Human tumors are highly heterogeneous at the cellular, molecular, genetic and functional levels. Tumor heterogeneity has tremendous impact on cancer progression and treatment responses. However, the ...mechanisms for tumor heterogeneity have been poorly understood due to the lack of experimental models.
This study provides a novel exploration and analysis of the impacts of cellular and molecular heterogeneity of human lung epithelial cells on their malignant transformation following chronic exposure to cigarette smoke extracts.
The ability of cigarette smoke extract (CSE) to cause malignant transformation of the human bronchial epithelial cells (16HBE) is dependent on the sizes of the cells. Epithelial-mesenchymal transition (EMT) plays an important role in this process. Mechanistically, CSE-induced malignant transformation of 16HBE cells was closely linked to the reduced relative telomere length of the larger 16HBE cells, thereby up-regulation of the expression of stemness genes.
These findings provide novel insights for understanding the impact of cellular heterogeneity in lung cancer development. The in vitro transformation model described in this study could be extrapolated to studying the pathogenesis of other malignancies, as well as for mechanistic studies that are not feasible in vivo.
Ubiquitination-directed protein degradation is important in many cancers for tumor initiation and maintenance, and E3 ligases containing HECT domains are emerging as new therapeutic targets. In ...contrast to many other E3 ligases, the role of HUWE1 in ovarian cancer where HUWE1 is dysregulated has been unclear. Here we report that genetic deletion of Huwe1 in the mouse inhibits transformation of ovary surface epithelium cells without significantly affecting cell survival and apoptosis, and that Huwe1 deletion after tumors have been initiated inhibits tumor growth. In Huwe1-deficient cells, expression of histone H1.3 increased, inhibiting the expression of noncoding RNA
silencing phenocopied the effects of Huwe1 deficiency, whereas H1.3 silencing partially rescued the expression of
and the Huwe1-null phenotype. Inducible silencing of HUWE1 in human ovarian cancer cells produced a similar phenotype. Mechanistically, HUWE1 bound and ubiquitinated H1.3, which was consequently marked for destruction by proteasomes. Our results establish that HUWE1 plays an essential role in promoting ovarian cancer.
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Background & Aims Loss of parietal cells causes the development of spasmolytic polypeptide-expressing metaplasia (SPEM) through transdifferentiation of chief cells. In the presence of inflammation, ...SPEM can advance into a more proliferative metaplasia with increased expression of intestine-specific transcripts. We used L635 to induce acute SPEM with inflammation in mice and investigated the roles of inflammatory cells in the development of SPEM. Methods To study the adaptive immune system, Rag1 knockout, interferon-γ–deficient, and wild-type (control) mice received L635 for 3 days. To study the innate immune system, macrophages were depleted by intraperitoneal injection of clodronate liposomes 2 days before and throughout L635 administration. Neutrophils were depleted by intraperitoneal injection of an antibody against Ly6G 2 days before and throughout L635 administration. Pathology and immunohistochemical analyses were used to determine depletion efficiency, metaplasia, and proliferation. To characterize SPEM in each model, gastric tissues were collected and levels of Cftr , Dmbt1 , and Gpx2 mRNAs were measured. Markers of macrophage polarization were used to identify subpopulations of macrophages recruited to the gastric mucosa. Results Administration of L635 to Rag1 knockout, interferon-γ–deficient, and neutrophil-depleted mice led to development of proliferative SPEM and up-regulation of intestine-specific transcripts in SPEM cells, similar to controls. However, macrophage-depleted mice given L635 showed significant reductions in numbers of SPEM cells, SPEM cell proliferation, and expression of intestine-specific transcripts, compared with control mice given L635. In mice given L635, as well as patients with intestinal metaplasia, M2 macrophages were the primary inflammatory component. Conclusions Results from studies of mouse models and human metaplastic tissues indicate that M2 macrophages promote the advancement of SPEM in the presence of inflammation.
