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1.
Ashok Chakraborty Christos Hatzis Michael P. DiGiovanna 《Breast cancer research and treatment》2017,163(1):37-50
Purpose
Interactions between HER2, estrogen receptor (ER), and insulin-like growth factor I receptor (IGF1R) are implicated in resistance to monotherapies targeting these receptors. We have previously shown in pre-clinical studies synergistic anti-tumor effects for co-targeting each pairwise combination of HER2, IGF1R, and ER. Strikingly, synergy for HER2/IGF1R targeting occurred not only in a HER2+ model, but also in a HER2-normal model. The purpose of the current study was therefore to determine the generalizability of synergistic anti-tumor effects of co-targeting HER2/IGF1R, the anti-tumor activity of triple-targeting HER2/IGF1R/ER in hormone-dependent cell lines, and the effect of using the multi-targeting drugs neratinib (pan-HER) and BMS-754807 (dual IGF1R/insulin receptor).Methods
Proliferation and apoptosis assays were performed in a large panel of cell lines representing varying receptor expression levels. Mechanistic effects were studied using phospho-protein immunoblotting. Analyses of drug interaction effects were performed using linear mixed-effects regression models.Results
Enhanced anti-proliferative effects of HER/IGF-insulin co-targeting were seen in most, though not all, cell lines, including HER2-normal lines. For ER+ lines, triple targeting with inclusion of anti-estrogen generally resulted in the greatest anti-tumor effects. Double or triple targeting generally resulted in marked increases in apoptosis in the sensitive lines. Mechanistic studies demonstrated that the synergy between drugs was correlated with maximal inhibition of Akt and ERK pathway signaling.Conclusions
Dual HER/IGF-insulin targeting, and triple targeting with inclusion of anti-estrogen drugs, shows striking anti-tumor activity across breast cancer types, and drugs with broader receptor specificity may be more effective than single receptor selective drugs, particularly for ER? cells.2.
Noemi Eiro Lucía González Anxo Martínez-Ordoñez Belen Fernandez-Garcia Luis O. González Sandra Cid Francisco Dominguez Román Perez-Fernandez Francisco J. Vizoso 《Cellular oncology (Dordrecht)》2018,41(4):369-378
Purpose
It has been reported that stromal cell features may affect the clinical outcome of breast cancer patients. Cancer associated fibroblasts (CAFs) represent one of the most abundant cell types within the breast cancer stroma. Here, we aimed to explore the influence of CAFs on breast cancer gene expression, as well as on invasion and angiogenesis.Methods
qRT-PCR was used to evaluate the expression of several cancer progression related genes (S100A4, TGFβ, FGF2, FGF7, PDGFA, PDGFB, VEGFA, IL-6, IL-8, uPA, MMP2, MMP9, MMP11 and TIMP1) in the human breast cancer-derived cell lines MCF-7 and MDA-MB-231, before and after co-culture with CAFs. Stromal mononuclear inflammatory cell (MIC) MMP11 expression was used to stratify primary tumors. In addition, we assessed the in vitro effects of CAFs on both MDA-MB-231 breast cancer cell invasion and endothelial cell (HUVEC) tube formation.Results
We found that the expression levels of most of the genes tested were significantly increased in both breast cancer-derived cell lines after co-culture with CAFs from either MMP11+ or MMP11- MIC tumors. IL-6 and IL-8 showed an increased expression in both cancer-derived cell lines after co-culture with CAFs from MMP11+ MIC tumors. We also found that the invasive and angiogenic capacities of, respectively, MDA-MB-231 and HUVEC cells were increased after co-culture with CAFs, especially those from MMP11+ MIC tumors.Conclusions
Our data indicate that tumor-derived CAFs can induce up-regulation of genes involved in breast cancer progression. Our data additionally indicate that CAFs, especially those derived from MMP11+ MIC tumors, can promote breast cancer cell invasion and angiogenesis.3.
