scholarly journals Aging predisposes to acute inflammatory induced pathology after tumor immunotherapy

2013 ◽  
Vol 210 (11) ◽  
pp. 2223-2237 ◽  
Author(s):  
Myriam N. Bouchlaka ◽  
Gail D. Sckisel ◽  
Mingyi Chen ◽  
Annie Mirsoian ◽  
Anthony E. Zamora ◽  
...  
Keyword(s):  
Critical Role ◽  
The Elderly ◽  
Mouse Tumor ◽  
Aged Mice ◽  
Liver Histopathology ◽  
Multiple Organs ◽  
The Impact ◽  
Young Mice

Cancer commonly occurs in the elderly and immunotherapy (IT) is being increasingly applied to this population. However, the majority of preclinical mouse tumor models assessing potential efficacy and toxicities of therapeutics use young mice. We assessed the impact of age on responses to systemic immune stimulation. In contrast to young mice, systemic cancer IT regimens or LPS given to aged mice resulted in rapid and lethal toxicities affecting multiple organs correlating with heightened proinflammatory cytokines systemically and within the parenchymal tissues. This inflammatory response and increased morbidity with age was independent of T cells or NK cells. However, prior in vivo depletion of macrophages in aged mice resulted in lesser cytokine levels, increased survival, and decreased liver histopathology. Furthermore, macrophages from aged mice and normal human elderly volunteers displayed heightened TNF and IL-6 production upon in vitro stimulation. Treatment of both TNF knockout mice and in vivo TNF blockade in aged mice resulted in significant increases in survival and lessened pathology. Importantly, TNF blockade in tumor-bearing, aged mice receiving IT displayed significant anti-tumor effects. These data demonstrate the critical role of macrophages in the age-associated hyper-inflammatory cytokine responses to systemic immunostimulation and underscore the importance of performing preclinical assessments in aged mice.

scholarly journals Splenic Stromal Cells from Aged Mice Produce Higher Levels of IL-6 Compared to Young Mice

2014 ◽  
Vol 2014 ◽  
pp. 1-9 ◽  
Author(s):  
Jihyun Park ◽  
Takuya Miyakawa ◽  
Aya Shiokawa ◽  
Haruyo Nakajima-Adachi ◽  
Masaru Tanokura ◽  
...  
Keyword(s):  
Mrna Expression ◽  
Stromal Cells ◽  
The Elderly ◽  
Cell Types ◽  
Aged Mice ◽  
Chronic Inflammatory Condition ◽  
Inflammatory State ◽  
Principle Objective ◽  
Young Mice

Inflamm-aging indicates the chronic inflammatory state resulting from increased secretion of proinflammatory cytokines and mediators such as IL-6 in the elderly. Our principle objective was to identify cell types that were affected with aging concerning IL-6 secretion in the murine model. We compared IL-6 production in spleen cells from both young and aged mice and isolated several types of cells from spleen and investigated IL-6 mRNA expression and protein production. IL-6 protein productions in cultured stromal cells from aged mice spleen were significantly high compared to young mice upon LPS stimulation. IL-6 mRNA expression level of freshly isolated stromal cells from aged mice was high compared to young mice. Furthermore, stromal cells of aged mice highly expressed IL-6 mRNA after LPS injection in vivo. These results suggest that stromal cells play a role in producing IL-6 in aged mice and imply that they contribute to the chronic inflammatory condition in the elderly.

scholarly journals MicroRNA-28-5p Regulates Liver Cancer Stem Cell Expansion via IGF-1 Pathway

2019 ◽  
Vol 2019 ◽  
pp. 1-16 ◽  
Author(s):  
Qing Xia ◽  
Tao Han ◽  
Pinghua Yang ◽  
Ruoyu Wang ◽  
Hengyu Li ◽  
...  
Keyword(s):  
Stem Cells ◽  
Cancer Stem Cells ◽  
Liver Cancer ◽  
Critical Role ◽  
Self Renewal ◽  
Sorafenib Treatment ◽  
The Impact

