Notch activity regulates tumor biology in a context-dependent and complex manner. Notch may act as an oncogene or a tumor suppressor gene even within the same tumor type. Recently, Notch signaling has been implicated in cellular senescence. Yet, it remains unclear as to how cellular senescence checkpoint functions may interact with Notch-mediated oncogenic and tumor suppressor activities. Herein, we used genetically engineered human esophageal keratinocytes and esophageal squamous cell carcinoma cells to delineate the functional consequences of Notch activation and inhibition along with pharmacological intervention and RNA interference (RNAi) experiments. When expressed in a tetracycline-inducible manner, the ectopically expressed activated form of Notch1 (ICN1) displayed oncogene-like characteristics inducing cellular senescence corroborated by the induction of G0/G1 cell-cycle arrest, Rb dephosphorylation, flat and enlarged cell morphology and senescence-associated β-galactosidase activity. Notch-induced senescence involves canonical CSL/RBPJ-dependent transcriptional activity and the p16INK4A-Rb pathway. Loss of p16INK4A or the presence of human papilloma virus (HPV) E6/E7 oncogene products not only prevented ICN1 from inducing senescence, but permitted ICN1 to facilitate anchorage-independent colony formation and xenograft tumor growth with increased cell proliferation and reduced squamous-cell differentiation. Moreover, Notch1 appears to mediate replicative senescence as well as TGF-β-induced cellular senescence in non-transformed cells and that HPV E6/E7 targets Notch1 for inactivation to prevent senescence, revealing a tumor suppressor attribute of endogenous Notch1. In aggregate, cellular senescence checkpoint functions may influence dichotomous Notch activities in the neoplastic context.
JARID1 proteins are histone demethylases that both regulate normal cell fates during development and contribute to the epigenetic plasticity that underlies malignant transformation. This H3K4 demethylase family participates in multiple repressive transcriptional complexes at promoters and has broader regulatory effects on chromatin that remain ill-defined. There is growing understanding of the oncogenic and tumor suppressive functions of JARID1 proteins, which are contingent on cell context and the protein isoform. Their contributions to stem cell-like de-differentiation, tumor aggressiveness, and therapy resistance in cancer have sustained interest in the development of JARID1 inhibitors. Here we review the diverse and context-specific functions of the JARID1 proteins that may impact the utilization of emerging targeted inhibitors of this histone demethylase family in cancer therapy.
Objectives/Hypothesis Delineate factors impacting creation and use of patient-derived xenografts (PDXs) of human papilloma virus-related (HPV+) head and neck squamous cell carcinomas (HNSCCs). Study Design Laboratory-based translational study. Methods 51 surgically resected HNSCCs, including 31 HPV+ cancers, were implanted into NOD/SCID/IL-2Rγ−/− (NSG) mice using standardized methodology. Clinical and pathologic factors were tested for association with engraftment. The gross, histologic, and molecular features of established HPV+ PDXs were analyzed in comparison to their tumors of origin. Results Negative HPV status and perineural invasion (PNI) were independent, additive factors associated with increased PDX formation. Epstein-Barr Virus-positive (EBV+) human large B-cell lymphomas grew from 32% of HPV+ HNSCC cases that failed to engraft. Successfully established HPV+ PDXs retained basaloid histology and often developed cystic growth patterns typical of HPV+ nodal metastases. They also maintained elevated p16INK4A levels and expression of E6/E7 viral oncogene transcripts. Conclusion Reduced engraftment by HPV+ tumors lacking PNI likely results in selection biases in HNSCC PDX models. Formation of EBV+ lymphomas in NSG mice further reduces generation of HPV+ models and must be ruled out before long-term use of PDXs. Nevertheless, retention of distinctive pathologic traits and viral oncogene expression by HPV+ PDXs provides a viable in vivo platform for basic and translational studies as well as a resource for generating advanced in vitro models.
The sperm protein fertilinbeta, a member of the ADAM family of proteins, is implicated in sperm-egg binding in all mammals studied to date. Multivalent inhibitors containing the three amino acid binding sequence of fertilinbeta, ECD, have been shown previously to be more effective inhibitors of fertilization than their monovalent counterparts. Here, we probed sperm-egg interactions with ruthenium-catalyzed ring-opening metathesis polymers that contained from 3 to 70 ECD pharmacophores in densities ranging from 10% to 100%. Evaluation of the polymer potencies, and synthesis of a triblock copolymer from two building blocks, revealed that two multivalent contacts are sufficient for maximal inhibition, and that the distance between ECD pharmacophores required is 7-9 monomers spanning 4-5 nm. We conclude that inhibition requires recruitment of two receptors on the egg surface into an inhibitory complex.
