Tumor therapy by targeting extracellular hydroxyapatite using novel drugs: A paradigm shift.

Background: It has been shown that tumor microenvironment (TME) hydroxyapatite (HAP) is typically associated with many malignancies and plays a role in tumor progression and growth. Additionally, acidosis in the TME has been reported to play a key role in selecting for a more aggressive tumor phenotype, drug resistance and desensitization to immunotherapy for many types of cancers. TME-HAP is an attractive target for tumor detection and treatment development since HAP is generally absent from normal soft tissue.

Non-Oncogene Addiction of -Mutant Cancers to IL-1β via Versican and Mononuclear IKKβ.

-mutant cancers are frequent, metastatic, lethal, and largely undruggable. While interleukin (IL)-1β and nuclear factor (NF)-κB inhibition hold promise against cancer, untargeted treatments are not effective. Here, we show that human -mutant cancers are addicted to IL-1β via inflammatory versican signaling to macrophage inhibitor of NF-κB kinase (IKK) β.

ATP spreads inflammation to other limbs through crosstalk between sensory neurons and interneurons.

Neural circuits between lesions are one mechanism through which local inflammation spreads to remote positions. Here, we show the inflammatory signal on one side of the joint is spread to the other side via sensory neuron-interneuron crosstalk, with ATP at the core. Surgical ablation or pharmacological inhibition of this neural pathway prevented inflammation development on the other side.

Stimulating TAM-mediated anti-tumor immunity with mannose-decorated nanoparticles in ovarian cancer.

Background: Current cancer immunotherapies have made tremendous impacts but generally lack high response rates, especially in ovarian cancer. New therapies are needed to provide increased benefits. One understudied approach is to target the large population of immunosuppressive tumor-associated macrophages (TAMs).

Panobinostat enhances olaparib efficacy by modifying expression of homologous recombination repair and immune transcripts in ovarian cancer.

Histone deacetylase inhibitors (HDACi) sensitize homologous recombination (HR)-proficient human ovarian cancer cells to PARP inhibitors (PARPi). To investigate mechanisms of anti-tumor effects of combined HDACi/PARPi treatment we performed transcriptome analysis in HR- proficient human ovarian cancer cells and tested drug effects in established immunocompetent mouse ovarian cancer models. Human SKOV-3 cells were treated with vehicle (Con), olaparib (Ola), panobinostat (Pano) or Pano+Ola and RNA-seq analysis performed.

Increasing Area Deprivation Index negatively impacts ovarian cancer survival.

Introduction: While individual-level measures of socioeconomic status have been well-studied in relation to ovarian cancer survival, no studies to date have examined both state and national-level Area Deprivation Indices (ADIs), which incorporate neighborhood affluence and resources.

Methods: We abstracted clinical data from medical records for ovarian cancer cases from the Vanderbilt University Medical Center and obtained ADIs from the Neighborhood Atlas®. Associations with clinical characteristics were assessed with Spearman correlations and Kruskal-Wallis tests; associations with progression-free survival (PFS) and overall survival (OS) were assessed with Cox proportional-hazards regression.

Increased canonical NF-kappaB signaling specifically in macrophages is sufficient to limit tumor progression in syngeneic murine models of ovarian cancer.

Background: New treatment options for ovarian cancer are urgently required. Tumor-associated macrophages (TAMs) are an attractive target for therapy; repolarizing TAMs from M2 (pro-tumor) to M1 (anti-tumor) phenotypes represents an important therapeutic goal. We have previously shown that upregulated NF-kappaB (NF-κB) signaling in macrophages promotes M1 polarization, but effects in the context of ovarian cancer are unknown.

Expression of p52, a non-canonical NF-kappaB transcription factor, is associated with poor ovarian cancer prognosis.

Background: The canonical and non-canonical nuclear factor-kappaB (NF-κB) signaling pathways have key roles in cancer, but studies have previously evaluated only the association of canonical transcription factors and ovarian cancer survival. Although a number of in vitro and in vivo studies have demonstrated mechanisms by which non-canonical NF-κB signaling potentially contributes to ovarian cancer progression, a prognostic association has yet to be shown in the clinical context.

Methods: We assayed p65 and p52 (major components of the canonical and non-canonical NF-κB pathways) by immunohistochemistry in epithelial ovarian tumor samples; nuclear and cytoplasmic staining were semi-quantified by H-scores and dichotomized at median values.

Enhanced Expression of Catalase in Mitochondria Modulates NF-κB-Dependent Lung Inflammation through Alteration of Metabolic Activity in Macrophages.