Background. MicroRNAs (miRNAs) play a critical role in the regulation of cancer stem cells (CSCs). However, the role of miRNAs in liver CSCs has not been fully elucidated. Methods. Real-time PCR was used to detect the expression of miR-miR-28-5p in liver cancer stem cells (CSCs). The impact of miR-28-5p on liver CSC expansion was investigated both in vivo and in vitro. The correlation between miR-28-5p expression and sorafenib benefits in HCC was further evaluated in patient-derived xenografts (PDXs). Results. Our data showed that miR-28-5p was downregulated in sorted EpCAM- and CD24-positive liver CSCs. Biofunctional investigations revealed that knockdown miR-28-5p promoted liver CSC self-renewal and tumorigenesis. Consistently, miR-28-5p overexpression inhibited liver CSC’s self-renewal and tumorigenesis. Mechanistically, we found that insulin-like growth factor-1 (IGF-1) was a direct target of miR-28-5p in liver CSCs, and the effects of miR-28-5p on liver CSC’s self-renewal and tumorigenesis were dependent on IGF-1. The correlation between miR-28-5p and IGF-1 was confirmed in human HCC tissues. Furthermore, the miR-28-5p knockdown HCC cells were more sensitive to sorafenib treatment. Analysis of patient-derived xenografts (PDXs) further demonstrated that the miR-28-5p may predict sorafenib benefits in HCC patients. Conclusion. Our findings revealed the crucial role of the miR-28-5p in liver CSC expansion and sorafenib response, rendering miR-28-5p an optimal therapeutic target for HCC.

scholarly journals Can Hypoxic Conditioning Improve Bone Metabolism? A Systematic Review

2019 ◽  
Vol 16 (10) ◽  
pp. 1799 ◽  
Author(s):  
Marta Camacho-Cardenosa ◽  
Alba Camacho-Cardenosa ◽  
Rafael Timón ◽  
Guillermo Olcina ◽  
Pablo Tomas-Carus ◽  
...  
Keyword(s):  
Bone Metabolism ◽  
Critical Role ◽  
Hypoxia Inducible Factor ◽  
Experimental Studies ◽  
Hormonal Responses ◽  
Hypoxia Exposure ◽  
Ambient Oxygen ◽  
The Impact

Among other functions, hypoxia-inducible factor plays a critical role in bone–vascular coupling and bone formation. Studies have suggested that hypoxic conditioning could be a potential nonpharmacological strategy for treating skeletal diseases. However, there is no clear consensus regarding the bone metabolism response to hypoxia. Therefore, this review aims to examine the impact of different modes of hypoxia conditioning on bone metabolism. The PubMed and Web of Science databases were searched for experimental studies written in English that investigated the effects of modification of ambient oxygen on bone remodelling parameters of healthy organisms. Thirty-nine studies analysed the effect of sustained or cyclic hypoxia exposure on genetic and protein expression and mineralisation capacity of different cell models; three studies carried out in animal models implemented sustained or cyclic hypoxia; ten studies examined the effect of sustained, intermittent or cyclic hypoxia on bone health and hormonal responses in humans. Different modes of hypoxic conditioning may have different impacts on bone metabolism both in vivo and in vitro. Additional research is necessary to establish the optimal cyclical dose of oxygen concentration and exposure time.

scholarly journals IGF-I Regulates Pheochromocytoma Cell Proliferation and Survival In Vitro and In Vivo

Endocrinology ◽  
2012 ◽  
Vol 153 (8) ◽  
pp. 3724-3734 ◽  
Author(s):  
María Celia Fernández ◽  
Marcela Venara ◽  
Susana Nowicki ◽  
Héctor E. Chemes ◽  
Marta Barontini ◽  
...  
Keyword(s):  
Critical Role ◽  
Tumor Development ◽  
Receptor Expression ◽  
Vascular Density ◽  
Receptor System ◽  
Igf I ◽  
Tumor Phenotype ◽  
The Impact