Elisa Robles-Escajeda Umashankar Das Nora M. Ortega Karla Parra Giulio Francia Jonathan R. Dimmock Armando Varela-Ramirez Renato J. Aguilera 《Cellular oncology (Dordrecht)》2016,39(3):265-277
Purpose
According to the World Health Organization (WHO), breast cancer is the most common cancer affecting women worldwide. In the USA ~12.3 % of all women are expected to be diagnosed with various types of breast cancer, exhibiting varying degrees of therapeutic response rates. Therefore, the identification of novel anti-breast cancer drugs is of paramount importance.Methods
The 1,5-diaryl-3-oxo-1,4-pentadienyl pharmacophore was incorporated into a number of cytotoxins. Three of the resulting dienones, 2a, 2b and 2c, were tested for their anti-neoplastic potencies in a variety of human breast cancer-derived cell lines, including the triple negative MDA-MB-231 cell line and its metastatic variant, using a live-cell bio-imaging method. Special emphasis was put on dienone 2c, since its anti-cancer activity and its mode of inflicting cell death have so far not been reported.Results
We found that all three dienones exhibited potent cytotoxicities towards the breast cancer-derived cell lines tested, whereas significantly lower toxicities were observed towards the non-cancerous human breast cell line MCF-10A. The dienones 2b and 2c exhibited the greatest selective cytotoxicity at submicromolar concentration levels. We found that these two dienones induced phosphatidylserine externalization in MDA-MB-231 cells in a concentration-dependent manner, suggesting that their cytotoxic effect might be mediated by apoptosis. This possibility was confirmed by our observation that the dienone 2c can induce mitochondrial depolarization, caspase-3 activation, cell cycle disruption and DNA fragmentation in MDA-MB-231 cells.Conclusion
Our findings indicate that dienone 2c uses the mitochondrial/intrinsic pathway to inflict apoptosis in triple negative MDA-MB-231 breast cancer-derived cells. This observation warrants further assessment of dienone 2c as a potential anti-breast cancer drug.4.
Rosalba D’Alessandro Maria Grazia Refolo Catia Lippolis Nicola Carella Caterina Messa Aldo Cavallini Brian Irving Carr 《Cellular oncology (Dordrecht)》2018,41(3):283-296
Purpose
Emerging evidence indicates that combining Sorafenib with vitamin K1 (VK1) may result in a synergistic inhibition of hepatocellular carcinoma (HCC) cell migration and proliferation. Despite this synergy, its benefits may be limited due to drug resistance resulting from cross-talk with the tumor microenvironment. Insulin-like growth factor-1 (IGF1) signaling acts as an important modulator of HCC cell growth, motility and drug resistance. Therefore, we aimed to explore the effects of Sorafenib in combination with VK1 and/or IGF1-R antagonists on HCC cells.Methods
Scratch wound migration assays were performed to assess the motility of HCC-derived PLC/PRF/5, HLF and Hep3B cells. The synergistic, additive or antagonistic effects of Sorafenib, VK1 and IGF1-R antagonists on HCC cell motility were assessed using CompuSyn software. The effects mediated by these various compounds on HCC cytoskeleton organization were evaluated using DyLight 554 Phalloidin staining. Proliferation and migration-associated signaling pathways were analyzed in PLC/PRF/5 cells using Erk1/2 and Akt activation kits and Western blotting (Mek, JNK, Akt, Paxillin and p38), respectively.Results
The effects of the IGF1-R antagonists GSK1838705A and OSI-906 on HCC cell migration inhibition after Sorafenib and/or VK1 administration, individually or in combination, were evaluated. We found a synergistic effect in PLC/PRF/5, HLF and Hep3B cells for combinations of fixed doses of GSK1838705A or OSI-906 together with different doses of Sorafenib and/or VK1. The levels of synergy were found to be stronger at higher Sorafenib and/or VK1 concentrations and lower or absent at lower concentrations, with some variation among the different cell lines tested. In addition, we found that in PLC/PRF/5 and HLF cells IGF1-R blockage strongly enhanced the reduction and redistribution of F-actin induced by Sorafenib and/or VK1 through alterations in the phosphorylation levels of some of the principal proteins involved in the MAPK signaling cascade, which is essential for cell migration.Conclusions
Our results indicate that modulation of the efficacy of Sorafenib through combinations with VK1 and/or IGF1-R antagonists results in synergistic inhibition of HCC cell migration.5.
