Abstract PO-128: Lack of Aurora kinase signaling leads cancer cells to adopt an endocycle and form polyploid multinucleated giant cells that resist antimitotic drugs

2020 ◽  
Author(s):  
Vural Tagal ◽  
Michael G. Roth
Keyword(s):  
Cancer Cells ◽  
Aurora Kinase ◽  
Giant Cells ◽  
Multinucleated Giant Cells ◽  
Kinase Signaling ◽  
Antimitotic Drugs

scholarly journals Loss of Aurora kinase signaling allows lung cancer cells to adopt an alternative cell cycle and form multinucleated polyploid giant cells that resist anti-mitotic drugs

2019 ◽  
Author(s):  
Vural Tagal ◽  
Michael G. Roth
Keyword(s):  
Lung Cancer ◽  
Cell Cycle ◽  
Cancer Cells ◽  
Molecular Mechanisms ◽  
Aurora Kinase ◽  
Giant Cells ◽  
Cell Number ◽  
Lung Cancer Cells ◽  
Aurora Kinases ◽  
Proliferative Cell

AbstractPolyploid multinucleated (PP/MN) giant cancer cells are common in tumors and have been associated with resistance to cancer therapy, tumor relapse, malignancy, immunosuppression, metastasis, cancer stem cell production and modulation of the tumor microenvironment. However, the molecular mechanisms that cause these cells to form are yet known. In this study, we discover that Aurora kinases are synergistic determinants of a switch from the proliferative cell cycle to polyploid growth and multinucleation in lung cancer cell lines. When Aurora kinases are inhibited together, lung cancer cells uniformly grow into PP/MN giant cells. These cells have adopted an endocycle in which the genome replicates, mitosis is omitted and cells grow in size. Consequently, such cells continue to safely grow in the presence of antimitotic agents. These polyploid multinucleated cancer cells can re-enter the proliferative cell cycle and grow in cell number when the treatment is terminated.

CLINICAL AND MORPHOLOGICAL CORRELATIONS AND HISTOPATHOLOGY OF JOINT DAMAGE IN PATIENTS WITH DIFFUSE-TYPE TENOSYNOVIAL GIANT CELL TUMOR

2019 ◽  
Vol 72 (12) ◽  
Author(s):  
Olena O Dyadyk ◽  
Anastasiia Hryhorovska
Keyword(s):  
Giant Cell Tumor ◽  
Giant Cell ◽  
Cell Size ◽  
Giant Cells ◽  
Cell Tumor ◽  
Multinucleated Giant Cells ◽  
Diffuse Type ◽  
Association Coefficient ◽  
Mean Values ◽  
Tenosynovial Giant Cell Tumor

