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1.
Yayoi Adachi Mayumi Yoshimura Keiko Nishida Hisanobu Usuki Keiko Shibata Masaya Hattori Naoto Kondo Yasushi Yatabe Hiroji Iwata Toyone Kikumori Yasuhiro Kodera Hayao Nakanishi 《Breast cancer research and treatment》2018,167(2):439-450
Purpose
Circulating tumor cells (CTCs) can provide a potentially minimal invasive source for monitoring chemotherapeutic effects. However, detailed in vivo dynamics of CTC after chemotherapy remain largely unknown.Methods
We monitored CTC number and morphology early after chemotherapy using a newly developed cytology-based CTC detection device and triple-negative breast cancer mouse CTC models with spontaneous lung metastatic potential.Results
Paclitaxel inhibited cell growth of breast cancer cells by mainly G2/M cell cycle arrest and partly apoptosis, whereas doxorubicin inhibited cell growth mainly by apoptosis and partly G2 cell cycle arrest in vitro. The number of CTCs was significantly increased 3–10 days after paclitaxel and doxorubicin chemotherapy and decreased thereafter in two mouse CTC models. The transiently increased CTCs early post-chemotherapy consisted of not only G2/M arrested cells (apoptotic cells), but also morphologically near-intact live cells. This heterogeneous cell population of CTCs was similar to that of primary tumor tissue after chemotherapy.Conclusions
These results indicate that CTCs can be mobilized from the primary tumor in rapid response to chemotherapy and suggest the possibility that CTC monitoring from both numerical and morphological viewpoints early after chemotherapy using a cytology-based CTC detection device would be a useful diagnostic tool for predicting drug sensitivity/resistance in preclinical and clinical setting.2.
Purpose
Cisplatin is commonly used in non-small-cell lung cancer (NSCLC) chemotherapy; however, chemoresistance to cisplatin remains a great clinical challenge. Octamer-binding protein 4 (OCT4) has been reported to be overexpressed in NSCLC. In this study, we aimed to investigate the potential role of OCT4 in NSCLC with chemoresistance to cisplatin.Methods
Expressions of OCT4 was detected in NSCLC tissues and cell lines. We utilized siRNA to knock down OCT4 expression in human NSCLC cells and analyzed their phenotypic changes.Results
We found that the difference of OCT4 expression between NSCLC and the adjacent non-tumourous tissues was statistically significant. Knockdown of OCT4 in NSCLC cells could decrease cell proliferation, and potentiate apoptosis induced by cisplatin, suggesting OCT4 may contribute to cisplatin resistance in NSCLC.Conclusion
Our findings indicate that targeting OCT4 could improve cisplatin effect in NSCLC, confirming their role in modulating cisplatin sensitivity.3.
Purpose
Circulating tumor cells (CTCs) with epithelial-to-mesenchymal transition (EMT) phenotypes might be related to tumor progression while OCT4 expression is involved in tumor metastasis and poor prognosis. But the possible clinical significance of EMT phenotypes of CTCs from non-small-cell lung cancer (NSCLC) patients has still to be demonstrated. Furthermore, none has been investigated the expression of OCT4 in CTCs. We therefore identified the EMT phenotype-based subsets of CTCs and determined the OCT4 expression status of CTCs in NSCLC patients, to explore their possible clinical relevance.Methods
37 NSCLC patients and ten healthy volunteers were enrolled, respectively. The Canpatrol? CTC enrichment technique was used to isolate and identify the EMT phenotype-based subsets of CTCs. OCT4 expression in each CTC was also determined. Results were correlated with patients’ clinico-pathological features.Results
CTCs were detected in 33 of 37 (89.2%) NSCLC patients, and no CTCs were identified in ten healthy volunteers. Three CTCs phenotypes, including epithelial, biophenotypic, and mesenchymal CTCs were identified based on the expression of EMT markers. Mesenchymal CTCs were more commonly found in patients with distant metastasis. Patients with distant metastasis tended to have a higher median CTCs number. OCT4-positive was observed in 21 of 28 (75.0%) patients. High expression of OCT4 tended to occur in advanced patients as well as in distant metastatic patients.Conclusions
The findings suggest that identification of CTCs by EMT markers as well as evaluation of OCT4 expression status by assessment of OCT4 expression in CTCs could serve as potential adjuncts for evaluating metastasis and prognosis in NSCLC patients.4.