Habib A. M. Sakil Marina Stantic Johanna Wolfsberger Suzanne Egyhazi Brage Johan Hansson Margareta T. Wilhelm 《Cellular oncology (Dordrecht)》2017,40(6):631-638
Purpose
Multidrug resistance (MDR) is a major cause of treatment failure. In cancer cells, MDR is often caused by an increased efflux of therapeutic drugs mediated by an up-regulation of ATP binding cassette (ABC) transporters. It has previously been shown that oncogenic ΔNp73 plays an important role in chemo-resistance. Here we aimed at unraveling the role of ΔNp73 in regulating multidrug resistance in breast cancer and melanoma cells.Methods
KEGG pathway analysis was used to identify pathways enriched in breast cancer samples with a high ΔNp73 expression. We found that the ABC transporter pathway was most enriched. The expression of selected ABC transporters was analyzed using qRT-PCR upon siRNA/shRNA-mediated knockdown or exogenous overexpression of ΔNp73 in the breast cancer-derived cell lines MCF7 and MDA-MB-231, as well as in primary melanoma samples and in the melanoma-derived cell line SK-MEL-28. The ability to efflux doxorubicin and the concomitant effects on cell proliferation were assessed using flow cytometry and WST-1 assays.Results
We found that high ΔNp73 levels correlate with a general up-regulation of ABC transporters in breast cancer samples. In addition, we found that exogenous expression of ΔNp73 led to an increase in the expression of ABCB1 and ABCB5 in the breast cancer-derived cell lines tested, while knocking down of ΔNp73 resulted in a reduction in ABCB1 and ABCB5 expression. In addition, we found that ΔNp73 reduction leads to an intracellular retention of doxorubicin in MDA-MB-231 and MCF7 cells and a concomitant decrease in cell proliferation. The effect of ΔNp73 on ABCB5 expression was further confirmed in metastases from melanoma patients and in the melanoma-derived cell line SK-MEL-28.Conclusions
Our data support a role for ΔNp73 in the multidrug-resistance of breast cancer and melanoma cells.6.
Purpose
Despite a growing body of evidence indicating a potential efficacy of the anti-diabetic metformin as anti-cancer agent, the exact mechanism underlying this efficacy has remained largely unknown. Here, we aimed at assessing putative mechanisms associated with the ability of metformin to reduce the proliferation and migration of breast cancer cells.Methods
A battery of in vitro assays including MTT, colony formation, NBT and scratch wound healing assays were performed to assess the viability, proliferation, anti-oxidative potential and migration of breast cancer-derived MCF-7, MDA-MB-231 and T47D cells, respectively. Reactive oxygen species (ROS) assays along with fluorescence microscopy were used to assess apoptotic parameters. Quantification of SOD, Bcl-2, Bax, MMPs, miR-21 and miR-155 expression was performed using qRT-PCR.Results
We found that metformin inhibited the growth, proliferation and clonogenic potential of the breast cancer-derived cells tested. ROS levels were found to be significantly reduced by metformin and, concomitantly, superoxide dismutase (SOD) isoforms were found to be upregulated. Mitochondrial dysfunction was observed in metformin treated cells, indicating apoptosis. In metastatic MDA-MB-231 cells, migration was found to be suppressed by metformin through deregulation of the matrix metalloproteinases MMP-2 and MMP-9. The oncogenic microRNAs miR-21 and miR-155 were found to be downregulated by metformin, which may be correlated with the suppression of cell proliferation and/or migration.Conclusions
Our data indicate that metformin may play a pivotal role in modulating the anti-oxidant system, including the SOD machinery, in breast cancer-derived cells. Our observations were validated by in silico analyses, indicating a close interaction between SOD and metformin. We also found that metformin may inhibit breast cancer-derived cell proliferation through apoptosis induction via the mitochondrial pathway. Finally, we found that metformin may modulate the pro-apoptotic Bax, anti-apoptotic Bcl-2, MMP-2, MMP-9, miR-21 and miR-155 expression levels. These findings may be instrumental for the clinical management and/or (targeted) treatment of breast cancer.7.