Introduction: Tenosynovial giant cell tumor (TSGCT) (synonym – pigmented villonodular synovitis) – is a rare benign proliferative lesion of the synovial sheath, localized in the joint capsule, bursa or tendon sheath and characterized by locally destructive growth. Depending on the prevalence within the joint elements, the presence of a capsule around the tumor, histophotographic features of cell structure and clinical behavior TSGCT can be divided to localized or diffuse type. The aim of the study was researching of histopathological properties of diffuse-type TSGCT, determine the parameters its morphological indicators and to find out the correlation between these morphological and clinical parameters. Materials and methods: The research material was used biopsy (resect) of pathological lesions from 50 patients who were diagnosed and histologically verified diffuse-type TSGCT. Microscopic examinations of the stained sections and their photo archiving were carried out with use of a Olympus-CX 41 light optical microscope. Group measurable parameters (mean values and Pearson tetrachoric index (association coefficient) were calculated in groups of comparison for morphological and clinical indices of TSGCT. The mean values were compared by Student’s test, P value of ≤0.1 was considered statistically significant. Results:Correlation analysis of indicators that accounted for the pairs of cases «clinic – morphology» revealed the relationships, that had the highest parameters of the association coefficient between such indicators: «presence of villous growths» - «severity of hemosiderosis» (if hypertrophied synovial villi available, with vascular injection and pronounced proliferation of synovial cells, there is also a significant accumulation of hemosiderin pigment); «presence of villous growths» - «type of predominant cellular proliferates» (if cells of TSGCT diffuse type consists of monotonous sheets of stromal cells, with uniform, oval to reniform nuclei, the proliferation of villi in synovial layer is non-distinctive); «presence of nodes» - «kind of stroma» (if nodes predominate, their histological structure is mainly represented by polymorphic clusters of synovitis cells in the form of cells, strands, chains, solid formations, among immature connective tissue with low hyalinosis); «cell size (area, cm²)» - «severity of haemosiderosis» and «cell size (area, cm²)» - «the number of multinucleated giant cells» (there is a pronounced deposition of pigment and accumulation of osteoclast-like multinucleated giant cells type, although usually their number is relatively small compared to the localized type of TSGCT). Conclusions: Morphological parameters, that we have identified, characterize pathological changes in the tissues of TSGCT; careful analysis of the frequency of their occurrence in the different comparison groups made it possible to establish intergroup differences and correlations between individual indicators, which were previously unknown or not obvious. Our study was determine to analyze of incidence rates and correlation relationships, revealed some previously unknown differences and dependencies that are important for understanding the pathogenesis, improvement of diagnosis and prognosis of diffuse-type TSGCT.

scholarly journals Antagonizing the spindle assembly checkpoint silencing enhances paclitaxel and Navitoclax-mediated apoptosis with distinct mechanistic

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Ana C. Henriques ◽  
Patrícia M. A. Silva ◽  
Bruno Sarmento ◽  
Hassan Bousbaa
Keyword(s):  
Cell Death ◽  
Cancer Cells ◽  
Cell Fate ◽  
Spindle Assembly Checkpoint ◽  
Spindle Assembly ◽  
Time Lapse ◽  
Antimitotic Drugs ◽  
Mitotic Slippage ◽  
Mitotic Death ◽  
Chronic Activation

AbstractAntimitotic drugs arrest cells in mitosis through chronic activation of the spindle assembly checkpoint (SAC), leading to cell death. However, drug-treated cancer cells can escape death by undergoing mitotic slippage, due to premature mitotic exit. Therefore, overcoming slippage issue is a promising chemotherapeutic strategy to improve the effectiveness of antimitotics. Here, we antagonized SAC silencing by knocking down the MAD2-binding protein p31comet, to delay mitotic slippage, and tracked cancer cells treated with the antimitotic drug paclitaxel, over 3 days live-cell time-lapse analysis. We found that in the absence of p31comet, the duration of mitotic block was increased in cells challenged with nanomolar concentrations of paclitaxel, leading to an additive effects in terms of cell death which was predominantly anticipated during the first mitosis. As accumulation of an apoptotic signal was suggested to prevent mitotic slippage, when we challenged p31comet-depleted mitotic-arrested cells with the apoptosis potentiator Navitoclax (previously called ABT-263), cell fate was shifted to accelerated post-mitotic death. We conclude that inhibition of SAC silencing is critical for enhancing the lethality of antimitotic drugs as well as that of therapeutic apoptosis-inducing small molecules, with distinct mechanisms. The study highlights the potential of p31comet as a target for antimitotic therapies.

scholarly journals Co-relation with novel phosphorylation sites of IκBα and necroptosis in breast cancer cells

BMC Cancer ◽  
2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Sung Hoon Choi ◽  
Hee-Sub Yoon ◽  
Shin-Ae Yoo ◽  
Sung Ho Yun ◽  
Joo-Hee Park ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Phosphorylation Site ◽  
Aurora Kinase ◽  
Serine Phosphorylation ◽  
Flight Mass Spectrometry ◽  
Iκb Kinase ◽  
Orbitrap Mass Spectrometer ◽  
Nf Kappab

