scholarly journals Modular self-assembly system for development of oligomeric, highly internalizing and potent cytotoxic conjugates targeting fibroblast growth factor receptors

2021 ◽  
Vol 28 (1) ◽  
Author(s):  
Marta Poźniak ◽  
Natalia Porębska ◽  
Kamil Jastrzębski ◽  
Mateusz Adam Krzyścik ◽  
Marika Kucińska ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Self Assembly ◽  
Cell Biology ◽  
Assembly System ◽  
Specific Marker ◽  
Fibroblast Growth Factor Receptors ◽  
Protein Biochemistry ◽  
Specific Attachment ◽  
Efficient Uptake ◽  
Recognition Molecule

Abstract Background Overexpression of FGFR1 is observed in numerous tumors and therefore this receptor constitutes an attractive molecular target for selective cancer treatment with cytotoxic conjugates. The success of cancer therapy with cytotoxic conjugates largely relies on the precise recognition of a cancer-specific marker by a targeting molecule within the conjugate and its subsequent cellular internalization by receptor mediated endocytosis. We have recently demonstrated that efficiency and mechanism of FGFR1 internalization are governed by spatial distribution of the receptor in the plasma membrane, where clustering of FGFR1 into larger oligomers stimulated fast and highly efficient uptake of the receptor by simultaneous engagement of multiple endocytic routes. Based on these findings we aimed to develop a modular, self-assembly system for generation of oligomeric cytotoxic conjugates, capable of FGFR1 clustering, for targeting FGFR1-overproducing cancer cells. Methods Engineered FGF1 was used as FGFR1-recognition molecule and tailored for enhanced stability and site-specific attachment of the cytotoxic drug. Modified streptavidin, allowing for controlled oligomerization of FGF1 variant was used for self-assembly of well-defined FGF1 oligomers of different valency and oligomeric cytotoxic conjugate. Protein biochemistry methods were applied to obtain highly pure FGF1 oligomers and the oligomeric cytotoxic conjugate. Diverse biophysical, biochemical and cell biology tests were used to evaluate FGFR1 binding, internalization and the cytotoxicity of obtained oligomers. Results Developed multivalent FGF1 complexes are characterized by well-defined architecture, enhanced FGFR1 binding and improved cellular uptake. This successful strategy was applied to construct tetrameric cytotoxic conjugate targeting FGFR1-producing cancer cells. We have shown that enhanced affinity for the receptor and improved internalization result in a superior cytotoxicity of the tetrameric conjugate compared to the monomeric one. Conclusions Our data implicate that oligomerization of the targeting molecules constitutes an attractive strategy for improvement of the cytotoxicity of conjugates recognizing cancer-specific biomarkers. Importantly, the presented approach can be easily adapted for other tumor markers.

Adenosine Analogues as Opposite Modulators of the Cisplatin Resistance of Ovarian Cancer Cells

2019 ◽  
Vol 19 (4) ◽  
pp. 473-486 ◽  
Author(s):  
Katarzyna Bednarska-Szczepaniak ◽  
Damian Krzyżanowski ◽  
Magdalena Klink ◽  
Marek Nowak
Keyword(s):  
Cell Cycle ◽  
Ovarian Cancer ◽  
Cancer Cells ◽  
Cancer Cell ◽  
Cell Biology ◽  
Immune Cell ◽  
Immunosuppressive Agents ◽  
Cell Activity ◽  
Ovarian Cancer Cells ◽  
Adenosine Analogues

Background: Adenosine released by cancer cells in high amounts in the tumour microenvironment is one of the main immunosuppressive agents responsible for the escape of cancer cells from immunological control. Blocking adenosine receptors with adenosine analogues and restoring immune cell activity is one of the methods considered to increase the effectiveness of anticancer therapy. However, their direct effects on cancer cell biology remain unclear. Here, we determined the effect of adenosine analogues on the response of cisplatinsensitive and cisplatin-resistant ovarian cancer cells to cisplatin treatment. Methods: The effects of PSB 36, DPCPX, SCH58261, ZM 241385, PSB603 and PSB 36 on cisplatin cytotoxicity were determined against A2780 and A2780cis cell lines. Quantification of the synergism/ antagonism of the compounds cytotoxicity was performed and their effects on the cell cycle, apoptosis/necrosis events and cisplatin incorporation in cancer cells were determined. Results: PSB 36, an A1 receptor antagonist, sensitized cisplatin-resistant ovarian cancer cells to cisplatin from low to high micromolar concentrations. In contrast to PSB 36, the A2AR antagonist ZM 241385 had the opposite effect and reduced the influence of cisplatin on cancer cells, increasing their resistance to cisplatin cytotoxicity, decreasing cisplatin uptake, inhibiting cisplatin-induced cell cycle arrest, and partly restoring mitochondrial and plasma membrane potentials that were disturbed by cisplatin. Conclusion: Adenosine analogues can modulate considerable sensitivity to cisplatin of ovarian cancer cells resistant to cisplatin. The possible direct beneficial or adverse effects of adenosine analogues on cancer cell biology should be considered in the context of supportive chemotherapy for ovarian cancer.