Antonia Wenners Felix Hartmann Arne Jochens Anna Maria Roemer Ibrahim Alkatout Wolfram Klapper Marion van Mackelenbergh Christoph Mundhenke Walter Jonat Maret Bauer 《International journal of clinical oncology / Japan Society of Clinical Oncology》2016,21(3):548-556
Background
Stromal fibroblasts influence tumor growth and progression. We evaluated two aldo–keto reductases, AKR1C1 and AKR1C2, in stromal fibroblasts and carcinoma cells as prognostic factors in primary human breast cancer. They are involved in intratumoral progesterone metabolism.Methods
Immunohistochemistry was performed on tissue microarrays from 504 core biopsies from breast cancer patients. Primary endpoints were disease-free (DFS) and overall (OS) survival.Results
AKR1C1 and AKR1C2 expression in fibroblasts and tumor cells correlated with favorable tumor characteristics, such as small tumor size and negative nodal status. In univariate analysis, AKR1C1 expression in carcinoma cells correlated positively with DFS und OS; AKR1C2 expression in both fibroblasts and tumor cells also showed a positive correlation with DFS and OS. In multivariate analysis, AKR1C1 expression in carcinoma cells was an independent prognostic marker.Conclusion
It can be assumed that our observations are due to the independent regulatory function of AKR1C1/2 in progesterone metabolism and therefore provide a basis for new hormone-based therapy options for breast cancer patients, independent of classic hormone receptor status.8.
Nikolai Havn Sæther Elina Skuja Arvids Irmejs Jelena Maksimenko Edvins Miklasevics Gunta Purkalne Janis Gardovskis 《Hereditary cancer in clinical practice》2018,16(1):9
Background
There is increasing evidence of high platinum sensitivity in BRCA-associated breast cancer. However, evidence from randomized trials is lacking. The aim of this study was to analyze the results of platinum-based chemotherapy for BRCA1-positive breast cancer in a neoadjuvant setting.Methods
A retrospective study was performed by obtaining information from patient files. The results were compared with the available data from a literature review.Results
Twelve female patients with BRCA1 gene mutations who had stage I to III breast cancers were eligible for evaluation. They received platinum-based neoadjuvant chemotherapy between 2011 and 2016. Eleven patients received a combination of cisplatin and doxorubicin, and one patient received carboplatin and docetaxel. All patients underwent mastectomy after chemotherapy. Ten patients (83%) achieved pathological complete remission (pCR). The observed pCR rate was comparable to existing results found in similar studies.Conclusion
The results of the study confirm the high pCR rate in BRCA1-positive breast cancer after platinum-based neoadjuvant chemotherapy. Larger randomized studies and longer follow-up times are necessary to evaluate the role of platinum-based therapies in BRCA1-positive breast cancer.9.
