MacroH2A impedes metastatic growth by enforcing a discrete dormancy program in disseminated cancer cells

AbstractMacroH2A variants have been associated with tumor suppression through inhibition of proliferation and metastasis, as well as their role in cellular senescence. However, their role in regulating the dormant state of disseminated cancer cells (DCCs) remains unclear. Here we reveal that solitary dormant DCCs display increased levels of macroH2A variants in head and neck squamous cell carcinoma PDX models and patient samples compared to proliferating primary or metastatic lesions. We further demonstrate that microenvironmental and stress adaptive signals such as TGFβ2 and p38α/β, which induce DCC dormancy, upregulate macroH2A expression. Functionally, we find that overexpression of macroH2A variants is sufficient to induce tumor cells into dormancy and notably, inducible expression of the macroH2A2 variant suppresses the growth of DCCs into overt metastasis. However, this dormant state does not require well-characterized dormancy factors such as DEC2 and NR2F1, suggesting alternate pathways. Our transcriptomic analyses reveal that macroH2A2 overexpression inhibits E2F, RAS and MYC signaling programs, while upregulating inflammatory cytokines commonly secreted by senescent cells. Taken together, our results demonstrate that macroH2A2 enforces a stable dormant phenotype in DCCs by activating a select subset of dormancy and senescence genes that limit metastasis initiation.

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Interferon Beta and Interferon Alpha 2a Differentially Protect Head and Neck Cancer Cells from Vesicular Stomatitis Virus-Induced Oncolysis

Journal of Virology ◽

10.1128/jvi.00757-15 ◽

2015 ◽

Vol 89 (15) ◽

pp. 7944-7954 ◽

Cited By ~ 17

Author(s):

Marlena M. Westcott ◽

Jingfang Liu ◽

Karishma Rajani ◽

Ralph D'Agostino ◽

Douglas S. Lyles ◽

...

Keyword(s):

Squamous Cell Carcinoma ◽

Cell Carcinoma ◽

Head And Neck ◽

Cancer Cells ◽

Tumor Cells ◽

Vesicular Stomatitis Virus ◽

Oncolytic Viruses ◽

Type I ◽

Normal Cells ◽

Vesicular Stomatitis

ABSTRACTOncolytic viruses (OV) preferentially kill cancer cells due in part to defects in their antiviral responses upon exposure to type I interferons (IFNs). However, IFN responsiveness of some tumor cells confers resistance to OV treatment. The human type I IFNs include one IFN-β and multiple IFN-α subtypes that share the same receptor but are capable of differentially inducing biological responses. The role of individual IFN subtypes in promoting tumor cell resistance to OV is addressed here. Two human IFNs which have been produced for clinical use, IFN-α2a and IFN-β, were compared for activity in protecting human head and neck squamous cell carcinoma (HNSCC) lines from oncolysis by vesicular stomatitis virus (VSV). Susceptibility of HNSCC lines to killing by VSV varied. VSV infection induced increased production of IFN-β in resistant HNSCC cells. When added exogenously, IFN-β was significantly more effective at protecting HNSCC cells from VSV oncolysis than was IFN-α2a. In contrast, normal keratinocytes and endothelial cells were protected equivalently by both IFN subtypes. Differential responsiveness of tumor cells to IFN-α and -β was further supported by the finding that autocrine IFN-β but not IFN-α promoted survival of HNSCC cells during persistent VSV infection. Therefore, IFN-α and -β differentially affect VSV oncolysis, justifying the evaluation and comparison of IFN subtypes for use in combination with VSV therapy. Pairing VSV with IFN-α2a may enhance selectivity of oncolytic VSV therapy for HNSCC by inhibiting VSV replication in normal cells without a corresponding inhibition in cancer cells.IMPORTANCEThere has been a great deal of progress in the development of oncolytic viruses. However, a major problem is that individual cancers vary in their sensitivity to oncolytic viruses. In many cases this is due to differences in their production and response to interferons (IFNs). The experiments described here compared the responses of head and neck squamous cell carcinoma cell lines to two IFN subtypes, IFN-α2a and IFN-β, in protection from oncolytic vesicular stomatitis virus. We found that IFN-α2a was significantly less protective for cancer cells than was IFN-β, whereas normal cells were equivalently protected by both IFNs. These results suggest that from a therapeutic standpoint, selectivity for cancer versus normal cells may be enhanced by pairing VSV with IFN-α2a.