scholarly journals Evidence that polyploidy in esophageal adenocarcinoma originates from mitotic slippage caused by defective chromosome attachments

2021 ◽  
Author(s):  
Stacey J. Scott ◽  
Xiaodun Li ◽  
Sriganesh Jammula ◽  
Ginny Devonshire ◽  
Catherine Lindon ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Esophageal Adenocarcinoma ◽  
Cell Biology ◽  
Time Lapse ◽  
Rna Seq ◽  
Cancer Evolution ◽  
Mitotic Slippage ◽  
Quantitative Immunofluorescence ◽  
Cancer Types ◽  
Eac Cells

AbstractPolyploidy is present in many cancer types and is increasingly recognized as an important factor in promoting chromosomal instability, genome evolution, and heterogeneity in cancer cells. However, the mechanisms that trigger polyploidy in cancer cells are largely unknown. In this study, we investigated the origin of polyploidy in esophageal adenocarcinoma (EAC), a highly heterogenous cancer, using a combination of genomics and cell biology approaches in EAC cell lines, organoids, and tumors. We found the EAC cells and organoids present specific mitotic defects consistent with problems in the attachment of chromosomes to the microtubules of the mitotic spindle. Time-lapse analyses confirmed that EAC cells have problems in congressing and aligning their chromosomes, which can ultimately culminate in mitotic slippage and polyploidy. Furthermore, whole-genome sequencing, RNA-seq, and quantitative immunofluorescence analyses revealed alterations in the copy number, expression, and cellular distribution of several proteins known to be involved in the mechanics and regulation of chromosome dynamics during mitosis. Together, these results provide evidence that an imbalance in the amount of proteins implicated in the attachment of chromosomes to spindle microtubules is the molecular mechanism underlying mitotic slippage in EAC. Our findings that the likely origin of polyploidy in EAC is mitotic failure caused by problems in chromosomal attachments not only improves our understanding of cancer evolution and diversification, but may also aid in the classification and treatment of EAC and possibly other highly heterogeneous cancers.

Cell biology: How cancer cells coerce normal cells into tumorigenesis

2021 ◽  
Vol 31 (15) ◽  
pp. R957-R959
Author(s):  
Sushila Ganguli ◽  
Helen K. Matthews
Keyword(s):  
Cancer Cells ◽  
Cell Biology ◽  
Normal Cells

scholarly journals TRPM8 in prostate cancer cells: a potential diagnostic and prognostic marker with a secretory function?

2006 ◽  
Vol 13 (1) ◽  
pp. 27-38 ◽  
Author(s):  
Lei Zhang ◽  
Gregory J Barritt
Keyword(s):  
Prostate Cancer ◽  
Cancer Cells ◽  
Prognostic Marker ◽  
Cell Biology ◽  
Transient Receptor Potential ◽  
Sensory Nerve ◽  
Receptor Potential ◽  
Activation Mechanism ◽  
Prostate Cancer Cells ◽  
Genetic Interventions

During the past 5 years it has emerged that the transient receptor potential (TRP) family of Ca2+-and Na+-permeable channels plays a diverse and important role in cell biology and in pathology. One member of this family, TRPM8, is highly expressed in prostate cancer cells but the physiological and pathological functions of TRPM8 in these cells are not known. Here we address these questions, and the issue of whether or not TRPM8 is an effective diagnostic and prognostic marker in prostate cancer. TRPM8 is known to be activated by cool stimuli (17–25 °C) and cooling compounds such as menthol. The activation mechanism(s) involves voltage sensing of membrane potential, phosphatidylinositol 4,5-bisphosphate and Ca2+. In addition to prostate cancer cells, TRPM8 is expressed in sensory neurons where it acts as a sensor of cold. In prostate epithelial cells, expression of TRPM8 is regulated by androgen and is elevated in androgen-sensitive cancerous cells compared with normal cells. While there is some evidence that in prostate cancer cells Ca2+ and Na+ inflow through TRPM8 is necessary for survival and function, including secretion at the apical membrane, the function of TRPM8 in these cells is not really known. It may well differ from the role of TRPM8 as a cool sensor in sensory nerve cells. Androgen unresponsive prostate cancer is difficult to treat effectively and there are limited diagnostic and prognostic markers available. TRPM8 is a potential tissue marker in differential diagnosis and a potential prognostic marker for androgen-unresponsive and metastatic prostate cancer. As a consequence of its ability to convey Ca2+ and Na+ and its expression in only a limited number of cell types, TRPM8 is considered to be a promising target for pharmaceutical, immunological and genetic interventions for the treatment of prostate cancer.