Yu-Lun Chen Tsung-Ying Yang Kun-Chieh Chen Chieh-Liang Wu Shih-Lan Hsu Chi-Mei Hsueh 《Cellular oncology (Dordrecht)》2016,39(5):411-433
Background
Non-small cell lung cancers (NSCLCs) frequently exhibit resistance to therapeutic drugs, which seriously hampers their treatment. Here, we set out to assess the roles of the multidrug resistance protein 1 (MRP1) and P-glycoprotein (P-gp) in the doxorubicin (DOX) resistance of NSCLC cells, as well as the putative therapeutic efficacy of MRP1 and P-gp blockers on DOX-treated NSCLC cells.Methods
The impact of DOX on cell survival, DOX efflux and MRP1 and P-gp expression was assessed in 5 different NSCLC-derived cell lines (parental CH27, A549, H1299, H460, and DOX resistant CH27) in the absence or presence of MK571 (MRP1 inhibitor) or Verapamil (P-gp inhibitor), under both normoxic and hypoxic conditions.Results
We found that in response to DOX treatment, NSCLC cells that express high levels of MRP1 and P-gp (such as CH27) showed a better DOX efflux and a higher DOX resistance. MK571 and Verapamil were found to abolish DOX resistance and to act as chemosensitizers for DOX therapy in all cell lines tested. We also found that hypoxia could inhibit MRP1 and P-gp expression in a HIF-1α-dependent manner, abolish DOX resistance and boost the chemosensitizer effect of MK571 and Verapamil on DOX treatment of all the NSCLC cells tested, except the DOX-resistant CH27 cells.Conclusions
From our data we conclude that MRP1 and P-gp play critical roles in the DOX resistance of the NSCLC cells tested. MRP1 and P-gp targeted therapy using MK571, Verapamil, CoCl2 or ambient hypoxia appeared to be promising in abolishing the DOX efflux and DOX resistance of the NSCLC cells. The putative therapeutic efficacies of MRP1 and/or P-gp blockers on NSCLC cells are worthy of note.5.
Background
Sialyltransferase I (ST6Gal-I) is an enzyme involved in tumor metastasis that processes sialic acid precursors into their mature form, enabling them to regulate gene expression. However, the effect of ST6Gal-I on the biological behavior of cancer cells remain unclear. This study was the first to demonstrate the influence of ST6Gal-I on cisplatin sensitivity in cervical cancer cells.Methods
Knockdown of ST6Gal-I was performed by shRNA and HeLa cells combination with cisplatin were tested.Results
We showed that down-regulation of ST6Gal-I promoted cell apoptosis and inhibited proliferation and invasion in cervical cancer cells. Knockdown of ST6Gal-I by RNA interference increased the sensitivity of HeLa cells to cisplatin in vitro, and reduced tumor volume and suppressed subcutaneous tumor growth in response to cisplatin treatment in a xenograft mouse model in vivo.Conclusions
The results provide new information that ST6Gal-I plays an important role in several biological or pathological processes including drug resistance in cervical cancer and may be a potential therapeutic target to improve the response to chemotherapy in cervical cancer patients.6.
Purpose of Review
To introduce recent progress on circulating tumor cell (CTC) research in colorectal cancer (CRC) and to highlight clinical application of CTCs from detection to assessment of treatment response.Recent Findings
CTC biological characteristics in CRC play an important role in the detection of CTCs. The in vitro culture of CTCs from CRC patients (cell lines and organoids) can potentially facilitate rapid drug testing and treatment prediction. CTC detection should be standardized with improved detection rate in CRC; further, clinical investigation is still needed to clarify its potential as a tool for early CRC detection, a predictive and prognostic marker to ultimately guide treatment.Summary
Gaining an improved understanding of CTCs characteristics and ultimately, integration of CTC detection and utilization of CTCs may lead to optimized tumor treatment and facilitate precision medicine.7.