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Cancer metabolism and intervention therapy

Molecular Biomedicine ◽

10.1186/s43556-020-00012-1 ◽

2021 ◽

Vol 2 (1) ◽

Author(s):

Huakan Zhao ◽

Yongsheng Li

Keyword(s):

Cancer Cells ◽

Tumor Cells ◽

Cancer Metabolism ◽

Aerobic Glycolysis ◽

Acid Synthesis ◽

Pentose Phosphate ◽

Metabolic Reprogramming ◽

Cancer Therapies ◽

Proliferation And Metastasis ◽

Immunosuppressive Microenvironment

AbstractMetabolic reprogramming with heterogeneity is a hallmark of cancer and is at the basis of malignant behaviors. It supports the proliferation and metastasis of tumor cells according to the low nutrition and hypoxic microenvironment. Tumor cells frantically grab energy sources (such as glucose, fatty acids, and glutamine) from different pathways to produce a variety of biomass to meet their material needs via enhanced synthetic pathways, including aerobic glycolysis, glutaminolysis, fatty acid synthesis (FAS), and pentose phosphate pathway (PPP). To survive from stress conditions (e.g., metastasis, irradiation, or chemotherapy), tumor cells have to reprogram their metabolism from biomass production towards the generation of abundant adenosine triphosphate (ATP) and antioxidants. In addition, cancer cells remodel the microenvironment through metabolites, promoting an immunosuppressive microenvironment. Herein, we discuss how the metabolism is reprogrammed in cancer cells and how the tumor microenvironment is educated via the metabolic products. We also highlight potential metabolic targets for cancer therapies.

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Multifaceted Aspects of Metabolic Plasticity in Human Cholangiocarcinoma: An Overview of Current Perspectives

Cells ◽

10.3390/cells9030596 ◽

2020 ◽

Vol 9 (3) ◽

pp. 596

Author(s):

Mirella Pastore ◽

Giulia Lori ◽

Alessandra Gentilini ◽

Maria Letizia Taddei ◽

Giovanni Di Maira ◽

...

Keyword(s):

Cell Growth ◽

Cancer Cells ◽

Tumor Cells ◽

Malignant Tumor ◽

Warburg Effect ◽

Signaling Networks ◽

Metabolic Plasticity ◽

Tumor Onset ◽

Key Players ◽

Proliferation And Metastasis

Cholangiocarcinoma (CCA) is a deadly tumor without an effective therapy. Unique metabolic and bioenergetics features are important hallmarks of tumor cells. Metabolic plasticity allows cancer cells to survive in poor nutrient environments and maximize cell growth by sustaining survival, proliferation, and metastasis. In recent years, an increasing number of studies have shown that specific signaling networks contribute to malignant tumor onset by reprogramming metabolic traits. Several evidences demonstrate that numerous metabolic mediators represent key-players of CCA progression by regulating many signaling pathways. Besides the well-known Warburg effect, several other different pathways involving carbohydrates, proteins, lipids, and nucleic acids metabolism are altered in CCA. The goal of this review is to highlight the main metabolic processes involved in the cholangio-carcinogeneis that might be considered as potential novel druggable candidates for this disease.

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Synthesis and Different Effects of Biotinylated PAMAM G3 Dendrimer Substituted with Nimesulide in Human Normal Fibroblasts and Squamous Carcinoma Cells

Biomolecules ◽

10.3390/biom9090437 ◽

2019 ◽

Vol 9 (9) ◽

pp. 437 ◽

Cited By ~ 1

Author(s):

Łukasz Uram ◽

Aleksandra Filipowicz-Rachwał ◽

Maria Misiorek ◽

Aleksandra Winiarz ◽

Elżbieta Wałajtys-Rode ◽

...

Keyword(s):