scholarly journals Tropism of Extracellular Vesicles and Cell-Derived Nanovesicles to Normal and Cancer Cells: New Perspectives in Tumor-Targeted Nucleic Acid Delivery

Pharmaceutics ◽  
2021 ◽  
Vol 13 (11) ◽  
pp. 1911
Author(s):  
Anastasiya Oshchepkova ◽  
Oleg Markov ◽  
Evgeniy Evtushenko ◽  
Alexander Chernonosov ◽  
Elena Kiseleva ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Extracellular Vesicles ◽  
Mammalian Cells ◽  
Cytochalasin B ◽  
Drug Carrier ◽  
Membrane Vesicles ◽  
Nucleic Acid Delivery ◽  
Isolation And Purification ◽  
Cellular Origin ◽  
Efficient Uptake

The main advantage of extracellular vesicles (EVs) as a drug carrier system is their low immunogenicity and internalization by mammalian cells. EVs are often considered a cell-specific delivery system, but the production of preparative amounts of EVs for therapeutic applications is challenging due to their laborious isolation and purification procedures. Alternatively, mimetic vesicles prepared from the cellular plasma membrane can be used in the same way as natural EVs. For example, a cytoskeleton-destabilizing agent, such as cytochalasin B, allows the preparation of membrane vesicles by a series of centrifugations. Here, we prepared cytochalasin-B-inducible nanovesicles (CINVs) of various cellular origins and studied their tropism in different mammalian cells. We observed that CINVs derived from human endometrial mesenchymal stem cells exhibited an enhanced affinity to epithelial cancer cells compared to myeloid, lymphoid or neuroblastoma cancer cells. The dendritic cell-derived CINVs were taken up by all studied cell lines with a similar efficiency that differed from the behavior of DC-derived EVs. The ability of cancer cells to internalize CINVs was mainly determined by the properties of recipient cells, and the cellular origin of CINVs was less important. In addition, receptor-mediated interactions were shown to be necessary for the efficient uptake of CINVs. We found that CINVs, derived from late apoptotic/necrotic cells (aCINVs) are internalized by in myelogenous (K562) 10-fold more efficiently than CINVs, and interact much less efficiently with melanocytic (B16) or epithelial (KB-3-1) cancer cells. Finally, we found that CINVs caused a temporal and reversible drop of the rate of cell division, which restored to the level of control cells with a 24 h delay.

scholarly journals Dual Targeting of Cancer Cells and MMPs with Self-Assembly Hybrid Nanoparticles for Combination Therapy in Combating Cancer

Pharmaceutics ◽  
2021 ◽  
Vol 13 (12) ◽  
pp. 1990
Author(s):  
Kai Zhang ◽  
Jingjing Li ◽  
Xiaofei Xin ◽  
Xiaoqing Du ◽  
Di Zhao ◽  
...  
Keyword(s):  
T Cells ◽  
Cancer Cells ◽  
Self Assembly ◽  
Chemotherapeutic Agents ◽  
Hybrid Nanoparticles ◽  
Control Group ◽  
Hyperthermia Treatment ◽  
Immune Modulators ◽  
Dual Targeting

The co-delivery of chemotherapeutic agents and immune modulators to their targets remains to be a great challenge for nanocarriers. Here, we developed a hybrid thermosensitive nanoparticle (TMNP) which could co-deliver paclitaxel-loaded transferrin (PTX@TF) and marimastat-loaded thermosensitive liposomes (MMST/LTSLs) for the dual targeting of cancer cells and the microenvironment. TMNPs could rapidly release the two payloads triggered by the hyperthermia treatment at the site of tumor. The released PTX@TF entered cancer cells via transferrin-receptor-mediated endocytosis and inhibited the survival of tumor cells. MMST was intelligently employed as an immunomodulator to improve immunotherapy by inhibiting matrix metalloproteinases to reduce chemokine degradation and recruit T cells. The TMNPs promoted the tumor infiltration of CD3+ T cells by 2-fold, including memory/effector CD8+ T cells (4.2-fold) and CD4+ (1.7-fold), but not regulatory T cells. Our in vivo anti-tumor experiment suggested that TMNPs possessed the highest tumor growth inhibitory rate (80.86%) compared with the control group. We demonstrated that the nanoplatform could effectively inhibit the growth of tumors and enhance T cell recruitment through the co-delivery of paclitaxel and marimastat, which could be a promising strategy for the combination of chemotherapy and immunotherapy for cancer treatment.