Marcus Vetter Julia Landin Barbara Maria Szczerba Francesc Castro-Giner Sofia Gkountela Cinzia Donato Ilona Krol Ramona Scherrer Catharina Balmelli Alexandra Malinovska Alfred Zippelius Christian Kurzeder Viola Heinzelmann-Schwarz Walter Paul Weber Christoph Rochlitz Nicola Aceto 《Breast cancer research : BCR》2018,20(1):141
Background
The presence of circulating tumor cells (CTCs) in patients with breast cancer correlates to a bad prognosis. Yet, CTCs are detectable in only a minority of patients with progressive breast cancer, and factors that influence the abundance of CTCs remain elusive.Methods
We conducted CTC isolation and enumeration in a selected group of 73 consecutive patients characterized by progressive invasive breast cancer, high tumor load and treatment discontinuation at the time of CTC isolation. CTCs were quantified with the Parsortix microfluidic device. Clinicopathological variables, blood counts at the time of CTC isolation and detailed treatment history prior to blood sampling were evaluated for each patient.Results
Among 73 patients, we detected at least one CTC per 7.5 ml of blood in 34 (46%). Of these, 22 (65%) had single CTCs only, whereas 12 (35%) featured both single CTCs and CTC clusters. Treatment with the monoclonal antibody denosumab correlated with the absence of CTCs, both when considering all patients and when considering only those with bone metastasis. We also found that low red blood cell count was associated with the presence of CTCs, whereas high CA 15-3 tumor marker, high mean corpuscular volume, high white blood cell count and high mean platelet volume associated specifically with CTC clusters.Conclusions
In addition to blood count correlatives to single and clustered CTCs, we found that denosumab treatment associates with most patients lacking CTCs from their peripheral circulation. Prospective studies will be needed to validate the involvement of denosumab in the prevention of CTC generation.8.
Lowes LE Lock M Rodrigues G D'Souza D Bauman G Ahmad B Venkatesan V Allan AL Sexton T 《Clinical & translational oncology》2012,14(2):150-156
Introduction
Within 10 years of radical prostatectomy (RP), up to 30% of prostate cancer (PCa) patients will have a rise in prostate-specific antigen (PSA), requiring radiation therapy (RT). However, with current technology, distinction between local and distant recurrent PCa is not possible. This lack of an accurate test constrains the decision whether to offer systemic or local treatment. We hypothesise tests for detecting circulating tumour cells (CTCs) within the blood may assist with clinical decision-making and in this pilot study we investigated whether CTCs could be detected in this patient population using the CellSearch® system.Materials and methods
Blood samples were collected from PCa patients (n=26) prior to RT and 3 months following completion of RT. Samples were analysed for PSA level via immunoassay and CTC number using the CellSearch® system.Results
CTCs could be detected in this patient population and following RT CTCs appeared to decrease. However, no association was observed between a higher PSA and an increased number of CTCs pre- or post-RT. Interestingly, patients who failed RT trended toward an increased/unchanged number of CTCs following RT vs. a decreased number in patients with RT response.Conclusions
Our results demonstrate that CTCs can be detected in early-stage PCa and suggest the possibility that post-treatment reduction in CTC levels may be indicative of RT response. We are currently evaluating CTCs in a larger cohort of patients to validate our preliminary findings and further investigate the prognostic value of CTCs in this patient population.9.
Bo Hultman Haile Mahteme Magnus Sundbom Martin Ljungman Rolf Larsson Peter Nygren 《Journal of experimental & clinical cancer research : CR》2014,33(1):110
Background
The choice of drugs for treatment of advanced gastric cancer (GC) is empirical. The purpose of the current study was to benchmark ex vivo the sensitivity of GC tumor cells from patients to standard cytotoxic and some newly introduced targeted drugs (TDs), as a basis for drug selection in the treatment of GC.Methods
Tumor cell samples from patients with GC were analyzed for sensitivity to 5-fluorouracil, cisplatin, oxaliplatin, irinotecan, mitomycin C, doxorubicin and docetaxel as well as for the targeted drugs bortezomib, sorafenib, sunitinib and rapamycin using a short-term in vitro assay based on retention of viable tumor cells of fluorescent fluorescein. Samples of normal mononuclear cells, chronic lymphocytic leukemia, ovarian cancer and colorectal cancer were included for comparison.Results
The GC samples were essentially as sensitive to the standard drugs and the TDs as those from colorectal cancer whereas the ovarian cancer samples were more sensitive. The individual GC samples varied considerably in sensitivity to increasing concentrations of the clinically used standard drugs. In GC, cisplatin was cross-resistant to oxaliplatin and 5-fluorouracil which, on the other hand, was not cross-resistant to the other cytotoxic drugs. The activity of sunitinib did not obviously correlate to that of the standard drugs.Conclusion
Ex vivo assessment of drug sensitivity of tumor cells from patients with GC is feasible and may provide information that could be useful for selection of drugs for treatment. Drug sensitivity varies considerably between and within individual samples arguing for individualized selection of drugs for chemotherapy.10.