The degree of heterogeneity among cancer stem cells (CSC) remains ill-defined and may hinder effective anti-CSC therapy. Evaluation of oral cancers for such heterogeneity identified two compartments within the CSC pool. One compartment was detected using a reporter for expression of the H3K4me3 demethylase JARID1B to isolate a JARID1Bhigh fraction of cells with stem cell-like function. JARID1Bhigh cells expressed oral CSC markers including CD44 and ALDH1 and showed increased PI3-kinase (PI3K) pathway activation. They were distinguished from a fraction in a G0-like cell cycle state characterized by low reactive oxygen species and suppressed PI3K/AKT signaling. G0-like cells lacked conventional CSC markers but were primed to acquire stem cell-like function by upregulating JARID1B, which directly mediated transition to a state expressing known oral CSC markers. The transition was regulated by PI3K signals acting upstream of JARID1B expression, resulting in PI3K inhibition depleting JARID1Bhigh cells but expanding the G0-like subset. These findings define a novel developmental relationship between two cell phenotypes that may jointly contribute to CSC maintenance. Expansion of the G0-like subset during targeted depletion of JARID1Bhigh cells implicates it as a candidate therapeutic target within the oral CSC pool.
Epidemiological studies and clinical trials show that selenium supplementation results in reduction of prostate cancer incidence; however, the form of selenium and mechanisms underlying protection remain largely unknown. Toward this end, we compared the effects of naturally occurring selenomethionine (SM) and Semethylselenocysteine (MSC) and synthetic 1,4-phenylenebis(methylene)selenocyanate (p-XSC) and p-xylylbis(methylselenide) p-XMS) organoselenium compounds in androgen responsive (AR) LNCaP and its androgen independent clone (AI) LNCaP C4-2 human prostate carcinoma cells on cell growth, secretion of prostate specific antigen (PSA), intracellular redox status and genomic profiles with emphasis on identifying redox sensitive genes. Both p-XSC and p-XMS reduced cell number and total protein concentration compared to control-treated AR and AI cells, while SM and MSC exhibited no effect on growth of AR and AI cells. SM, p-XSC and p-XMS but not MSC inhibited levels of secreted PSA in AR cells. SM, MSC and p-XMS increased glutathione (GSH) levels in AI LNCaP cells. By contrast, in both cell types, only p-XSC significantly decreased GSH concentrations to <50% of control suggesting either an increase in intracellular oxidative stress or a change in GSH/GSSG ratio. On the basis of RT-PCR analysis, SM and p-XSC increased p53 gene expression by 2-fold in AR cells but not in AI cells and only SM enhanced epidermal growth factor receptor in AR cells. Depending on the structure, organoselenium compounds exhibit differential effects on growth, PSA secretion, oxidative stress and selective gene responses in human prostate cancer cells and suggest the potential of developing novel organoselenium compounds as chemopreventive agents in models of human prostate cancer. ' 2006 Wiley-Liss, Inc.Key words: selenomethionine; Se-methylselenocysteine; 1,4-phenylenebis (methylene)selenocyanate; p-xylylbis(methylselenide); prostate specific antigen; prostate cancer; chemoprevention; glutathione Epidemiological studies, clinical intervention trials and preclinical models have provided evidence for a protective role of organoselenium compounds against development of human cancers, including prostate cancer.  Although the anticancer mechanism(s) of selenium-enriched supplements have not been clearly defined, the dramatic outcome of Clark's trial prompted additional clinical trials: Prevention of Cancer by Intervention with Selenium (PRECISE), in 3 European countries, SELECT in the United States, and the Australian Prostate Cancer Prevention Trial Using Selenium (APPOSE) trial.  On the basis of available knowledge, there are compelling viewpoints to investigate systematically how organoselenium compounds modulate the most commonly considered risk factors in the development of prostate cancer not only in cancer patients or in high risk populations but more importantly for chemopreventive measures in healthy males as intended in the SELECT trial. 11Numerous studies strongly support the feasibility of using organ...
The lack of treatment for ''worried well'' patients with highgrade prostatic intraepithelial neoplasia combined with issues of recurrence and hormone resistance in prostate cancer survivors remains a major public health obstacle. The long latency of prostate cancer development provides an ample opportunity to intervene with mechanistically based chemopreventive agents at various stages of disease progression. Our rationale for selenium intervention is based on current mechanistic knowledge derived solely from preclinical investigations. Clearly, there is sufficient scientific support for its entry into current clinical trials, the outcome of which will be highly valuable in assessing whether selenium can be recommended for cancer survivors.
Therapeutic innovation for human papilloma virus-related (HPV+) head and neck squamous cell carcinomas (HNSCCs) is impaired by inadequate preclinical models and the absence of accurate biomarkers. Our study establishes the first well-characterized panel of patient-derived xenografts (PDXs) and organoids from HPV+ HNSCCs while determining fidelity of the models to the distinguishing genetic features of this cancer type. Despite low engraftment rates, whole exome sequencing showed that PDXs retain multiple distinguishing features of HPV+ HNSCC lost in existing cell lines, including PIK3CA mutations, TRAF3 deletion and the absence of EGFR amplifications. Engrafted HPV+ tumors frequently contained NOTCH1 mutations, thus providing new models for a negatively prognostic alteration in this disease. Genotypephenotype associations in the models were then tested for prediction of tumor progression and survival in published clinical cohorts. Observation of high tumor mutational burdens (TMBs) in the faster-growing models facilitated identification of a
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