IGFs are involved in malignant transformation and growth of several tissues, including the adrenal medulla. The present study was designed to evaluate the impact of IGF-I on pheochromocytoma development. We used a murine pheochromocytoma (MPC) cell line (MPC4/30) and an animal model with a reduction of 75% in circulating IGF-I levels [liver-IGF-I-deficient (LID) mice] to perform studies in vitro and in vivo. We found that, in culture, IGF-I stimulation increases proliferation, migration, and anchorage-independent growth, whereas it inhibits apoptosis of MPC cells. When injected to control and to LID mice, MPC cells grow and form tumors with features of pheochromocytoma. Six weeks after cell inoculation, all control mice developed sc tumors. In contrast, in 73% of LID mice, tumor development was delayed to 7–12 wk, and the remaining 27% did not develop tumors up to 12 wk after inoculation. LID mice harboring MPC cells and treated with recombinant human IGF-I (LID+) developed tumors as controls. Tumors developed in control, LID, and LID+ mice had similar histology and were similarly positive for IGF-I receptor expression. The apoptotic index was higher in tumors from LID mice compared with those from control mice, whereas vascular density was decreased. In summary, our work demonstrates that IGF-I has a critical role in maintaining tumor phenotype and survival of already transformed pheochromocytoma cells and is required for the initial establishment of these tumors, providing encouragement to carry on research studies to address the IGF-I/IGF-I receptor system as a target of therapeutic strategies for pheochromocytoma treatment in the future.

scholarly journals The Impact of Carboxylesterases in Drug Metabolism and Pharmacokinetics

2019 ◽  
Vol 20 (2) ◽  
pp. 91-102 ◽  
Author(s):  
Li Di
Keyword(s):  
Tissue Distribution ◽  
Critical Role ◽  
Individual Variability ◽  
Human Pharmacokinetics ◽  
Metabolizing Enzymes ◽  
Soft Drugs ◽  
Hydrolysis Of Esters ◽  
The Impact

Background:Carboxylesterases (CES) play a critical role in catalyzing hydrolysis of esters, amides, carbamates and thioesters, as well as bioconverting prodrugs and soft drugs. The unique tissue distribution of CES enzymes provides great opportunities to design prodrugs or soft drugs for tissue targeting. Marked species differences in CES tissue distribution and catalytic activity are particularly challenging in human translation.Methods:Review and summarization of CES fundamentals and applications in drug discovery and development.Results:Human CES1 is one of the most highly expressed drug metabolizing enzymes in the liver, while human intestine only expresses CES2. CES enzymes have moderate to high inter-individual variability and exhibit low to no expression in the fetus, but increase substantially during the first few months of life. The CES genes are highly polymorphic and some CES genetic variants show significant influence on metabolism and clinical outcome of certain drugs. Monkeys appear to be more predictive of human pharmacokinetics for CES substrates than other species. Low risk of clinical drug-drug interaction is anticipated for CES, although they should not be overlooked, particularly interaction with alcohols. CES enzymes are moderately inducible through a number of transcription factors and can be repressed by inflammatory cytokines.Conclusion:Although significant advances have been made in our understanding of CESs, in vitro - in vivo extrapolation of clearance is still in its infancy and further exploration is needed. In vitro and in vivo tools are continuously being developed to characterize CES substrates and inhibitors.