Purpose
Several studies have provided evidence on the prognostic relevance of circulating tumor cells (CTCs) detected before and after chemotherapy regarding overall survival (OS) and progression-free survival (PFS) in early breast cancer (EBC). We provide data on the prevalence of CTCs 2 and 5 years after primary diagnosis in a cohort of patients with EBC.Methods
The SUCCESS study is a multicenter, prospective, randomized trial comparing PFS in primary breast cancer patients undergoing one of two adjuvant chemotherapy regimens followed by 2 versus 5 years of treatment with zoledronate. CTCs from patients without signs of breast cancer recurrence were analyzed in peripheral blood using the FDA cleared CellSearch® System (Veridex, USA) 2 and 5 years after primary diagnosis.Results
CTCs were detected at 2 and 5 years after primary diagnosis in 96 (16.7%) and 47 (8.2%) of the 574 patients, respectively. There were no associations between CTC status and patient and tumor characteristics or treatment regimens. In 442 (77.0%) patients, no CTCs were detected at either of the two time points, and in 11 patients (1.9%), CTCs were found at both 2 and 5 years after primary diagnosis. In 85 (14.8%) patients, CTCs were present 2 years after primary diagnosis but not after 5 years, while 36 (6.3%) patients had CTCs in their blood only at the 5-year follow-up.Conclusions
In patients with EBC, CTCs can be detected even 5 years after primary diagnosis without clinical signs of disease recurrence.11.
Q. Lv L. Gong T. Zhang J. Ye L. Chai C. Ni Y. Mao 《Clinical & translational oncology》2016,18(3):322-330
Objective
Metastatic breast cancer (MBC) remains the main cause of cancer-related death, and the clinical significance and prognostic role of circulating tumor cells (CTCs) in metastatic breast cancer are still controversial. Here, we conducted a meta-analysis to clarify the correlation between CTCs and the clinicopathological features and prognosis of MBC.Methods
We performed a comprehensive search of Pubmed and the ISI Web of Science through December 2014. Only articles that focused on MBC patients and detected CTCs using the CellSearch system were included. The associations between CTCs and survival rate and clinicopathological parameters, including molecular pattern, metastatic region and treatment response, were evaluated.Results
This meta-analysis included 24 studies (3701 MBC patients), 13 prospective studies and 11 retrospective studies. We found that CTCs were more frequently detected with HER2 + primary tumors (pooled RR = 0.73, 95 % CI = 0.63–0.84). Additionally, higher CTC numbers indicated a worse treatment response (RR = 0.56, 95 % CI = 0.40–0.79), poorer PFS (RR = 0.64, 95 % CI = 0.56–0.73) and poorer OS (RR = 0.69, 95 % CI = 0.64–0.75) in MBC patients.Conclusion
Based on these results, we propose that HER2 positivity could be a significant risk factor for the presence of CTCs. Additionally, CTCs have a significant prognostic value for MBC patients. Therefore, CTCs should be continually monitored to guide the treatment of MBC patients, especially those with HER2 + primary tumors.12.
Marzena Szwed Audrey Laroche-Clary Jacques Robert Zofia Jozwiak 《Cellular oncology (Dordrecht)》2016,39(2):107-118
Background
Doxorubicin (DOX) is a small molecular cytotoxic agent that can be transferred efficiently to cancer cells by nanocarriers. This anthracycline antibiotic serves as an effective anti-neoplastic drug against both hematological and solid malignancies. Here, we set out to assess the capacity of a novel doxorubicin - transferrin conjugate (DOX-TRF) to provoke apoptosis in human normal and leukemia cells through free radicals produced via a redox cycle of doxorubicin (DOX) when released from its conjugate.Methods
After DOX-TRF exposure, we determined the time-course of apoptotic and necrotic events, the generation of reactive oxygen species (ROS), changes in mitochondrial membrane potential, as well as alterations in cytochrome c levels and intracellular calcium concentrations in human leukemia-derived cell lines (CCRF-CEM, K562 and its doxorubicin-resistant derivative K562/DOX) and normal peripheral blood-derived mononuclear cells (PBMC).Results
We found that DOX-TRF can induce apoptosis in all leukemia-derived cell lines tested, which was associated with morphological changes and decreases in mitochondrial membrane potential. In comparison to free DOX treated cells, we observed a time-dependency between a higher level of ROS generation and a higher drop in mitochondrial membrane potential, particularly in the doxorubicin-resistant cell line. In addition, we found that the apoptotic cell death induced by DOX-TRF was directly associated with a release of cytochrome c from the mitochondria and an increase in intracellular calcium level in all human leukemia-derived cell lines tested.Conclusions
Our data indicate that DOX-TRF is considerably more cytotoxic to human leukemia cells than free DOX. In addition, we show that DOX-TRF can effectively produce free radicals, which are directly involved in apoptosis induction.13.