Squamous Cell Carcinoma ◽

Cell Carcinoma ◽

Cancer Cells ◽

Squamous Cell ◽

Caspase 3 ◽

Human Fibroblasts ◽

Normal Fibroblast ◽

Apoptosis Resistance ◽

Inhibition Of Proliferation ◽

Cox 2

Squamous cell carcinoma (SCC) remains a main cause of mortality in patients with neck and head cancers, with poor prognosis and increased prevalence despite of available therapies. Recent studies have identified a role of cyclooxygenases, particularly inducible isoform cyclooxygenase-2 (COX-2) and its metabolite prostaglandin E2 (PGE2) in cancer cell proliferation, and its inhibition become a target for control of cancer development, particularly in the view of recognized additive or synergic action of COX-2 inhibitors with other forms of therapy. Nimesulide (N), the selective COX-2 inhibitor, inhibits growth and proliferation of various types of cancer cells by COX-2 dependent and independent mechanisms. In the presented study, the conjugates of biotinylated third generation poly(amidoamine) dendrimer (PAMAM) with covalently linked 18 (G3B18N) and 31 (G3B31N) nimesulide residues were synthesized and characterized by NMR spectroscopy. Biological properties of conjugates were evaluated, including cytotoxicity, proliferation, and caspase 3/7 activities in relation to COX-2/PGE2 axis signaling in human normal fibroblast (BJ) and squamous cell carcinoma (SCC-15). Both conjugates exerted a selective cytotoxicity against SCC-15 as compared with BJ cells at low 1.25–10 µM concentration range and their action in cancer cells was over 250-fold stronger than nimesulide alone. Conjugates overcome apoptosis resistance and sensitized SCC-15 cells to the apoptotic death independently of COX-2/PGE2 axis. In normal human fibroblasts the same concentrations of G3B31N conjugate were less effective in inhibition of proliferation and induction of apoptosis, as measured by caspase 3/7 activity in a manner depending on increase of PGE2 production by either COX-1/COX-2.

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Role of exosomes in diagnosis and therapy of prostate cancer

I P Pavlov Russian Medical Biological Herald ◽

10.23888/pavlovj2020283399-405 ◽

2020 ◽

Vol 28 (3) ◽

pp. 399-405

Author(s):

Fabrizio Fontana ◽

Olga A. Babenko

Keyword(s):

Prostate Cancer ◽

Cancer Cells ◽

Tumor Cells ◽

Biological Fluids ◽

Diagnosis And Treatment ◽

Diagnosis And Therapy ◽

The Future ◽

Important Direction ◽

Potential Biomarkers

Aim of this letter is to attract the attention of journal readers to the study of exosomes as an important direction in the development of Oncology, in particular, in the diagnosis and treatment of prostate cancer. Exosomes are produced by tumor cells and regulate proliferation, metastasis, and the development of chemoresistance. Their extraction from biological fluids allows further use of these vesicles as potential biomarkers of prostate cancer. In the future, exosomes can be successfully used in the delivery of drugs and other anti-tumor substances to cancer cells.

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PD-L1 and survival in oral cavity squamous cell carcinoma

Periodontology ◽

10.33925/1683-3759-2020-25-4-287-294 ◽

2020 ◽

Vol 25 (4) ◽

pp. 287-294

Author(s):

S. I. Kutukova ◽

N. P. Beliak ◽

G. A. Raskin ◽

M. S. Mukhina ◽

Yu. V. Ivaskova ◽

...

Keyword(s):

Squamous Cell Carcinoma ◽

Oral Cavity ◽

Cell Carcinoma ◽

Tumor Cells ◽

Squamous Cell ◽

Immune Cells ◽

Negative Impact ◽

Progression Free Survival ◽

Negative Effect ◽

Effect Of Pd

Relevance. Prognostic value of PD-L1 expression in oral cavity squamous cell carcinoma (OCSCC) and its effect on survival is still controversial. It should be to determine the prognostic role of PD-L1 expression on tumor and immune cells of OCSCC and assess their effect on overall survival (OS) and progression-free survival (PFS).Materials and methods. A prospective study included 145 patients, first diagnosed with OCSCC. PD-L1 expression on tumor and immune cells, infiltrating tumor and its microenvironment, was assessed in all tumor samples by IHC, CPS was calculated. Cut-off values were determined by ROC analysis for identification of PD-L1 expression effect on OS and PFS.Results. Most patients with oral mucosa squamous cell carcinoma showed positive expression of PD-L1 on tumor (77.2%) and immune cells (92.4%). The median PD-L1 expression on tumor cells was 13.5% [1.0-40.0], the median PD-L1 expression on immune cells was 5.0% [1.0-11.0], and the median CPS – 18.0 [3.0-7.8]. Univariate and multivariate analyses revealed a significant negative effect of PD-L1 expression on immune cells ≤ 7% on OS (HR 0.66; 95% CI 0.45-0.93; p = 0.0498); PD-L1 expression in tumor cells ≤ 15% (HR 0.65; 95% CI 0.43-0.98; p = 0.0416) and CPS ≤ 21 (HR 0.62; 95% CI 0.44-0.92; p = 0.0183) for PFS. PD-L1 expression in tumor cells ≤ 6% (HR 0.71; 95% CI 0.47-1.08; p = 0.1096) and CPS ≤ 7 (RR 0.67; 95% CI 0.44-1.01; p = 0.0575) had a confident tendency to negative impact on OS.Conclusion. Positive PD-L1 expression in tumor and immune cells as well as CPS are effective additional factors in the prognosis of the disease course, OS and PFS in patients with OCSCC.