Trang H. Luu Jean-Marie Bard Delphine Carbonnelle Chloé Chaillou Jean-Michel Huvelin Christine Bobin-Dubigeon Hassan Nazih 《Cellular oncology (Dordrecht)》2018,41(1):13-24
Background
It has amply been documented that mammary tumor cells may exhibit an increased lipogenesis. Biliary acids are currently recognized as signaling molecules in the intestine, in addition to their classical roles in the digestion and absorption of lipids. The aim of our study was to evaluate the impact of lithocholic acid (LCA) on the lipogenesis of breast cancer cells. The putative cytotoxic effects of LCA on these cells were also examined.Methods
The effects of LCA on breast cancer-derived MCF-7 and MDA-MB-231 cells were studied using MTT viability assays, Annexin-FITC and Akt phosphorylation assays to evaluate anti-proliferative and pro-apoptotic properties, qRT-PCR and Western blotting assays to assess the expression of the bile acid receptor TGR5 and the estrogen receptor ERα, and genes and proteins involved in apoptosis (Bax, Bcl-2, p53) and lipogenesis (SREBP-1c, FASN, ACACA). Intracellular lipid droplets were visualized using Oil Red O staining.Results
We found that LCA induces TGR5 expression and exhibits anti-proliferative and pro-apoptotic effects in MCF-7 and MDA-MB-231 cells. Also, an increase in pro-apoptotic p53 protein expression and a decrease in anti-apoptotic Bcl-2 protein expression were observed after LCA treatment of MCF-7 cells. In addition, we found that LCA reduced Akt phosphorylation in MCF-7 cells, but not in MDA-MB-231 cells. We also noted that LCA reduced the expression of SREBP-1c, FASN and ACACA in both breast cancer-derived cell lines and that cells treated with LCA contained low numbers of lipid droplets compared to untreated control cells. Finally, a decrease in ERα expression was observed in MCF-7 cells treated with LCA.Conclusions
Our data suggest a potential therapeutic role of lithocholic acid in breast cancer cells through a reversion of lipid metabolism deregulation.10.
Quirine F. Manson Natalie D. ter Hoeve Horst Buerger Cathy B. Moelans Paul J. van Diest 《Targeted oncology》2018,13(6):769-777
Background
Male breast cancer is rare, as it represents less than 1% of all breast cancer cases. In addition, male breast cancer appears to have a different biology than female breast cancer. Programmed death-1 (PD-1) and its ligand, programmed death-ligand 1 (PD-L1), seem to have prognostic and predictive values in a variety of cancers, including female breast cancer. However, the role of PD-1 and PD-L1 expression in male breast cancer has not yet been studied.Objectives
To compare PD-1 and PD-L1 expression in male breast cancer to female breast cancer and to evaluate prognostic values in both groups.Patients and Methods
Tissue microarrays from formalin-fixed paraffin-embedded resection material of 247 female and 164 male breast cancer patients were stained for PD-1 and PD-L1 by immunohistochemistry.Results
PD-1 expression on tumor-infiltrating lymphocytes was significantly less frequent in male than in female cancers (48.9 vs. 65.3%, p?=?0.002). In contrast, PD-L1 expression on tumor and immune cells did not differ between the two groups. In male breast cancer, PD-1 and tumor PD-L1 were associated with grade 3 tumors. In female breast cancer, PD-1 and PD-L1 were associated with comparably worse clinicopathological variables. In a survival analysis, no prognostic value was observed for PD-1 and PD-L1 in either male and female breast cancer. In a subgroup analysis, female patients with grade 3/tumor PD-L1-negative or ER-negative/immune PD-L1-negative tumors had worse overall survival.Conclusions
PD-1 seems to be less often expressed in male breast cancer compared to female breast cancer. Although PD-1 and PD-L1 are not definite indicators for good or bad responses, male breast cancer patients may therefore respond differently to checkpoint immunotherapy with PD-1 inhibitors than female patients.11.
Purpose of review
This review summarizes current immunotherapies in breast cancer, with an emphasis on immune checkpoint inhibitors and vaccines.Recent findings
Combination immunotherapy with checkpoint inhibitors and cytotoxic therapies have shown promising results. Active clinical trials are ongoing in both early stage and metastatic settings for triple negative, HER2+, and hormone-positive breast cancer patients.Summary
Ongoing challenges remain in defining biomarkers that predict response to immunotherapy, determining the optimal combination immunotherapies, and enhancing the immunogenicity of breast cancer subtypes.12.