Abstract Background Phosphorylation of NF-kappaB inhibitor alpha (IκBα) is key to regulation of NF-κB transcription factor activity in the cell. Several sites of IκBα phosphorylation by members of the IκB kinase family have been identified, but phosphorylation of the protein by other kinases remains poorly understood. We investigated a new phosphorylation site on IκBα and identified its biological function in breast cancer cells. Methods Previously, we observed that aurora kinase (AURK) binds IκBα in the cell. To identify the domains of IκBα essential for phosphorylation by AURK, we performed kinase assays with a series of IκBα truncation mutants. AURK significantly promoted activation of IκBα at serine 32 but not serine 36; by contrast, IκB kinase (IKK) family proteins activated both of these residues. We also confirmed phosphorylation of IκBα by matrix-assisted laser-desorption/ionization time-of-flight mass spectrometry (MALDI-TOF/TOF MS) and nano-liquid chromatography hybrid quadrupole orbitrap mass spectrometer (nanoLC-MS/MS; Q-Exactive). Results We identified two novel sites of serine phosphorylation, S63 and S262. Alanine substitution of S63 and S262 (S63A and S262A) of IκBα inhibited proliferation and suppressed p65 transcription activity. In addition, S63A and/or S262A of IκBα regulated apoptotic and necroptotic effects in breast cancer cells. Conclusions Phosphorylation of IκBα by AURK at novel sites is related to the apoptosis and necroptosis pathways in breast cancer cells.

scholarly journals Kaposiform Hemangioendothelioma: clinicopathological characteristics of 8 cases of a rare vascular tumor and review of literature

2021 ◽  
Vol 16 (1) ◽  
Author(s):  
Qurratulain Chundriger ◽  
Muhammad Usman Tariq ◽  
Jamshid Abdul-Ghafar ◽  
Arsalan Ahmed ◽  
Nasir Ud Din
Keyword(s):  
Pediatric Population ◽  
Adult Population ◽  
Correct Diagnosis ◽  
Kaposi Sarcoma ◽  
Minor Component ◽  
Vascular Tumor ◽  
Giant Cells ◽  
Clinicopathological Characteristics ◽  
Multinucleated Giant Cells ◽  
Kaposiform Hemangioendothelioma

Abstract Background Kaposiform Hemangioendothelioma (KHE) is a rare vascular tumor of intermediate malignant potential which shows locally aggressive growth but only rarely metastasizes. It is mostly considered to be a tumor of pediatric population but its occurrence in the adults is not uncommon as once considered. Histologically, KHE can mimic other soft tissue neoplasms of different behaviors (e.g. Kaposi Sarcoma, hemangioma) and establishing the correct diagnosis is important for appropriate treatment. Herein, we describe the clinicopathological features of 8 cases of KHE which will be helpful in making their diagnosis. Methods We reviewed pathology reports, microscopy glass slides and obtained follow up information about 8 cases of KHE which were diagnosed at our institution from January 2008 till June 2020. Immunohistochemical stain for HHV8 was also performed. Results Age ranged from 7 months to 25 years. Seven patients were less than 20 years of age and one patient was 25 years old. Equal gender distribution was observed. Extremities were the most common sites of involvement, followed by head and neck, pancreas and ischiorectal region. 2 cases were resection specimen and all others were incisional biopsies. The largest tumor size was 5.5 cm in one of the resections. The incisional/fragmented tissues were all less than 5 cm in aggregate. Most cases showed predominance of nodular growth and a minor component of spindle cell population along with lymphangiomatosis like vascular channels, with evidence of microthrombi in 2 cases. Few multinucleated giant cells were observed in 2 cases. None of the cases exhibited significant nuclear atypia or mitotic activity. One of the cases arising in dermis showed underlying bone involvement. HHV8 was negative in 7/7 cases. Conclusions KHE can also involve adult population and it should always be considered in the differential diagnoses of a vascular lesion. Presence of multinucleated giant cells is a rare finding. Knowledge about histological features and potential mimics is helpful in avoiding misdiagnosis.

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