Briete Goorts Thiemo J. A. van Nijnatten Linda de Munck Martine Moossdorff Esther M. Heuts Maaike de Boer Marc B. I. Lobbes Marjolein L. Smidt 《Breast cancer research and treatment》2017,161(1):83-94
Purpose
Circulating tumor cell (CTC) is a well-established prognosis predictor for metastatic breast cancer (MBC), and CTC-cluster exhibits significantly higher metastasis-promoting capability than individual CTCs. Because measurement of CTCs and CTC-clusters at a single time point may underestimate their prognostic values, we aimed to analyze longitudinally collected CTCs and CTC-clusters in MBC prognostication.Methods
CTCs and CTC-clusters were enumerated in 370 longitudinally collected blood samples from 128 MBC patients. The associations between baseline, first follow-up, and longitudinal enumerations of CTCs and CTC-clusters with patient progression-free survival (PFS) and overall survival (OS) were analyzed using Cox proportional hazards models.Results
CTC and CTC-cluster counts at both baseline and first follow-up were significantly associated with patient PFS and OS. Time-dependent analysis of longitudinally collected samples confirmed the significantly unfavorable PFS and OS in patients with ≥5 CTCs, and further demonstrated the independent prognostic values by CTC-clusters compared to CTC-enumeration alone. Longitudinal analyses also identified a link between the size of CTC-clusters and patient OS: compared to the patients without any CTC, those with 2-cell CTC-clusters and ≥3-cell CTC-clusters had a hazard ratio (HR) of 7.96 [95 % confidence level (CI) 2.00–31.61, P = 0.003] and 14.50 (3.98–52.80, P < 0.001), respectively.Conclusions
In this novel time-dependent analysis of longitudinally collected CTCs and CTC-clusters, we showed that CTC-clusters added additional prognostic values to CTC enumeration alone, and a larger-size CTC-cluster conferred a higher risk of death in MBC patients.14.
15.
Nick Beije Jaco Kraan Michael A. den Bakker Alexander P.W.M. Maat Cor van der Leest Robin Cornelissen Ngoc M. Van John W.M. Martens Joachim G.J.V. Aerts Stefan Sleijfer 《Cellular oncology (Dordrecht)》2017,40(5):511-519
Purpose
There is a lack of robust and clinically utilizable markers for the diagnosis and prognostication of malignant pleural mesothelioma (MPM). This research was aimed at optimizing and exploring novel approaches to improve the diagnosis and prognostication of MPM in pleural effusions and peripheral blood samples.Methods
CellSearch-based and flow cytometry-based assays using melanoma cell adhesion molecule (MCAM) to identify circulating tumor cells (CTCs) in pleural effusions and peripheral blood samples of MPM patients were optimized, validated, explored clinically and, in case of pleural effusions, compared with cytological analyses. Additionally, tumor-associated circulating endothelial cells (CECs) were measured in peripheral blood samples. The assays were performed on a MPM cohort encompassing patients with histology-confirmed MPM (n=27) and in a control cohort of patients with alternative diagnoses (n=22). Exploratory analyses on the prognostic value of all assays were also performed.Results
The malignancy of MCAM-positive cells in pleural effusions from MPM patients was confirmed. The detection of MPM CTCs in pleural effusions by CellSearch showed a poor specificity. The detection of MPM CTCs in pleural effusions by flow cytometry showed a superior sensitivity (48%) to standard cytological analysis (15%) (p = 0.03). In peripheral blood, CTCs were detected in 26% of the MPN patients, whereas in 42% of the MPM patients tumor-associated CECs were detected above the upper limit of normal (ULN). In exploratory analyses the absence of CTCs in pleural effusions, and tumor-associated CECs in peripheral blood samples above the ULN, appeared to be associated with a worse overall survival.Conclusion
MCAM-based flow cytometric analysis of pleural effusions is more sensitive than routine cytological analysis. Flow cytometric analysis of pleural effusions and tumor-associated CECs in peripheral blood may serve as a promising approach for the prognostication of MPM patients and, therefore, warrants further study.16.