Effects of ALK1Fc treatment on prostate cancer cells interacting with bone and bone cells in bone metastasis models.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. e16576-e16576
Author(s):  
Marianna Kruithof-de Julio ◽  
Letizia Astrologo ◽  
Eugenio Zoni ◽  
Sofia Karkampouna ◽  
Peter C Gray ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Bone Metastasis ◽  
Cancer Cells ◽  
Bone Cells ◽  
Critical Role ◽  
Prostate Cancer Cells ◽  
Primary Prostate Cancer ◽  
The Impact

e16576 Background: Prostate cancer is the second most common cancer in men worldwide. Lethality is normally associated with the consequences of metastasis rather than the primary tumor. In particular, bone is the most frequent site of metastasis and once prostate tumor cells are engrafted in the skeleton, curative therapy is no longer possible. Bone morphogenetic proteins (BMPs) play a critical role in bone physiology and pathology. However, little is known about the role of BMP9 and its signaling receptors, ALK1 and ALK2, in prostate cancer and bone metastasis. In this context, we investigate the impact of BMP9 on primary prostate cancer and derived bone metastasis. Methods: The human ALK1 extracellular domain (ECD) binds BMP9 and BMP10 with high affinity. In order to study the effect of BMP9 in vitro and in vivo we use a soluble chimeric protein, consisting of ALK1 ECD fused to human Fc (ALK1Fc), for preventing the activation of endogenous signaling. ALK1Fc sequesters BMP9 and BMP10, preserving the activation of ALK1 through other ligands. Results: We show that ALK1Fc reduces BMP9-mediated signaling and decreases proliferation of highly metastatic and tumor initiating human prostate cancer cells in vitro. In line with these observations, we demonstrate that ALK1Fc reduces tumor growth in vivo in an orthotopic transplantation model. The propensity of the primary prostate cancer to metastasize to the bone is also investigated. In particular, we report how the ALK1Fc influences the prostate cancer cells in vitro and in vivo when these are probed in different bone settings (co-culture with bone cells and intraosseous transplantation in mice). Conclusions: Our study provides the first demonstration that ALK1Fc inhibits prostate cancer cells growth identifying BMP9 as a putative therapeutic target and ALK1Fc as a potential therapy. All together, these findings justify the ongoing clinical development of drugs blocking ALK1 and ALK2 receptor activity.

scholarly journals RhoH is critical for cell-microenvironment interactions in chronic lymphocytic leukemia in mice and humans

Blood ◽  
2012 ◽  
Vol 119 (20) ◽  
pp. 4708-4718 ◽  
Author(s):  
Anja Troeger ◽  
Amy J. Johnson ◽  
Jenna Wood ◽  
William G. Blum ◽  
Leslie A. Andritsos ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Critical Role ◽  
Disease Onset ◽  
Lymphocytic Leukemia ◽  
Cell Contact ◽  
Cell Microenvironment ◽  
The Impact ◽  
Cell Cell

Abstract Trafficking of B-cell chronic lymphocytic leukemia (CLL) cells to the bone marrow and interaction with supporting stromal cells mediates important survival and proliferation signals. Previous studies have demonstrated that deletion of Rhoh led to a delayed disease onset in a murine model of CLL. Here we assessed the impact of RhoH on homing, migration, and cell-contact dependent interactions of CLL cells. Rhoh−/− CLL cells exhibited reduced marrow homing and subsequent engraftment. In vitro migration toward the chemokines CXCL12 and CXCL13 and cell-cell interactions between Rhoh−/− CLL cells and the supporting microenvironment was reduced. In the absence of RhoH the distribution of phosphorylated focal adhesion kinase, a protein known to coordinate activation of the Rho GTPases RhoA and Rac, appeared less polarized in chemokine-stimulated Rhoh−/− CLL cells, and activation and localization of RhoA and Rac was dysregulated leading to defective integrin function. These findings in the Rhoh−/− CLL cells were subsequently demonstrated to closely resemble changes in GTPase activation observed in human CLL samples after in vitro and in vivo treatment with lenalidomide, an agent with known influence on microenvironment protection, and suggest that RhoH plays a critical role in prosurvival CLL cell-cell and cell-microenvironment interactions with this agent.

scholarly journals SREBP-1c/MicroRNA 33b Genomic Loci Control Adipocyte Differentiation

