20 research outputs found
An <em>In Vitro</em> Dormancy Model of Estrogen-sensitive Breast Cancer in the Bone Marrow: A Tool for Molecular Mechanism Studies and Hypothesis Generation
Reawakening of dormant estrogen-dependent human breast cancer cells by bone marrow stroma secretory senescence
Abstract Background Dormant estrogen receptor positive (ER+) breast cancer micrometastases in the bone marrow survive adjuvant chemotherapy and recur stochastically for more than 20 years. We hypothesized that inflammatory cytokines produced by stromal injury can re-awaken dormant breast cancer cells. Methods We used an established in vitro dormancy model of Michigan Cancer Foundation-7 (MCF-7) breast cancer cells incubated at clonogenic density on fibronectin-coated plates to determine the effects of inflammatory cytokines on reactivation of dormant ER+ breast cancer cells. We measured induction of a mesenchymal phenotype, motility and the capacity to re-enter dormancy. We induced secretory senescence in murine stromal monolayers by oxidation, hypoxia and estrogen deprivation with hydrogen peroxide (H2O2), carbonyl-cyanide m-chlorophenylhydrazzone (CCCP) and Fulvestrant (ICI 182780), respectively, and determined the effects on growth of co-cultivated breast cancer cells. Results Exogenous recombinant human (rh) interleukin (IL)-6, IL-8 or transforming growth factor β1 (TGFβ1) induced regrowth of dormant MCF-7 cells on fibronectin-coated plates. Dormant cells had decreased expression of E-cadherin and estrogen receptor α (ERα) and increased expression of N-cadherin and SNAI2 (SLUG). Cytokine or TGFβ1 treatment of dormant clones induced formation of growing clones, a mesenchymal appearance, increased motility and an impaired capacity to re-enter dormancy. Stromal injury induced secretion of IL-6, IL-8, upregulated tumor necrosis factor alpha (TNFα), activated TGFβ and stimulated the growth of co-cultivated MCF-7 cells. MCF-7 cells induced secretion of IL-6 and IL-8 by stroma in co-culture. Conclusions Dormant ER+ breast cancer cells have activated epithelial mesenchymal transition (EMT) gene expression programs and downregulated ERα but maintain a dormant epithelial phenotype. Stromal inflammation reactivates these cells, induces growth and a mesenchymal phenotype. Reactivated, growing cells have an impaired ability to re-enter dormancy. In turn, breast cancer cells co-cultured with stroma induce secretion of IL-6 and IL-8 by the stroma, creating a positive feedback loop
Mesenchymal Stem Cell–Secreted Extracellular Vesicles Instruct Stepwise Dedifferentiation of Breast Cancer Cells into Dormancy at the Bone Marrow Perivascular Region
The Consequences of Corruption on Inflation in Developing Countries: Evidence from Panel Cointegration and Causality Tests
Synthesis and Evaluation of Biological Activities for a Novel 1,2,3,4-Tetrahydroisoquinoline Conjugate with Dipeptide Derivatives: Insights from Molecular Docking and Molecular Dynamics Simulations
Targeting dormant micrometastases: rationale, evidence to date and clinical implications
Diffusion of indium along [001] SnGe interphase boundaries: Prewetting phase transition and critical phenomena
Synthesis and Evaluation of Biological Activities for a Novel 1,2,3,4-Tetrahydroisoquinoline Conjugate with Dipeptide Derivatives: Insights from Molecular Docking and Molecular Dynamics Simulations
Peptide synthesis
has opened new frontiers in the quest
for bioactive
molecules with limitless biological applications. This study presents
the synthesis of a series of novel isoquinoline dipeptides using advanced
spectroscopic techniques for characterization. These compounds were
designed with the goal of discovering unexplored biological activities
that could contribute to the development of novel pharmaceuticals.
We evaluated the biological activities of novel compounds including
their antimicrobial, antibacterial, and antifungal properties. The
results show promising activity against Escherichia
coli and potent antibacterial activity against MTCC
443 and MTCC 1688. Furthermore, these compounds demonstrate strong
antifungal activity, outperforming existing standard drugs. Computational
binding affinity studies of tetrahydroisoquinoline-conjugated dipeptides
against E. coli DNA gyrase displayed
significant binding interactions and binding affinity, which are reflected
in antimicrobial activities of compounds. Our integrative significant
molecular findings from both wet and dry laboratories would help pave
a path for the development of antimicrobial therapeutics. The findings
suggest that these isoquinoline-conjugated dipeptides could be excellent
candidates for drug development, with potential applications in the
fight against bacterial and fungal infections. This research represents
an exciting step forward in the field of peptide synthesis and its
potential to discover novel bioactive molecules with significant implications
for human health