NF-κB is a reduction-oxidation-sensitive transcription factor that plays a key role in regulating the immune response. In these studies, we intended to investigate the role of mitochondrial-derived reactive oxygen species in regulating NF-κB activation by studying transgenic mice that overexpress mitochondrial-targeted human catalase (mCAT). We treated wild-type (WT) and mCAT mice with intratracheal instillation of LPS and found that mCAT mice had exaggerated NF-κB activation in the lungs, increased neutrophilic alveolitis, and greater lung inflammation/injury compared with WT mice.

Optimizing Mannose "Click" Conjugation to Polymeric Nanoparticles for Targeted siRNA Delivery to Human and Murine Macrophages.

"Smart", dual pH-responsive, and endosomolytic polymeric nanoparticles have demonstrated great potential for localized drug delivery, especially for siRNA delivery to the cytoplasm of cells. However, targeted delivery to a specific cell phenotype requires an additional level of functionality. Copper-catalyzed azide-alkyne cycloaddition (CuAAC) is a highly selective bioconjugation reaction that can be performed in conjunction with other polymerization techniques without adversely affecting reaction kinetics, but there exists some concern for residual copper causing cytotoxicity.

Bipolar Tumor-Associated Macrophages in Ovarian Cancer as Targets for Therapy.

Ovarian cancer, a rare but fatal disease, has been a challenging area in the field of gynecological cancer. Ovarian cancer is characterized by peritoneal metastasis, which is facilitated by a cross-talk between tumor cells and other cells in the tumor microenvironment (TME). In epithelial ovarian cancer, tumor-associated macrophages (TAMs) constitute over 50% of cells in the peritoneal TME and malignant ascites, and are potential targets for therapy.

Immunity drives regulation in cancer through NF-κB.

Ten-eleven translocation enzymes (TET1, TET2, and TET3), which induce DNA demethylation and gene regulation by converting 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC), are often down-regulated in cancer. We uncover, in basal-like breast cancer (BLBC), genome-wide 5hmC changes related to regulation. We further demonstrate that repression is associated with high expression of immune markers and high infiltration by immune cells.

p52 expression enhances lung cancer progression.

While many studies have demonstrated that canonical NF-κB signaling is a central pathway in lung tumorigenesis, the role of non-canonical NF-κB signaling in lung cancer remains undefined. We observed frequent nuclear accumulation of the non-canonical NF-κB component p100/p52 in human lung adenocarcinoma. To investigate the impact of non-canonical NF-κB signaling on lung carcinogenesis, we employed transgenic mice with doxycycline-inducible expression of p52 in airway epithelial cells.

IκB Kinase α Is Required for Development and Progression of -Mutant Lung Adenocarcinoma.

Although oncogenic activation of NFκB has been identified in various tumors, the NFκB-activating kinases (inhibitor of NFκB kinases, IKK) responsible for this are elusive. In this study, we determined the role of IKKα and IKKβ in -mutant lung adenocarcinomas induced by the carcinogen urethane and by respiratory epithelial expression of oncogenic Using NFκB reporter mice and conditional deletions of IKKα and IKKβ, we identified two distinct early and late activation phases of NFκB during chemical and genetic lung adenocarcinoma development, which were characterized by nuclear translocation of B, IκBβ, and IKKα in tumor-initiated cells. IKKα was a cardinal tumor promoter in chemical and genetic -mutant lung adenocarcinoma, and respiratory epithelial IKKα-deficient mice were markedly protected from the disease.

Epithelial NF-κB signaling promotes EGFR-driven lung carcinogenesis via macrophage recruitment.

Several studies have demonstrated that NF-κB activation is common in lung cancer; however, the mechanistic links between NF-κB signaling and tumorigenesis remain to be fully elucidated. We investigated the function of NF-κB signaling in epidermal growth factor receptor (EGFR)-mutant lung tumors using a transgenic mouse model with doxycycline (dox)-inducible expression of oncogenic EGFR in the lung epithelium with or without a dominant inhibitor of NF-κB signaling. NF-κB inhibition resulted in a significant reduction in tumor burden in both EGFR tyrosine kinase inhibitor (TKI)-sensitive and resistant tumors.

Neutrophil-Derived IL-1β Impairs the Efficacy of NF-κB Inhibitors against Lung Cancer.