2016 ◽  
Vol 36 (7) ◽  
pp. 1180-1193 ◽  
Author(s):  
Nathan L. Price ◽  
Brandon Holtrup ◽  
Stephanie L. Kwei ◽  
Martin Wabitsch ◽  
Matthew Rodeheffer ◽  
...  
Keyword(s):  
Lipid Droplet ◽  
Target Genes ◽  
Adipocyte Differentiation ◽  
Regulatory Element ◽  
Critical Role ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
The Impact

White adipose tissue (WAT) is essential for maintaining metabolic function, especially during obesity. The intronic microRNAs miR-33a and miR-33b, located within the genes encoding sterol regulatory element-binding protein 2 (SREBP-2) and SREBP-1, respectively, are transcribed in concert with their host genes and function alongside them to regulate cholesterol, fatty acid, and glucose metabolism. SREBP-1 is highly expressed in mature WAT and plays a critical role in promotingin vitroadipocyte differentiation. It is unknown whether miR-33b is induced during or involved in adipogenesis. This is in part due to loss of miR-33b in rodents, precludingin vivoassessment of the impact of miR-33b using standard mouse models. This work demonstrates that miR-33b is highly induced upon differentiation of human preadipocytes, along withSREBP-1. We further report that miR-33b is an important regulator of adipogenesis, as inhibition of miR-33b enhanced lipid droplet accumulation. Conversely, overexpression of miR-33b impaired preadipocyte proliferation and reduced lipid droplet formation and the induction of peroxisome proliferator-activated receptor γ (PPARγ) target genes during differentiation. These effects may be mediated by targeting of HMGA2, cyclin-dependent kinase 6 (CDK6), and other predicted miR-33b targets. Together, these findings demonstrate a novel role of miR-33b in the regulation of adipocyte differentiation, with important implications for the development of obesity and metabolic disease.

scholarly journals Differential but Concerted Expression of HSD17B2, HSD17B3, SHBG and SRD5A1 Testosterone Tetrad Modulate Therapy Response and Susceptibility to Disease Relapse in Patients with Prostate Cancer

Cancers ◽  
2021 ◽  
Vol 13 (14) ◽  
pp. 3478
Author(s):  
Oluwaseun Adebayo Bamodu ◽  
Kai-Yi Tzou ◽  
Chia-Da Lin ◽  
Su-Wei Hu ◽  
Yuan-Hung Wang ◽  
...  
Keyword(s):  
Critical Role ◽  
Therapy Response ◽  
Migration And Invasion ◽  
Disease Relapse ◽  
Testosterone Metabolism ◽  
Aberrant Expression ◽  
Network Analyses ◽  
The Impact

