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Antibody drug conjugations (ADCs) are a new class of drugs with both targeted specificity and high activity of chemotherapy drugs, which has gradually become a novel generation of therapeutic models with great clinical application prospects. In recent years, ADCs composed of monoclonal antibodies against different tumor cell surface antigens and small molecule potent cytotoxic drugs have shown superior therapeutic effects on recurrent / metastatic breast cancer. This article reviews the clinical application and research progress of ADCs with different molecular targets in the field of breast cancer.
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Triple negative breast cancer (TNBC) is a highly aggressive subtype of breast cancer that is characterized by the lack of estro-gen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER-2), thereby making it difficult to treat. Owing to the aggressive clinical behavior of TNBC and the lack of recognized molecular targets for therapy, patients with TNBC have shown poorer outcomes than those with other subtypes of breast cancer. Chemotherapy is the primary established systemic treatment for TNBC. However, various novel therapeutic targets have come into focus with the advances in molecular characterization of TNBC. In recent years, several targeted drugs have undergone clinical trials and have shown certain curative effects with relatively mild adverse reactions. The Food and Drug Administration has approved some of these drugs. In the current review, we have summa-rized the advances in the targeted therapy of TNBC.
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Objective@#To investigate the effect and its mechanism of human trophoblast cell-surface antigen 2 (Trop2) gene expression was inhibited in squamous cell carcinoma of tongue on the proliferation and apoptosis of cancer cells.@*Methods@#A total of 46 patients from February 2014 to May 2016 received radical treatment of tongue cancer from oral and maxillofacial surgery of the First Affiliated Hospital of Zhengzhou University were enrolled in this study. Real time PCR and Western blotting were used to detect mRNA and protein expression of Trop2 in tongue squamous cell carcinoma and corresponding adjacent tissues; NC-siRNA and Trop2-siRNA were transfected into human tongue squamous cell carcinoma CAL-27 cells, a blank control group (control) was set, the expression of Trop2, Ki-67, cyclin D1, cleaved caspase3, Notch1, Hes1 protein after transfected for 48 h were detected by Western bloting; cell proliferation was detected by cell counting kit-8; cell cycle and apoptosis rate were detected by flow cytometry.@*Results@#The mRNA (5.72±1.13) and protein expression (0.77±0.06) of Trop2 gene in tongue squamous cell carcinoma were significantly higher than those in adjacent tissues (0.92±0.15, 0.11±0.01, P<0.05); Trop2 protein expression after transfeced Trop2-siRNA (0.08±0.01) in CAL-27 cells decreased significantly (0.46±0.05); the survival rate (64.28±4.12)%, S cells (14.54±1.02)% and Ki-67 (0.12±0.01), cyclin D1 (0.04±0.01) protein expression in Trop2-siRNA group were significantly lower than those in control group [(100.00±1.02)%, (27.33±1.11)%, (0.24±0.02), (0.20±0.02)] and NC-siRNA group [(96.55±2.43)%, (26.67±1.23)%, (0.26±0.03), (0.21±0.024)], the apoptosis rate (23.55±1.45)%, G0/G1 cells (72.32±0.94)% and the expression of cleaved caspase 3 (0.16±0.02), Notch1 (0.62±0.06) and Hes1 (0.50±0.05) protein were significantly higher than control group and NC-siRNA group (P<0.05).@*Conclusions@#The expression of Trop2 gene was inhibited in tongue squamous carcinoma cells can reduce the proliferation of cancer cells, block the cells in phase G1, and promote the apoptosis of cells. The mechanism is related to the up regulation of Notch1 signaling pathway.
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BACKGROUND: Trophoblast antigen 2 (TROP2) is a human trophoblast cell-surface glycoprotein that is overexpressed in several types of epithelial cancers, and is suggested to be associated with an unfavorable prognosis. BRAF mutations are the most common genetic alteration in papillary thyroid carcinoma (PTC). We evaluated the correlation between TROP2 expression and BRAF mutation in PTC. METHODS: First, we carried out pyrosequencing for BRAF mutations and immunohistochemistry for TROP2 expression with a tissue microarray consisting of 52 PTC cases. Membranous staining in at least 5% of tumor cells was designated as positive staining and we analyzed the relationship between TROP2 expression and diverse clinicopathological factors, including BRAF mutation. Second, we tested TROP2 mRNA expression in three thyroid cancer cell lines with BRAF mutations (BCPAP, SNU790, and 8505C) and a normal thyroid cell line. Additionally, we checked TROP2 protein levels in a normal thyroid cell line after introduction of the BRAF V600E mutation. RESULTS: In this study, 21 of 26 cases with BRAF mutation showed TROP2 immunoreactivity, whereas all 26 cases without BRAF mutation showed no immunoreactivity for TROP2 with a statistically significant difference (p<.001). Upregulation of TROP2 mRNA was observed in all three thyroid cancer cell lines, but not in the normal thyroid cell line. Interestingly, however, the TROP2 expression was increased in the normal thyroid cell line after introduction of the BRAF V600E mutation. CONCLUSIONS: Based on these results, we concluded that TROP2 expression is significantly associated with BRAF mutation and that TROP2 immunohistochemistry could be used for predicting BRAF mutations or diagnosing papillary thyroid carcinoma.