Anna Jakabova Zuzana Bielcikova Eliska Pospisilova Rafal Matkowski Bartlomiej Szynglarewicz Urszula Staszek-Szewczyk Milada Zemanova Lubos Petruzelka Petra Eliasova Katarina Kolostova Vladimir Bobek 《Breast cancer research and treatment》2017,166(3):695-700
Introduction
This study analyzes peripheral blood samples from breast cancer (BC) patients. CTCs from peripheral blood were enriched by size-based separation and were then cultivated in vitro. The primary aim of this study was to demonstrate the antigen independent CTC separation method with high CTC recovery. Subsequently, CTCs enriched several times during the treatment were characterized molecularly.Methods
Patients with different stages of BC (N = 167) were included into the study. All patients were candidates for surgery, surgical diagnostics, or were undergoing chemotherapy. In parallel, 20 patients were monitored regularly and in addition to CTC presence, also CTC character was examined by qPCR, with special focus on HER2 and ESR status.Results
CTC positivity in the cohort was 76%. There was no significant difference between the tested groups, but the highest CTC occurrence was identified in the group undergoing surgery and similarly in the group before the start of neoadjuvant treatment. On the other hand, the lowest CTC frequencies were observed in the menopausal patient group (56%), ESR+ patient group (60%), and DCIS group (44.4%). It is worth noting that after completion of neoadjuvant therapy (NACT) CTCs were present in 77.7% of cases. On the other hand, patients under hormonal treatment were CTC positive only in 52% of cases.Discussions
Interestingly, HER2 and ESR status of CTCs differs from the status of primary tumor. In 50% of patients HER2 status on CTCs changed not only from HER2+ to HER2?, but also from HER2– to HER2+ (33%). ESR status in CTCs changed only in one direction from ESR+ to ESR?.Conclusions
Data obtained from the present study suggest that BC is a heterogeneous disease but CTCs may be detected independently of the disease characteristics in 76% of patients at any time point during the course of the disease. This relatively high CTC occurrence in BC should be considered when planning the long-term patient monitoring.17.
Miodrag Dragoj Zorica Milosevic Jasna Bankovic Nikola Tanic Milica Pesic Tijana Stankovic 《Cellular oncology (Dordrecht)》2017,40(1):47-62
Background
Current high lung cancer mortality rates are mainly due to the occurrence of metastases and therapeutic resistance. Therefore, simultaneous targeting of these processes may be a valid approach for the treatment of this type of cancer. Here, we assessed relationships between CXC chemokine receptor type 4 (CXCR4) and focal adhesion kinase (FAK) gene expression levels and expression levels of the drug resistance-related genes ABCB1 and ABCC1, and tested the potential of CXCR4 and FAK inhibitors to reverse doxorubicin (DOX) resistance and to decrease the invasive capacity of non-small cell lung carcinoma (NSCLC) cells.Methods
qRT-PCR was used for gene expression analyses in primary lung tissue samples obtained from 30 NSCLC patients and the human NSCLC-derived cell lines NCI-H460, NCI-H460/R and COR-L23. MTT, flow cytometry, cell death and β-galactosidase activity assays were used to assess the in vitro impact of CXCR4 and FAK inhibitors on DOX sensitivity. In addition, invasion and gelatin degradation assays were used to assess the in vitro impact of the respective inhibitors on metastasis-related processes in combination with DOX treatment.Results
We found that ABCB1 over-expression was significantly associated with CXCR4 and FAK over-expression, whereas ABCC1 over-expression was associated with increased FAK expression. We also found that CXCR4 and FAK inhibitors strongly synergized with DOX in reducing cell viability, arresting the cell cycle in the S or G2/M phases and inducing senescence. Additionally, we found that DOX enhanced the anti-invasive potential of CXCR4 and FAK inhibitors by reducing gelatin degradation and invasion.Conclusions
From our data we conclude that targeting of CXCR4 and FAK may overcome ABCB1 and ABCC1-dependent DOX resistance in NSCLC cells and that simultaneous treatment of these cells with DOX may potentiate the anti-invasive effects of CXCR4 and FAK inhibitors.18.