The mechanisms involved in the progression from monoclonal gammopathy of undetermined significance (MGUS) and smoldering myeloma (SMM) to malignant multiple myeloma (MM) and plasma cell leukemia ...(PCL) are poorly understood but believed to involve the sequential acquisition of genetic hits. We performed exome and whole-genome sequencing on a series of MGUS (n=4), high-risk (HR)SMM (n=4), MM (n=26) and PCL (n=2) samples, including four cases who transformed from HR-SMM to MM, to determine the genetic factors that drive progression of disease. The pattern and number of non-synonymous mutations show that the MGUS disease stage is less genetically complex than MM, and HR-SMM is similar to presenting MM. Intraclonal heterogeneity is present at all stages and using cases of HR-SMM, which transformed to MM, we show that intraclonal heterogeneity is a typical feature of the disease. At the HR-SMM stage of disease, the majority of the genetic changes necessary to give rise to MM are already present. These data suggest that clonal progression is the key feature of transformation of HR-SMM to MM and as such the invasive clinically predominant clone typical of MM is already present at the SMM stage and would be amenable to therapeutic intervention at that stage.
In the last decade, the field of cancer metabolism transformed itself from being a description of the metabolic features of cancer cells to become a key component of cellular transformation. Now, the ...potential role of this field in cancer biology is ready to be unravelled.
This paper integrates various ideas about the tensor product (TP) model transformation into one conceptual framework and formulates it in terms of the Takagi-Sugeno (T-S) fuzzy model manipulation and ...control design framework. Several new extensions of the TP model transformation are proposed, such as the quasi and "full," compact and rank-reduced higher order singular-value-decomposition-based canonical form of T-S fuzzy models, and the bilinear-, multi, pseudo-, convex-, partial TP model transformations. All of these extensions together form the generalized TP model transformation, which provides an effective tool to freely and readily manipulate the antecedent sets and rules of T-S fuzzy models and also provides main fuzzy rule component analysis, as well as a means for complexity and accuracy tradeoffs. It is demonstrated in this paper that the proposed manipulation forms a new, effective, and necessary optimization step of T-S fuzzy or polytopic models and linear-matrix-inequality-based control design, and can also decrease conservativeness. Identification techniques are typically constructed according to the available data and measurement set, as well as the type of system to be identified. As a result, they may not always provide good representations for control design frameworks. This paper demonstrates that the proposed TP model transformation is unique in that it bridges between various soft-computing-based identification techniques and T-S fuzzy model-based approaches. Finally, this paper proposes the multi-TP model transformation, which is a tractable and nonheuristic framework to verify the stability of the result of fuzzy or various soft-computing-based control designs. The multi-TP model transformation could provide an answer to the frequently emerging criticisms regarding the lack of mathematical stability verification techniques in the soft-computing-based control design. Control examples are provided in this paper.
ORAI family channels have emerged as important players in malignant transformation, yet the way in which they reprogram cancer cells remains elusive. Here we show that the relative expression levels ...of ORAI proteins in prostate cancer are different from that in noncancerous tissue. By mimicking ORAI protein remodeling observed in primary tumors, we demonstrate in in vitro models that enhanced ORAI3 expression favors heteromerization with ORAI1 to form a novel channel. These channels support store-independent Ca2+ entry, thereby promoting cell proliferation and a smaller number of functional homomeric ORAI1-based store-operated channels, which are important in supporting susceptibility to apoptosis. Thus, our findings highlight disrupted dynamic equilibrium of channel-forming proteins as an oncogenic mechanism.
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•Disrupted dynamic equilibrium of ORAI channels determines cancer cell phenotype•Microenvironment perturbations induce ORAI1/3 association and Ca2+ entry remodeling•ORAI1/3 heteromers promote proliferation by arachidonic acid-mediated Ca2+ entry•The ORAI3 oncogenic switch represents a therapeutic target in prostate cancer
Dubois et al. find that overexpression of ORAI1 or ORAI3 in prostate cancer leads to remodeling of ORAI channels and formation of ORAI1/ORAI3 heteromers. The altered stoichiometry provides an oncogenic switch that promotes cancer cell proliferation and resistance to apoptosis.