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Humans , Cell Line , Glycoproteins , Immunohistochemistry , Prognosis , RNA, Messenger , Thyroid Gland , Thyroid Neoplasms , Trophoblasts , Up-RegulationABSTRACT
Objective To gain the virus like particles (VLPs) based on Trop2 targets ,which provided the basis for further in vi‐vo induced experiments and anti‐tumor vaccine studies .Methods Using molecular cloning method to constract eukaryotic expres‐sion vector of pCAGGs/Trop2 and baculovirus expression vector of pFastbac1/Trop2 ,expression product of pCAGGs/Trop2 in HeLa cells were intended to be to be anchored to the cell membrane by the methods of Immunohistochemistry ;pFastbac1/Trop2 were transformed into E .coliDH10bac isolates to gain recombinant bacmids ,which were transfected into insect cells to express re‐combinant baculovirus with Gag rBV ,then sucrose density gradient centrifugation ,Western Blot and electron microscope were per‐formed to purify and identify the Trop2 VLPs .Results Building recombinant bacmids which were transfected into insect cells to express recombinant baculovirus with Gag rBV ,gained the recombinant Virus like Particles .Conclusion Trop2 VLPs was success‐fully prepared ,which laid the foundation for the subsequent induction of humoral and cellular immune response .
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Objective To explore the effect of TNF-αon expression of TROP-2 and to explore the role of TROP-2 in the metastasis and invasion of colon cancer HCT-116 cells. Methods HCT-116 cells were cultured and treated with 0, 10, 20, 30, 50, 100 and 200μg/L TNF-α. Cell viability was assessed by MTT. The expression of TROP-2 was determined by western blot. The effects of 20μg/L TNF-αon cell migration and invasion were investigated by wound healing assay and Transwell method. Small interfering RNA (siRNA) was used to knock down endogenous TROP-2 expression. The transcrip?tion and translation levels of TROP-2 were detected by qPCR and Western blot respectively. The migratory and invasive ca?pability of HCT-116 cells transfected with TROP-2 siRNA were checked by wound healing assay and Transwell method re?spectively. Results There is no significant change of cell viability between HCT-116 cells treated with 0,10, 20, 30 and 50μg/L TNF-α, but cell viability of HCT-116 decreased significantly with treatment of 100μg/L and 200μg/L TNF-α. Low concentration of TNF-α(≤50μg/L) led to increase of TROP-2 protein expression that peaks when 20μg/L TNF-αwas add?ed. High concentration of TNF-α(100, 200μg/L) result in decrease of TROP-2 protein. TROP-2 siRNA significantly down-regulated the expression of TROP-2 at both mRNA and protein levels in colon cancer HCT-116 cells. Compared with con?trol group, silencing TROP-2 by TROP-2 siRNA inhibited the migratory and invasive capability of HCT-116 cells. Wound healing rate and the number of transwell cell both decreased in siRNA group compared with those of control group ( P <0.05). Conclusion The mechanism that low concentration of TNF-α promoted HCT-116 cells migration and invasion might be through up-regulating the expression of TROP-2.
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TROP2 (trophoblastic cell surface protein 2),a cell-surface glycoprotein,is named after its high expression only in trophoblast cells.Recent studies found that TROP2 protein is overexpressed in a variety of human epithelial cancers,and it is associated with the prognosis.However,the mechanism is still not clear.
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Objective To investigate the role of TROP2 in migration and invasion of human gastric cancer cells. Methods Small interfering RNA(siRNA) targeting TROP2 gene was constructed by gene cloning and transfection into gastric cancer cell line BGC-823. The expression of mRNA and protein were detected by Real-time quantitative PCR and Western blot assay after RNA interference. The proliferation was determined by MTT assay. Transwell assay was performed to assess the effect of TROP2 targeted RNA interference on the migratory and invasive properties of gastric cancer in vitro. Results Enzyme digestion analysis and DNA sequencing showed that TROP2 targeted RNA interference recombinant plasmids were successfully constructed. The most effective recombinant plasmid was selected. After transfection, knockdown of TROP2 significantly inhibited the proliferation, migration and invasion of BGC-823 cells in vitro(P <0. 05). Conclusion Interfering and down-regulating TROP2 gene can inhibit migration and invasion of gastric cancer cell line BGC-823 in vitro, indicating that TROP2 gene is a potential target for gastric cancer gene therapy.