The mitotic spindle protein CKAP2 potently increases formation and stability of microtubules

Cells increase microtubule dynamics to make large rearrangements to their microtubule cytoskeleton during cell division. Changes in microtubule dynamics are essential for the formation and function of the mitotic spindle, and misregulation can lead to aneuploidy and cancer. Using in vitro reconstitution assays we show that the mitotic spindle protein Cytoskeleton-Associated Protein 2 (CKAP2) has a strong effect on nucleation of microtubules by lowering the critical tubulin concentration 100-fold. CKAP2 increases the apparent rate constant ka of microtubule growth by 50-fold and increases microtubule growth rates. In addition, CKAP2 strongly suppresses catastrophes. Our results identify CKAP2 as the most potent microtubule growth factor to date. These finding help explain CKAP2's role as an important spindle protein, proliferation marker, and oncogene.

High BRCA1 gene expression increases the risk of early distant metastasis in ER+ breast cancers

Although the function of the BRCA1 gene has been extensively studied, the relationship between BRCA1 gene expression and tumor aggressiveness remains controversial in sporadic breast cancers. Because the BRCA1 protein is known to regulate estrogen signaling, we selected microarray data of ER+ breast cancers from the GEO public repository to resolve previous conflicting findings. The BRCA1 gene expression level in highly proliferative luminal B tumors was shown to be higher than that in luminal A tumors. Survival analysis using a cure model indicated that patients of early ER+ breast cancers with high BRCA1 expression developed rapid distant metastasis. In addition, the proliferation marker genes MKI67 and PCNA, which are characteristic of aggressive tumors, were also highly expressed in patients with high BRCA1 expression. The associations among high BRCA1 expression, high proliferation marker expression, and high risk of distant metastasis emerged in independent datasets, regardless of tamoxifen treatment. Tamoxifen therapy could improve the metastasis-free fraction of high BRCA1 expression patients. Our findings link BRCA1 expression with proliferation and possibly distant metastasis via the ER signaling pathway. We propose a testable hypothesis based on these consistent results and offer an interpretation for our reported associations.

Increased proliferation is associated with CNS invasion in meningiomas

Introduction Meningiomas are the most common benign intracranial neoplasms. CNS invasion in meningiomas has been integrated into the 2016 WHO classification of CNS tumors as a stand-alone criterion for atypia. Since then, its prognostic impact has been debated based on contradictory results from retrospective analyses. The aim of the study was to elucidate whether histopathological evidence of CNS invasion is associated with increased proliferative potential. Methods We have conducted a quantified measurement of the proliferation marker Ki67 and analyzed its association with CNS invasion determined by histology together with other established prognostic markers of progression. Routine, immunohistochemical staining for Ki67 were digitalized and automatic quantification was done using Image J software. Results Overall, 1718 meningiomas were assessed. Histopathological CNS invasion was seen in 108 cases (6.7%). Uni- and multivariate analysis revealed a significantly higher Ki67 proliferation rate in meningiomas with CNS invasion (p < 0.0001 and p = 0.0098, respectively). Conclusions Meningiomas with histopathological CNS invasion show a higher proliferative activity.

Centrosome, the Newly Identified Passenger through Tunneling Nanotubes, Increases Binucleation and Proliferation Marker in Receiving Cells

Type 1 tunneling nanotubes (TNTs-1) are long, cytoplasmic protrusions containing actin, microtubules and intermediate filaments that provide a bi-directional road for the transport of various components between distant cells. TNT-1 formation is accompanied by dramatic cytoskeletal reorganization offering mechanical support for intercellular communication. Although the centrosome is the major microtubule nucleating center and also a signaling hub, the relationship between the centrosome and TNTs-1 is still unexplored. We provide here the first evidence of centrosome localization and orientation towards the TNTs-1 protrusion site, which is implicated in TNT-1 formation. We also envision a model whereby synchronized reorientation of the Golgi apparatus along with the centrosome towards TNTs-1 ensures effective polarized trafficking through TNTs-1. Furthermore, using immunohistochemistry and live imaging, we observed for the first time the movement of an extra centrosome within TNTs-1. In this regard, we hypothesize a novel role for TNTs-1 as a critical pathway serving to displace extra centrosomes and potentially to either protect malignant cells against aberrant centrosome amplification or contribute to altering cells in the tumor environment. Indeed, we have observed the increase in binucleation and proliferation markers in receiving cells. The fact that the centrosome can be both as the base and the user of TNTs-1 offers new perspectives and new opportunities to follow in order to improve our knowledge of the pathophysiological mechanisms under TNT control.