Melissa A. Merritt Howard D. Strickler Mark H. Einstein Hannah P. Yang Mark E. Sherman Nicolas Wentzensen Jurriaan Brouwer-Visser Maria Jose Cossio Kathleen D. Whitney Herbert Yu Marc J. Gunter Gloria S. Huang 《Cancer causes & control : CCC》2016,27(6):737-748
Purpose
Experimental and observational data link insulin, insulin-like growth factor (IGF), and estrogens to endometrial tumorigenesis. However, there are limited data regarding insulin/IGF and sex hormone axes protein and gene expression in normal endometrial tissues, and very few studies have examined the impact of endometrial cancer risk factors on endometrial tissue biology.Methods
We evaluated endometrial tissues from 77 premenopausal and 30 postmenopausal women who underwent hysterectomy for benign indications and had provided epidemiological data. Endometrial tissue mRNA and protein levels were measured using quantitative real-time PCR and immunohistochemistry, respectively.Results
In postmenopausal women, we observed higher levels of phosphorylated IGF-I/insulin receptor (pIGF1R/pIR) in diabetic versus non-diabetic women (p value =0.02), while women who reported regular nonsteroidal anti-inflammatory drug use versus no use had higher levels of insulin and progesterone receptors (both p values ≤0.03). We also noted differences in pIGF1R/pIR staining with OC use (postmenopausal women only), and the proportion of estrogen receptor-positive tissues varied by the number of live births and PTEN status (premenopausal only) (p values ≤0.04). Compared to premenopausal proliferative phase women, postmenopausal women exhibited lower mRNA levels of IGF1, but higher IGFBP1 and IGFBP3 expression (all p values ≤0.004), and higher protein levels of the receptors for estrogen, insulin, and IGF-I (all p values ≤0.02). Conversely, pIGF1R/pIR levels were higher in premenopausal proliferative phase versus postmenopausal endometrium (p value =0.01).Conclusions
These results highlight links between endometrial cancer risk factors and mechanistic factors that may contribute to early events in the multistage process of endometrial carcinogenesis.13.
14.
Background
Early life exposures, including diet, have been implicated in the etiology of breast cancer.Methods
A nested case-control study was conducted among participants in the Nurses' Health Study who completed a 24-item questionnaire about diet during high school. There were 843 eligible cases diagnosed between onset of study (1976) and before the return of the high school diet questionnaire (1986), who were matched 10:1 with controls on the basis of age.Results
Women who had, during adolescence, a higher consumption of eggs, vegetable fat and fiber had a lower risk of breast cancer, whereas risk of breast cancer was increased among women who consumed more butter.Conclusions
A possible association of elements of adolescent diet with risk of breast cancer is reported, but the findings require confirmation in prospective study.15.
Michelle Ferris Douglas F Easton Rebecca J Doherty Brian HJ Briggs Michelle Newman Ifthikhar M Saraf Sarah Scambler Lyndon Wagman Michael T Wyndham Ann Ward Rosalind A Eeles 《Hereditary cancer in clinical practice》2007,5(3):157-160
Objectives
To conduct a pilot population-based study within a general practice catchment area to determine whether the incidence of breast cancer was increased in the Ashkenazi population.Design
Population-based cohort study.Setting
A single general practice catchment area in North London.Participants
1947 women over the age of 16 who responded to a questionnaire about ethnicity and breast cancer.Main outcome measures
Incidence of breast cancer, ethnicity.Results
This study showed a 1.5-fold (95% CI 0.93–2.39) increase in breast cancer risk in the Ashkenazim compared with the non-Ashkenazi white population. The increased incidence was for both premenopausal and postmenopausal breast cancer (expected incidence pre:post is 1:4 whereas in the Ashkenazim it was 1:1; 51 and 52% of cases respectively). This increase was not shown in the Sephardim. Asians had a reduction in incidence (OR = 0.44; 95% CI 0.10–1.89). Results were adjusted for other risk factors for breast cancer.Conclusion
This study showed a 1.5-fold increase in breast cancer rates in Ashkenazim compared with the non-Jewish white population when adjusted for age (i.e. corrections were made to allow comparison of age groups) and this is not observed in the Sephardic population. The proportion of premenopausal breast cancer was just over double that of the general population. This is the first general practice population-based study in the UK to address this issue and has implications for general practitioners who care for patients from the Ashkenazi community.16.