Although epithelial NF-κB signaling is important for lung carcinogenesis, NF-κB inhibitors are ineffective for cancer treatment. To explain this paradox, we studied mice with genetic deletion of IKKβ in myeloid cells and found enhanced tumorigenesis in Kras(G12D) and urethane models of lung cancer. Myeloid-specific inhibition of NF-κB augmented pro-IL-1β processing by cathepsin G in neutrophils, leading to increased IL-1β and enhanced epithelial cell proliferation.

Manipulating the NF-κB pathway in macrophages using mannosylated, siRNA-delivering nanoparticles can induce immunostimulatory and tumor cytotoxic functions.

Tumor-associated macrophages (TAMs) are critically important in the context of solid tumor progression. Counterintuitively, these host immune cells can often support tumor cells along the path from primary tumor to metastatic colonization and growth. Thus, the ability to transform protumor TAMs into antitumor, immune-reactive macrophages would have significant therapeutic potential.

IL-1β and Inflammasome Activity Link Inflammation to Abnormal Fetal Airway Development.

Inflammation in the developing preterm lung leads to disrupted airway morphogenesis and chronic lung disease in human neonates. However, the molecular mechanisms linking inflammation and the pathways controlling airway morphogenesis remain unclear. In this article, we show that IL-1β released by activated fetal lung macrophages is the key inflammatory mediator that disrupts airway morphogenesis.

Activation of NF-κB drives the enhanced survival of adipose tissue macrophages in an obesogenic environment.

Objective: Macrophage accumulation in adipose tissue (AT) during obesity contributes to inflammation and insulin resistance. Recruitment of monocytes to obese AT has been the most studied mechanism explaining this accumulation. However, recent evidence suggests that recruitment-independent mechanisms may also regulate pro-inflammatory AT macrophage (ATM) numbers.

p52 Overexpression Increases Epithelial Apoptosis, Enhances Lung Injury, and Reduces Survival after Lipopolysaccharide Treatment.

Although numerous studies have demonstrated a critical role for canonical NF-κB signaling in inflammation and disease, the function of the noncanonical NF-κB pathway remains ill-defined. In lung tissue from patients with acute respiratory distress syndrome, we identified increased expression of the noncanonical pathway component p100/p52. To investigate the effects of p52 expression in vivo, we generated a novel transgenic mouse model with inducible expression of p52 in Clara cell secretory protein-expressing airway epithelial cells.

Microenvironmental effects limit efficacy of thymoquinone treatment in a mouse model of ovarian cancer.

Background: Ovarian cancer is the most lethal gynecologic malignancy, with limited treatment options for chemoresistant disease. An important link between inflammation and peritoneal spread of ovarian cancer is NF-κB signaling. Thymoquinone (TQ) exerts multiple anti-tumorigenic cellular effects, including NF-κB inhibition.

Aberrant activation of NF-κB signaling in mammary epithelium leads to abnormal growth and ductal carcinoma in situ.

Background: Approximately 1 in 5 women diagnosed with breast cancer are considered to have in situ disease, most often termed ductal carcinoma in situ (DCIS). Though recognized as a risk factor for the development of more invasive cancer, it remains unclear what factors contribute to DCIS development. It has been shown that inflammation contributes to the progression of a variety of tumor types, and nuclear factor kappa B (NF-κB) is recognized as a master-regulator of inflammatory signaling.

NF-κB-dependent airway inflammation triggers systemic insulin resistance.

Inflammatory lung diseases (e.g., pneumonia and acute respiratory distress syndrome) are associated with hyperglycemia, even in patients without a prior diagnosis of Type 2 diabetes.

Thymoquinone enhances cisplatin-response through direct tumor effects in a syngeneic mouse model of ovarian cancer.

Background: Ovarian cancer is the most lethal gynecologic malignancy characterized by the frequent development of resistance to platinum chemotherapy. Finding new drug combinations to overcome platinum resistance is a key clinical challenge. Thymoquinone (TQ) is a component of black seed oil that exerts multiple anti-tumorigenic effects on cells, including inhibition of NF-κB and promotion of DNA damage.

Interleukin-5 facilitates lung metastasis by modulating the immune microenvironment.

Although the lung is the most common metastatic site for cancer cells, biologic mechanisms regulating lung metastasis are not fully understood. Using heterotopic and intravenous injection models of lung metastasis in mice, we found that IL5, a cytokine involved in allergic and infectious diseases, facilitates metastatic colonization through recruitment of sentinel eosinophils and regulation of other inflammatory/immune cells in the microenvironment of the distal lung. Genetic IL5 deficiency offered marked protection of the lungs from metastasis of different types of tumor cells, including lung cancer, melanoma, and colon cancer.