Targeting neurons in the tumor microenvironment with bupivacaine nanoparticles reduces breast cancer progression and metastases.
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ABSTRACT:
SUBMITTER: Kaduri M
PROVIDER: S-EPMC8494443 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Breast cancer brain metastases (BCBMs) represent a major cause of morbidity and mortality among patients with breast cancer. Chemotherapy, which is widely used to treat tumors outside of the brain, is often ineffective on BCBMs due to its inability to efficiently cross the blood-brain barrier (BBB). Although the BBB is partially disrupted in tumor lesions, it remains intact enough to prevent most therapeutics from entering the brain. Here, we report a nanotechnology approach that can overcome the BBB through synthesis of lexiscan-loaded, AMD3100-conjugated, shrinkable NPs, or LANPs. LANPs respond to neutrophil elastase-enriched tumor microenvironment by shrinking in size and disrupt the BBB in tumors through lexiscan-mediated modulation. LANPs recognize tumor cells through the interaction between AMD3100 and CXCR4, which are expressed in metastatic tumor cells. We demonstrate that the integration of tumor responsiveness, tumor targeting, and BBB penetration enables LANPs to penetrate metastatic lesions in the brain with high efficiency, and, when doxorubicin was encapsulated, LANPs effectively inhibited tumor growth and prolonged the survival of tumor-bearing mice. Due to their high efficiency in penetrating the BBB for BCBMs treatment, LANPs have the potential to be translated into clinical applications for improved treatment of patients with BCBMs.
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Project description:To better understand the role of tumor microenvironment in breast cancer progression, we combined laser capture microdissection and microarray analysis to provide a comprehensive catalog of gene expression changes in both tumor and tumor-associated stroma. Experiment Overall Design: We used LCM to isolate the epithelial and stroma compartments separately from each of 14 fresh frozen primary breast cancer biopsies. In the epithelial compartment, we captured normal (N) and malignant (DCIS or IDC or both where available) epithelium from each tissue slide. In the stroma compartment, we captured both normal stroma away from the malignant lesion (NSS) and the DCIS-associated stroma (ISS) and/or IDC-associated stroma (INVS) whenever possible.
| S-ECPF-GEOD-14548 | biostudies-other
Project description:Malignant gliomas can be counted to the most devastating tumors in humans. Novel therapies do not achieve significant prolonged survival rates. The cancer cells have an impact on the surrounding vital tissue and form tumor zones, which make up the tumor microenvironment. We investigated the effects of sunitinib, a small molecule multitargeted receptor tyrosine kinase inhibitor, on constituents of the tumor microenvironment such as gliomas, astrocytes, endothelial cells, and neurons. Sunitinib has a known anti-angiogenic effect. We found that sunitinib normalizes the aberrant tumor-derived vasculature and reduces tumor vessel pathologies (i.e. auto-loops). Sunitinib has only minor effects on the normal, physiological, non-proliferating vasculature. We found that neurons and astrocytes are protected by sunitinib against glutamate-induced cell death, whereas sunitinib acts as a toxin towards proliferating endothelial cells and tumor vessels. Moreover, sunitinib is effective in inducing glioma cell death. We determined the underlying pathways by which sunitinib operates as a toxin on gliomas and found vascular endothelial growth factor receptor 2 (VEGFR2, KDR/Flk1) as the main target to execute gliomatoxicity. The apoptosis-inducing effect of sunitinib can be mimicked by inhibition of VEGFR2. Knockdown of VEGFR2 can, in part, foster the resistance of glioma cells to receptor tyrosine kinase inhibitors. Furthermore, sunitinib alleviates tumor-induced neurodegeneration. Hence, we tested whether temozolomide treatment could be potentiated by sunitinib application. Here we show that sunitinib can amplify the effects of temozolomide in glioma cells. Thus, our data indicate that combined treatment with temozolomide does not abrogate the effects of sunitinib. In conclusion, we found that sunitinib acts as a gliomatoxic agent and at the same time carries out neuroprotective effects, reducing tumor-induced neurodegeneration. Thus, this report uncovered sunitinib's actions on the brain tumor microenvironment, revealing novel aspects for adjuvant approaches and new clinical assessment criteria when applied to brain tumor patients.
| S-EPMC4399021 | biostudies-literature
Project description:This SuperSeries is composed of the SubSeries listed below.