scholarly journals Musashi proteins are post-transcriptional regulators of the epithelial-luminal cell state

eLife ◽  
2014 ◽  
Vol 3 ◽  
Author(s):  
Yarden Katz ◽  
Feifei Li ◽  
Nicole J Lambert ◽  
Ethan S Sokol ◽  
Wai-Leong Tam ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Cell Biology ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
State Regulation ◽  
Ribosome Profiling ◽  
Luminal Cell ◽  
Mesenchymal Transition ◽  
Cell State

The conserved Musashi (Msi) family of RNA binding proteins are expressed in stem/progenitor and cancer cells, but generally absent from differentiated cells, consistent with a role in cell state regulation. We found that Msi genes are rarely mutated but frequently overexpressed in human cancers and are associated with an epithelial-luminal cell state. Using ribosome profiling and RNA-seq analysis, we found that Msi proteins regulate translation of genes implicated in epithelial cell biology and epithelial-to-mesenchymal transition (EMT), and promote an epithelial splicing pattern. Overexpression of Msi proteins inhibited the translation of Jagged1, a factor required for EMT, and repressed EMT in cell culture and in mammary gland in vivo. Knockdown of Msis in epithelial cancer cells promoted loss of epithelial identity. Our results show that mammalian Msi proteins contribute to an epithelial gene expression program in neural and mammary cell types.

scholarly journals TO ASSESS THE SENSITIVITY AND SPECIFICITY OF SERUM ANTICYCLIC CITRULLINATED PEPTIDE ANTIBODY IN PATIENTS WITH RHEUMATOID ARTHRITIS IN A COMMUNITY HOSPITAL IN LAHORE, PAKISTAN

1969 ◽  
Vol 4 (2) ◽  
pp. 503-507
Author(s):  
BUSHRA GOHAR SHAH ◽  
HAMID JAVAID QURESHI ◽  
IZAZ UR REHMAN
Keyword(s):  
Rheumatoid Arthritis ◽  
Rheumatoid Factor ◽  
Sensitivity And Specificity ◽  
Cell Biology ◽  
Venous Blood ◽  
Research Work ◽  
Specific Marker ◽  
Cross Sectional ◽  
Peptide Antibody ◽  
Citrullinated Peptide

OBJECTIVES: To compare the sensitivity and specificity of serum anti-Cyclic Citrullinated Peptideantibody (anti-CCP) with serum rheumatoid factor in diagnosing rheumatoid arthritis (RA) in acommunity hospital in Lahore, Pakistan.DESIGN: Cross-sectional analytical study.PLACE & DURATION OF STUDY: Subjects were recruited from Fatima Memorial Hospital,Rheumatology Outpatient Department from January, 2010 to December, 2010. The research work wasconducted at Department of Physiology and Cell Biology of University of Health Sciences, Lahore.SUBJECTS & METHODS: Eighty diagnosed patients of rheumatoid arthritis and thirty normalhealthy controls were included in the study. After selection of subjects, written informed consent wasobtained. The venous blood sample was taken and secured in vacutainers. Serum was extracted bycentrifugation and stored at -20°C till analysis. Titers of anti-CCP and rheumatoid factor weredetermined by ELISA. The data obtained was analyzed by using SPSS version 16.0.RESULTS: The sensitivity and specificity of serum anti-CCP was found to be 58.6% and 86.7%respectively as compared to 47.5% and 83.3% for serum rheumatoid factor (RF) in diagnosingrheumatoid arthritis. Sensitivity of anti-CCP antibody in RF negative sub-group was 32.1%.CONCLUSION: Serum anti-CCP antibody is more sensitive and specific marker for diagnosis ofrheumatoid arthritis as compared to the rheumatoid factor.KEY WORDS: Rheumatoid Arthritis, Anti- Cyclic Citrullinated Peptide Antibody (ACCP), Rheumatoid Factor

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