WHO grade I meningiomas that show regrowth after gamma knife radiosurgery often show 1p36 loss

WHO grade I meningiomas occasionally show regrowth after radiosurgical treatment, which cannot be predicted by clinical features. There is increasing evidence that certain biomarkers are associated with regrowth of meningiomas. The aim of this retrospective study was to asses if these biomarkers could be of value to predict regrowth of WHO grade I meningiomas after additive radiosurgery. Forty-four patients with WHO grade I meningiomas who underwent additive radiosurgical treatment between 2002 and 2015 after Simpson IV resection were included in this study, of which 8 showed regrowth. Median follow-up time was 64 months (range 24–137 months). Tumors were analyzed for the proliferation marker Ki-67 by immunohistochemistry and for deletion of 1p36 by fluorescence in situ hybridization (FISH). Furthermore, genomic DNA was analyzed for promoter hypermethylation of the genes NDRG1–4, SFRP1, HOXA9 and MGMT. Comparison of meningiomas with and without regrowth after radiosurgery revealed that loss of 1p36 (p = 0.001) and hypermethylation of NDRG1 (p = 0.046) were correlated with regrowth free survival. Loss of 1p36 was the only parameter that was significantly associated with meningioma regrowth after multivariate analysis (p = 0.01). Assessment of 1p36 loss in tumor tissue prior to radiosurgery might be considered an indicator of prognosis/regrowth. However, this finding has to be validated in an independent larger set of tumors.

Characterization of Cytokines and Proliferation Marker Ki67 in Chronic Rhinosinusitis with Nasal Polyps: A Pilot Study

Background and Objectives: Chronic rhinosinusitis (CRS) is a condition that affects as much as 10.9% of the population and, along with presence of nasal polyps, is associated with significant morbidity and decreased quality of life. Studies on molecular pathways that have been activated in nasal polyp tissue are mainly based on cytokine concentration detection. Therefore, our aim is to investigate the complex appearance, relative distribution and interlinks of IL-1, IL-4, IL-6, IL-7, IL-8, IL-10, IL-12 and Ki 67 in chronic rhinosinusitis with nasal polyps (CRSwNP) affected human nasal mucosa. Materials and Methods: Samples of nasal polyps were obtained from 12 patients with previously diagnosed CRSwNP and no prior surgery. Control group consisted of samples from 17 otherwise healthy individuals with isolated nasal septum deviation. Tissues were stained for IL-1, IL-4, IL-6, IL-7, IL-8, IL-10, IL-12 and Ki67 immunohistochemically. Non-parametric statistic, Mann–Whitney U test and Spearman’s rank correlation coefficient were used. Results: All factors, except connective tissue cytokine IL-10 and proliferation marker Ki-67, had increased presence in connective tissue and decreased presence in epithelium of nasal polyps when compared to controls. Very strong and strong positive correlations between factors were observed. Conclusions: Decreased appearance of IL-1α, IL-4, IL-6, IL-7, IL-8, IL-10, IL-12 positive structures in the nasal epithelium with selective increase of IL-1α and IL-12 in nasal subepithelial connective tissue characterize the cytokine endotype with dysfunctional epithelial barrier and local stimulation of immune response in the connective tissue in case of chronic rhinosinusitis with polyps. Decrease of IL-6 in both—epithelium and connective tissue with strong correlation between it and IL-7 and IL-10 in connective tissue suggests significant stimulation of this regulatory cytokine and, possibly, the important role in pathogenesis of the development in nasal polyps. Correlations between Ki67 and cytokines indicate possible involvement of IL-4, IL-7 and IL-12 in regulation of cellular proliferation.

Challenging, Accurate and Feasible: CAF-1 as a Tumour Proliferation Marker of Diagnostic and Prognostic Value

The discovery of novel biomarkers of diagnostic, prognostic, and therapeutic value is a major challenge of current cancer research. The assessment of tumour cell proliferative capacity is pivotal for grading and clinical decision-making, highlighting the importance of proliferation markers as diagnostic and prognostic tools. Currently, the immunohistochemical analysis of Ki-67 expression levels is routinely used in clinical settings to assess tumour proliferation. Inasmuch as the function of Ki-67 is not fully understood and its evaluation lacks standardization, there is interest in chromatin regulator proteins as alternative proliferation markers of clinical value. Here, we review recent evidence demonstrating that chromatin assembly factor 1 (CAF-1), a histone chaperone selectively expressed in cycling cells, is a proliferation marker of clinical value. CAF-1 expression, when evaluated by immunocytochemistry in breast cancer cytology smears and immunohistochemistry in cancer biopsies from several tissues, strongly correlates with the expression of Ki-67 and other proliferation markers. Notably, CAF-1 expression is upregulated in almost all cancers, and CAF-1 overexpression is significantly associated, in most cancer types, with high histological tumour grade, advanced stage, recurrence, metastasis, and decreased patient survival. These findings suggest that CAF-1 is a robust, reproducible, and feasible proliferation marker of prognostic importance. CAF-1 may represent an attractive alternative or complementary to Ki-67 for cancer stratification and clinical guidance.

Expression of BCL-2 and KI-67 in Cyclical Endometrium and in Endometrial Hyperplasia

The Present study attempts to determine the relationship between proliferation and the inhibition of apoptosis in normal endometrium and hyperplasia, using monoclonal antibodies against the proliferation marker, Ki-67 and the anti-apoptotic protein, Bcl-2 and to determine the expression of B-cell lymphoma 2 (Bcl – 2) and Ki – 67 in cyclical endometrium in proliferative and secretory phase. The Present study includes the expression of Bcl – 2 and Ki – 67 in endometrial hyperplasia.