Katayoon Pakravan Sadegh Babashah Majid Sadeghizadeh Seyed Javad Mowla Majid Mossahebi-Mohammadi Farangis Ataei Nasim Dana Mohammad Javan 《Cellular oncology (Dordrecht)》2017,40(5):457-470
Background
Human mesenchymal stem cells (MSCs) have been shown to be involved in the formation and modulation of tumor stroma and in interacting with tumor cells, partly through their secretome. Exosomes are nano-sized intraluminal multi-vesicular bodies secreted by most types of cells and have been found to mediate intercellular communication through the transfer of genetic information via coding and non-coding RNAs to recipient cells. Since exosomes are considered as protective and enriched sources of shuttle microRNAs (miRNAs), we hypothesized that exosomal transfer of miRNAs from MSCs may affect tumor cell behavior, particularly angiogenesis.Methods
Exosomes derived from MSCs were isolated and characterized by scanning electron microscopy analyses, dynamic light scattering measurements, and Western blotting. Fold changes in miR-100 expression levels were calculated in exosomes and their corresponding donor cells by qRT-PCR. The effects of exosomal transfer of miR-100 from MSCs were assessed by qRT-PCR and Western blotting of the mTOR/HIF-1α/VEGF signaling axis in breast cancer cells. The quantification of secreted VEGF protein was determined by enzyme-linked immunosorbent assay. The putative paracrine effects of MSC-derived exosomes on tumor angiogenesis were explored by in vitro angiogenesis assays including endothelial cell proliferation, migration and tube formation assays.Results
We found that MSC-derived exosomes induce a significant and dose-dependent decrease in the expression and secretion of vascular endothelial growth factor (VEGF) through modulating the mTOR/HIF-1α signaling axis in breast cancer-derived cells. We also found that miR-100 is enriched in MSC-derived exosomes and that its transfer to breast cancer-derived cells is associated with the down-regulation of VEGF in a time-dependent manner. The putative role of exosomal miR-100 transfer in regulating VEGF expression was substantiated by the ability of anti-miR-100 to rescue the inhibitory effects of MSC-derived exosomes on the expression of VEGF in breast cancer-derived cells. In addition, we found that down-regulation of VEGF mediated by MSC-derived exosomes can affect the vascular behavior of endothelial cells in vitro.Conclusions
Overall, our findings suggest that exosomal transfer of miR-100 may be a novel mechanism underlying the paracrine effects of MSC-derived exosomes and may provide a means by which these vesicles can modulate vascular responses within the microenvironment of breast cancer cells.17.
Timothy?A?Jamieson David?M?Brizel J?Keith?Killian Yoshihiko?Oka Hong-Seok?Jang Xiaolong?Fu Robert?W?Clough Robin?T?Vollmer Mitchell?S?Anscher Randy?L?Jirtle
Background
The mannose 6-phosphate/insulin-like growth factor 2 receptor (M6P/IGF2R) encodes for a multifunctional receptor involved in lysosomal enzyme trafficking, fetal organogenesis, cytotoxic T cell-induced apoptosis and tumor suppression. The purpose of this investigation was to determine if the M6P/IGF2R tumor suppressor gene is mutated in human head and neck cancer, and if allelic loss is associated with poor patient prognosis.Methods
M6P/IGF2R loss of heterozygosity in locally advanced squamous cell carcinoma of the head and neck was assessed with six different gene-specific nucleotide polymorphisms. The patients studied were enrolled in a phase 3 trial of twice daily radiotherapy with or without concurrent chemotherapy; median follow-up for surviving patients is 76 months.Results
M6P/IGF2R was polymorphic in 64% (56/87) of patients, and 54% (30/56) of the tumors in these informative patients had loss of heterozygosity. M6P/IGF2R loss of heterozygosity was associated with a significantly reduced 5 year relapse-free survival (23% vs. 69%, p = 0.02), locoregional control (34% vs. 75%, p = 0.03) and cause specific survival (29% vs. 75%, p = 0.02) in the patients treated with radiotherapy alone. Concomitant chemotherapy resulted in a better outcome when compared to radiotherapy alone only in those patients whose tumors had M6P/IGF2R loss of heterozygosity.Conclusions
This study provides the first evidence that M6P/IGF2R loss of heterozygosity predicts for poor therapeutic outcome in patients treated with radiotherapy alone. Our findings also indicate that head and neck cancer patients with M6P/IGF2R allelic loss benefit most from concurrent chemotherapy.18.
