analyzed.Diagnosis was confirmed by pathology in all the cases.All patients were post-menopausal and ER-positive.501 patients were given tamoxifen(TAM 2.5 mg qd,po),232 patients were given aromatase inhibitors(Letrozole 10 mg bid,po).The follow-up time ranged from 36 to 90 months.Median follow-up time was 46 months.Results The disease-free-survival(DFS)rate of Luminal B breast cancer patients in aromatase inhibitors(AIS)group was higherthan that in TAM group(90.6% vs.88.6%,P=0.038).In TAM group,subgroup analysis showed 3-year DFS of node-positive with HER2(+)is lower than that of node-positive with Her-2-negative(88.2% vs.90.4%,P=0.037);3-year DFS of ER+/PR+ group in HER2(+) patients was higher than that of ER+/PR-group(90.8% vs.89.5%.P=0.032).In AIs group,in spite of the axillary lymph node status,there was no significant difference of 3-year DFS between HER2(+)patients and HER2(-)ones(P>0.05).3-year DFS of ER+/PR+with HER2(+) patients was higher than that of ER+/PR-ones with HER2(+)(91.9% vs.90.5%,P=0.029).Hot flush,vaginal bleeding and thromboembolics in AIS group is less frequent,but muscle pain and bone fracture is more common than that in TAM group(P<0.05).Conclusion Compared to TAM, AIs is more effective and safer with postmenopausal Luminal B patients,and the effect is independent on node stams.