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Faculty Opinions recommendation of Intraosseous growth of human prostate cancer in implanted adult human bone: relationship of prostate cancer cells to osteoclasts in osteoblastic metastatic lesions.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1161153.621626 ◽

2009 ◽

Author(s):

Dietmar Werner Hutmacher ◽

Maria Woodruff

Keyword(s):

Prostate Cancer ◽

Cancer Cells ◽

Human Bone ◽

Human Prostate ◽

Human Prostate Cancer ◽

Prostate Cancer Cells ◽

Adult Human ◽

Metastatic Lesions ◽

Relationship Of

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Recent Advances on Therapeutic Peptides for Breast Cancer Treatment

Current Protein and Peptide Science ◽

10.2174/1389203721999201117123616 ◽

2020 ◽

Vol 21 ◽

Author(s):

Samad Beheshtirouy ◽

Farhad Mirzaei ◽

Shirin Eyvazi ◽

Vahideh Tarhriz

Keyword(s):

Breast Cancer ◽

Cancer Cells ◽

Tumor Cells ◽

Breast Cancer Cells ◽

Specific Binding ◽

High Specificity ◽

The Novel ◽

Anti Cancer ◽

Therapeutic Peptides ◽

Low Toxicity

: Breast cancer is a heterogeneous malignancy which is the second cause of mortality among women in the world. Increasing the resistance to anti-cancer drugs in breast cancer cells persuades researchers to search the novel therapies approaches for the treatment of the malignancy. Among the novel methods, therapeutic peptides which target and disrupt tumor cells have been of great interest. Therapeutic peptides are short amino acids monomer chains with high specificity to bind and modulate a protein interaction of interest. Several advantages of peptides such as specific binding on tumor cells surface, low molecular weight and low toxicity on normal cells make the peptides as an appealing therapeutic agents against solid tumors, particularly breast cancer. Also, National Institutes of Health (NIH) describes therapeutic peptides as suitable candidate for the treatment of drug-resistant breast cancer. In this review, we attempt to review the different therapeutic peptides against breast cancer cells which can be used in treatment and diagnosis of the malignancy. Meanwhile, we presented an overview of peptide vaccines which have been developed for the treatment of breast cancer.

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Bone Invasive Properties of Oral Squamous Cell Carcinoma and its Interactions with Alveolar Bone Cells: An In Vitro Study

Current Cancer Drug Targets ◽

10.2174/1568009618666181102144317 ◽

2019 ◽

Vol 19 (8) ◽

pp. 631-640 ◽

Cited By ~ 1

Author(s):

Omel Baneen Qallandar ◽

Faeza Ebrahimi ◽

Farhadul Islam ◽

Riajul Wahab ◽

Bin Qiao ◽

...

Keyword(s):

Squamous Cell Carcinoma ◽

Oral Squamous Cell Carcinoma ◽

Cell Carcinoma ◽

Cancer Cells ◽

Alveolar Bone ◽

Cultured Cells ◽

Bone Cells ◽

Bone Invasion ◽

Alveolar Bone Cells

Background: Co-culture of cancer cells with alveolar bone cells could modulate bone invasion and destructions. However, the mechanisms of interaction between oral squamous cell carcinoma (OSCC) and bone cells remain unclear. Objective: The aim of this study is to analyse the direct and indirect effects of OSCC cells in the stimulation of osteolytic activity and bone invasion. Methods: Direct co-culture was achieved by culturing OSCC (TCA8113) with a primary alveolar bone cell line. In the indirect co-culture, the supernatant of TCA8113 cells was collected to culture the alveolar bone cells. To assess the bone invasion properties, in vitro assays were performed. Results: The proliferation of co-cultured cancer cells was significantly (p<0.05) higher in comparison to the monolayer control cells. However, the proliferation rates were not significantly different between direct and indirect co-cultured cells with indirect co-cultured cells proliferated slightly more than the direct co-cultured cells. Invasion and migration capacities of co-cultured OSCC and alveolar bone cells enhanced significantly (p<0.05) when compared to that of control monolayer counterparts. Most importantly, we noted that OSCC cells directly co-cultured with alveolar bone cells stimulated pronounced bone collagen destruction. In addition, stem cells and epithelialmesenchymal transition markers have shown significant changes in their expression in co-cultured cells. Conclusion: In conclusion, the findings of this study highlight the importance of the interaction of alveolar bone cells and OSCC cells in co-culture setting in the pathogenesis of bone invasion. This may help in the development of potential future biotherapies for bone invasion in OSCC.

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