Sarita Das Anmada Nayak Sumit Siddharth Deepika Nayak Satya Narayan Chanakya Nath Kundu 《Cellular oncology (Dordrecht)》2017,40(6):593-607
Purpose
Previously, we reported that quinacrine (QC) may cause apoptosis in breast and colon cancer cells by activating the death receptor 5 (DR5), resulting in autophagic cell death through p21 modulation. Here, we systematically evaluated the combined role of p21 and DR5 and their crosstalk in QC-mediated autophagy and apoptosis in breast cancer cells using in vitro and in vivo models.Methods
Multiple breast cancer-derived cell lines (MCF-7, ZR-75-1, T47D, MDA-MB-231 and MCF-10A-Tr) and a mouse xenograft model were used. Also, multiple assays, including Western blotting, immunoprecipitation, staining for autophagy and apoptosis, gene silencing, hematoxylin and eosin staining, immunohistochemistry, cell viability assessment, fluorescence imaging and cell sorting were used.Results
We found that QC activates p21 and DR5 in combination with the apoptosis inducer TRAIL in the breast cancer-derived cells tested. Combined TRAIL and QC treatment increased autophagy and apoptosis by increasing the interaction between, and co-localization of, p21 and DR5 in the death-inducing signaling complex (DISC). We found that this combination also inhibited the mTOR/PI3K/AKT signaling cascade and modulated reactive oxygen species (ROS) and nitric oxide (NO) production. Reductions in autophagy and apoptosis in DR5-knockout cells and a lack of change in p21-DR5-silenced cells were noted after TRAIL + QC treatment. This result explains dependence of the death (autophagy and apoptosis) cascade on these two key regulatory proteins. In addition, we found in an in vivo mouse xenograft model that increased expression and enhanced co-localization of p21 and DR5 after TRAIL + QC treatment supported a joint regulatory role of these proteins in the co-prevalence of autophagy and apoptosis.Conclusion
Our data suggest that a combined treatment of TRAIL and QC causes cell death in breast cancer-derived cells via autophagy and apoptosis by increasing the interaction of p21 and DR5, as indicated by both in vitro and in vivo studies.19.
Wojciech Lubiński Stanisław Zajączek Zbigniew Sych Krzysztof Penkala Olgierd Palacz Jan Lubiński 《Hereditary cancer in clinical practice》2004,2(4):193-196
Purpose
To asses the retinal pigment epithelium (RPE) function measured by EOG testing in patients with neurofibromatosis type 1 (NF-1). Our preliminary EOG results suggested dysfunction of the RPE in individuals with NF-1. In order to confirm our initial results we performed EOG examination on a larger group of NF-1 patients.Patients
Studies were performed on 36 patients with clinically diagnosed NF-1 and compared to normal healthy controls.Methods
Standard EOG recordings were performed in accordance with the International Society for Clinical Electrophysiology of Vision (ISCEV) standards.Results
In NF-1 patients the Arden indexes of the EOG test were significantly higher primarily due to the lower values of dark troughs. Supernormal EOGs (exceeding the value of the mean + 2 SD from the control group) were present in 58% of NF-1 patients.Conclusions
Dysfunction of the RPE is a characteristic feature of individuals with NF-1.20.