Background: Testosterone plays a critical role in prostate development and pathology. However, the impact of the molecular interplay between testosterone-associated genes on therapy response and susceptibility to disease relapse in PCa patients remains underexplored. Objective: This study investigated the role of dysregulated or aberrantly expressed testosterone-associated genes in the enhanced dissemination, phenoconversion, and therapy response of treatment-resistant advanced or recurrent PCa. Methods: Employing a combination of multi-omics big data analyses, in vitro, ex vivo, and in vivo assays, we assessed the probable roles of HSD17B2, HSD17B3, SHBG, and SRD5A1-mediated testosterone metabolism in the progression, therapy response, and prognosis of advanced or castration-resistant PCa (CRPC). Results: Our bioinformatics-aided gene expression profiling and immunohistochemical staining showed that the aberrant expression of the HSD17B2, HSD17B3, SHBG, and SRD5A1 testosterone metabolic tetrad characterize androgen-driven PCa and is associated with disease progression. Reanalysis of the TCGA PRAD cohort (n = 497) showed that patients with SRD5A1-dominant high expression of the tetrad exhibited worse mid-term to long-term (≥5 years) overall survival, with a profoundly shorter time to recurrence, compared to those with low expression. More so, we observed a strong association between enhanced HSD17B2/SRD5A1 signaling and metastasis to distant lymph nodes (M1a) and bones (M1b), while upregulated HSD17B3/SHBG signaling correlated more with negative metastasis (M0) status. Interestingly, increased SHBG/SRD5A1 ratio was associated with metastasis to distant organs (M1c), while elevated SRD5A1/SHBG ratio was associated with positive biochemical recurrence (BCR) status, and shorter time to BCR. Molecular enrichment and protein–protein connectivity network analyses showed that the androgenic tetrad regulates testosterone metabolism and cross-talks with modulators of drug response, effectors of cell cycle progression, proliferation or cell motility, and activators/mediators of cancer stemness. Moreover, of clinical relevance, SHBG ectopic expression (SHBG_OE) or SRD5A1 knockout (sgSRD5A1) induced the acquisition of spindle fibroblastoid morphology by the round/polygonal metastatic PC-3 and LNCaP cells, attenuated their migration and invasion capability, and significantly suppressed their ability to form primary or secondary tumorspheres, with concomitant downregulation of stemness KLF4, OCT3/4, and drug resistance ABCC1, ABCB1 proteins expression levels. We also showed that metronomic dutasteride synergistically enhanced the anticancer effect of low-dose docetaxel, in vitro, and in vivo. Conclusion: These data provide proof of concept that re-reprogramming of testosterone metabolism through “SRD5A1 withdrawal” or “SHBG induction” is a workable therapeutic strategy for shutting down androgen-driven oncogenic signals, reversing treatment resistance, and repressing the metastatic/recurrent phenotypes of patients with PCa.

scholarly journals Tumor-associated myeloid cells provide critical support for T-ALL

Blood ◽  
2020 ◽  
Vol 136 (16) ◽  
pp. 1837-1850 ◽  
Author(s):  
Aram Lyu ◽  
Todd A. Triplett ◽  
Seo Hee Nam ◽  
Zicheng Hu ◽  
Dhivya Arasappan ◽  
...  
Keyword(s):  
T Cell ◽  
Mouse Models ◽  
Lymphoblastic Leukemia ◽  
Myeloid Cells ◽  
Clinical Samples ◽  
Multiple Organs ◽  
Primary Mouse ◽  
The Impact

Abstract Despite harboring mutations in oncogenes and tumor suppressors that promote cancer growth, T-cell acute lymphoblastic leukemia (T-ALL) cells require exogenous cells or signals to survive in culture. We previously reported that myeloid cells, particularly dendritic cells, from the thymic tumor microenvironment support the survival and proliferation of primary mouse T-ALL cells in vitro. Thus, we hypothesized that tumor-associated myeloid cells would support T-ALL in vivo. Consistent with this possibility, in vivo depletion of myeloid cells results in a significant reduction in leukemia burden in multiple organs in 2 distinct mouse models of T-ALL and prolongs survival. The impact of the myeloid compartment on T-ALL growth is not dependent on suppression of antitumor T-cell responses. Instead, myeloid cells provide signals that directly support T-ALL cells. Transcriptional profiling, functional assays, and acute in vivo myeloid-depletion experiments identify activation of IGF1R as a critical component of myeloid-mediated T-ALL growth and survival. We identify several myeloid subsets that have the capacity to directly support survival of T-ALL cells. Consistent with mouse models, myeloid cells derived from human peripheral blood monocytes activate IGF1R and directly support survival of primary patient T-ALL cells in vitro. Furthermore, enriched macrophage gene signatures in published clinical samples correlate with inferior outcomes for pediatric T-ALL patients. Collectively, these data reveal that tumor-associated myeloid cells provide signals critical for T-ALL growth in multiple organs in vivo and implicate tumor-associated myeloid cells and associated signals as potential therapeutic targets.

Sign in / Sign up

Export Citation Format

Share Document