Background
MLH1 plays a critical role in maintaining the fidelity of DNA replication, and defects in human MLH1 have been reported. However, the role of MLH1 in endometrial carcinoma has not been fully investigated. Therefore, we aimed to study the role of MLH1 in the sensitivity of human endometrial carcinoma cells to cisplatin.Methods
In this study, we detected the expression of MLH1 in Ishikawa and RL95–2 cells. MLH1-siRNA and ADV-MLH1 were adopted for the silencing and overexpression of MLH1, respectively. Real-time polymerase chain reaction, Western blotting, cell proliferation assays, and cell cycle and apoptotic analyses by flow cytometry were employed to explore the underlying mechanism. A mouse xenograft model was used to investigate the effect of MLH1 on tumor growth after treatment with cisplatin.Results
Over-expression of MLH1 in Ishikawa cells dramatically increased the sensitivity of cells to cisplatin and enhanced cell apoptosis. By contrast, knockdown of MLH1 yielded the opposite effects in vitro. Mechanistically, cisplatin induced the MLH1/c-Abl apoptosis signaling pathway in ADV-MLH1-infected endometrial carcinoma cells, and these effects involved c-Abl, caspase-9, caspase-3 and PARP. Altogether, our results indicate that ADV-MLH1 might attenuate Ishikawa cell growth in vivo, resulting in increased cisplatin sensitivity.Conclusions
MLH1 may render endometrial carcinoma cells more sensitive to cisplatin by activating the MLH1/c-Abl apoptosis signaling pathway. In addition, an applicable adenovirus vector (ADV-MLH1) for MLH1 overexpression in endometrial carcinoma was generated. Thus, ADV-MLH1 might be a novel potential therapeutic target for endometrial carcinoma.19.
L. Yang Z. Lv W. Xia W. Zhang Y. Xin H. Yuan Y. Chen X. Hu Y. Lv Q. Xu X. Weng C. Ni 《Clinical & translational oncology》2018,20(7):912-921
Purpose
Aspirin could reduce the risk of cancer metastasis. Circulating tumor cells (CTCs) are a key factor of cancer metastasis, but no evidence has revealed how aspirin affects CTCs and its epithelial–mesenchymal transition (EMT). Here, we conducted a clinical trial to investigate how aspirin affects CTCs in metastatic colorectal cancer (MCC) and breast cancer patients (MBC).Methods
The trial is retrospective registered at clinicaltrials.gov (NCT02602938). The eligible patients are given 100 mg aspirin q.d. for 8 weeks, and CTCs are evaluated at baseline, 4 and 8 weeks for absolute number, phenotype (epithelial type, E+, mesenchymal type, M+, and biophenotypic type, B+), and vimentin expression.Results
Data on 21 MCC and 19 MBC patients are analyzed, and it revealed that the CTC numbers decreased with aspirin treatment in MCC (p < 0.001) but not MBC (p = 0.0532); besides, ratio of E+ CTCs increased (p = 0.037) and M+ CTCs decreased at 2 months in MCC (p = 0.013), but neither the ratio of E+ or M+ CTCs changes significantly in MBC; vimentin expression of M+ CTCs is higher than E+ and B+ CTCs either in MBC or MCC patients at baseline (p < 0.01); and aspirin suppresses the vimentin expression in M+ (p = 0.002)and B+ (p = 0.006) CTCs of MCC and M+ CTCs of MBC (p = 0.004); besides it find vimentin expression in B+ (p = 0.004) or M+ (p < 0.001), CTCs are markedly decreased in patients with total CTC numbers declined.Conclusion
Aspirin could decrease CTCs numbers and block EMT transition in MCC patients and part of MBC patients.20.
Erin Kobetz Julia Seay Tulay Koru-Sengul Jordan Baeker Bispo Dinah Trevil Martha Gonzalez Andrew Brickman Olveen Carrasquillo 《Cancer causes & control : CCC》2018,29(9):793-801