Wnt signaling in cancer Zhan, T; Rindtorff, N; Boutros, M
Oncogene,
03/2017, Volume:
36, Issue:
11
Journal Article
Peer reviewed
Open access
Wnt signaling is one of the key cascades regulating development and stemness, and has also been tightly associated with cancer. The role of Wnt signaling in carcinogenesis has most prominently been ...described for colorectal cancer, but aberrant Wnt signaling is observed in many more cancer entities. Here, we review current insights into novel components of Wnt pathways and describe their impact on cancer development. Furthermore, we highlight expanding functions of Wnt signaling for both solid and liquid tumors. We also describe current findings how Wnt signaling affects maintenance of cancer stem cells, metastasis and immune control. Finally, we provide an overview of current strategies to antagonize Wnt signaling in cancer and challenges that are associated with such approaches.
The vapochromic single‐crystal‐to‐single‐crystal (SCSC) transformation of a highly luminescent PtII complex bearing an N‐heterocyclic carbene Pt(CN)2(tBu‐impy) ...(tBu‐impyH+=1‐tert‐butyl‐3‐(2‐pyridyl)‐1H‐imidazolium) is reported. The trihydrate form of the complex, which exhibits blue 3MMLCT emission owing to weak Pt⋅⋅⋅Pt interactions, changed its luminescence color from blue to yellowish‐green upon the desorption of water molecules while keeping the high emission quantum yield of more than 0.45. Variable‐temperature and continuous in‐situ tracking of single‐crystal X‐ray diffraction measurements revealed that the SCSC transformation proceeds reversibly by the release and reabsorption of water molecules, thereby changing the stacked structure slightly. As a result, the dynamics of vapor‐induced SCSC transformation were elucidated: that the anhydrous form returned to the original trihydrate form in a two‐step process under a water vapor atmosphere. In addition, the PtII complex exhibited a similar SCSC response accompanied by a luminescence color change in the presence of methanol vapor, while being inactive toward ethanol vapor.
Out of the blue: The blue color of the luminescence of a PtII complex bearing an N‐heterocyclic carbene changes in response to the vapor atmosphere, although the single crystallinity and luminescence intensity are maintained. The vapor‐induced reversible and stepwise single‐crystal‐to‐single‐crystal (SCSC) transformations were elucidated by variable‐temperature and continuous in‐situ tracking of single‐crystal X‐ray diffraction measurements.
Aims
Epigenetics refers to changes in cell characteristics that occur independently of modifications to the DNA sequence. Oral carcinogenesis is influenced by modifications in epigenetic mechanisms, ...including changes in histones, which are proteins that support chromatin remodelling for the dynamic regulation of gene expression and silencing. The dysregulation of histone acetylation can lead to the uncontrolled activity of different genes, thereby triggering events associated with malignant transformation. The aim of this study was to analyse the expression of acetyl‐histone H3 at lys9 (H3K9ac) in oral leucoplakia (OL) and oral squamous cell carcinoma (OSCC) in addition to its association with cell proliferation, epithelial–mesenchymal transition (EMT) and clinical‐pathological findings.
Methods and results
Samples of normal oral mucosa (NOM), OL and OSCC were submitted to immunohistochemical analysis using anti‐H3K9ac, Ki67 and vimentin. Slides were submitted to quantitative analysis regarding the percentage of positive cells. OSCC presented less expression of H3K9ac in comparison to OL (P < 0.01), whereas Ki67 and vimentin levels increased from OL to OSCC (P < 0.001 and P = 0.03, respectively). OSCC patients with poor prognosis had less H3K9ac expression (P = 0.04). The Kaplan–Meier cumulative survival curves also revealed lower survival rates in patients with less H3K9ac expression (P < 0.01).
Conclusions
The present findings suggest that changes in H3K9ac occur during the process of oral carcinogenesis along with an increase in cell proliferation and EMT. The results demonstrate that H3K9ac may be a useful novel prognostic marker for OSCC.
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