2024-03-22 | GSE261780 | GEO
Project description:Systemic exposure to starch-coated iron oxide nanoparticles (IONPs) can stimulate antitumor T cell responses, even when little IONP is retained within the tumor. Here, we demonstrate in mouse models of metastatic breast cancer that IONPs can alter the host immune landscape leading to systemic immune-mediated disease suppression. We report that a single intravenous injection of IONPs can inhibit primary tumor growth, suppress metastases, and extend survival. Gene expression analysis revealed activation of Toll-like receptor (TLR) pathways involving signaling via Toll/Interleukin-1 Receptor domain-containing adaptor-inducing IFN-β (TRIF), a TLR pathway adaptor protein. Requisite participation of TRIF in suppressing tumor progression was demonstrated with histopathologic evidence of upregulated IFN-regulatory factor 3 (IRF3), a downstream protein, and confirmed in a TRIF knockout syngeneic mouse model of metastatic breast cancer. Neither starch-coated polystyrene nanoparticles lacking iron, nor iron-containing dextran-coated parenteral iron replacement agent induced significant antitumor effects suggesting a dependence on the type of IONP formulation. Analysis of multiple independent clinical databases support a hypothesis that upregulation of TLR3 and IRF3 correlates with increased overall survival among breast cancer patients. Taken together, these data support a compelling rationale to re-examine IONP formulations as harboring anti-cancer immune (nano)adjuvant properties to generate therapeutic benefit without requiring uptake by cancer cells. HuHER2 transgenic mice that developed palpable primary mammary tumors were assigned randomly into one of two groups (n = 3/group) to receive either PBS or BP (5 mg Fe/mouse). Mice were sacrificed 7 days after treatment and tumors, lungs, livers, spleens, lymph nodes, and bone marrows were collected. All nanoparticle-containing organs collected from BP treated mice were divided into two equal sections except for lungs (no detectable nanoparticle accumulation). One section was processed for RNA isolation from whole organ. The other tissue/organ section was further processed for magnetic sorting. These were digested to provide single cells as described before28,38 and nanoparticle associated cells were separated magnetically to obtain the nanoparticle-associated fraction (BP-NA). RNA was isolated from BP-NA cells from each organ and tumor and used for sequencing. For Nanostring analysis, HuHER2 transgenic tumor bearing mice were treated with PBS or BP (5 mg Fe) on the day of tumor detection (n = 12/group). Three mice from each group were sacrificed on day 1, 3, 7, or 31 and primary tumors collected for RNA isolation and gene expression analysis by Nanostring using the pan-immune cell marker panel.
2024-03-22 | GSE261779 | GEO
Project description:BackgroundSyndecan-1 (Sdc1), a cell surface heparan sulfate proteoglycan normally expressed primarily by epithelia and plasma cells, is aberrantly induced in stromal fibroblasts of breast carcinomas. Stromal fibroblast-derived Sdc1 participates in paracrine growth stimulation of breast carcinoma cells and orchestrates stromal extracellular matrix fiber alignment, thereby creating a migration and invasion-permissive microenvironment. Here, we specifically tested the role of stromal Sdc1 in metastasis.MethodsThe metastatic potential of the aggressive mouse mammary carcinoma cell lines, 4T1 and E0776, was tested in wild-type and genetically Sdc1-deficient host animals. Metastatic lesions were characterized by immunohistochemical analysis.ResultsAfter orthotopic inoculation, the lung metastatic burden was reduced in Sdc1-/- animals by 97% and more than 99%, in BALB/cJ and C57BL/6 animals, respectively. The difference in metastatic efficiency was maintained when the tumor cells were injected into the tail vein, suggesting that host Sdc1 exerts its effect during later stages of the metastatic cascade. Co-localization studies identified Sdc1 expression in stromal fibroblasts within the metastatic microenvironment and in normal airway epithelial cells but not in other cells (endothelial cells, ?-smooth muscle actin positive cells, leucocytes, macrophages). The Ki67 proliferation index and the rate of apoptosis of the metastatic tumor cells were diminished in Sdc1-/- vs. Sdc1+/+ animals, and leucocyte density was indistinguishable. Sdc1-mediated metastatic efficiency was abolished when the animals were housed at a thermoneutral ambient temperature of 31 °C, suggesting that the host Sdc1 effect on metastasis requires mild cold stress.ConclusionsIn summary, Sdc1 is induced in the lung microenvironment after mammary carcinoma cell dissemination and promotes outgrowth of metastases in a temperature-dependent manner.
| S-EPMC6034333 | biostudies-literature
Project description:Systemic exposure to starch-coated iron oxide nanoparticles (IONPs) can stimulate antitumor T cell responses, even when little IONP is retained within the tumor. Here, we demonstrate in mouse models of metastatic breast cancer that IONPs can alter the host immune landscape leading to systemic immune-mediated disease suppression. We report that a single intravenous injection of IONPs can inhibit primary tumor growth, suppress metastases, and extend survival. Gene expression analysis revealed activation of Toll-like receptor (TLR) pathways involving signaling via Toll/Interleukin-1 Receptor domain-containing adaptor-inducing IFN-β (TRIF), a TLR pathway adaptor protein. Requisite participation of TRIF in suppressing tumor progression was demonstrated with histopathologic evidence of upregulated IFN-regulatory factor 3 (IRF3), a downstream protein, and confirmed in a TRIF knockout syngeneic mouse model of metastatic breast cancer. Neither starch-coated polystyrene nanoparticles lacking iron, nor iron-containing dextran-coated parenteral iron replacement agent induced significant antitumor effects suggesting a dependence on the type of IONP formulation. Analysis of multiple independent clinical databases support a hypothesis that upregulation of TLR3 and IRF3 correlates with increased overall survival among breast cancer patients. Taken together, these data support a compelling rationale to re-examine IONP formulations as harboring anti-cancer immune (nano)adjuvant properties to generate therapeutic benefit without requiring uptake by cancer cells.
2024-03-22 | GSE261778 | GEO
Project description:The bone marrow constitutes an unique microenvironment for cancer cells in three specific aspects. First, the bone marrow actively recruits circulating tumor cells where they find a sanctuary rich in growth factors and cytokines that promote their proliferation and survival. When in the bone marrow, tumor cells profoundly affect the homeostasis of the bone and the balance between osteogenesis and osteolysis. As a consequence, growth and survival factors normally sequestered into the bone matrix are released, further fueling cancer progression. Second, tumor cells actively recruit bone marrow-derived precursor cells into their own microenvironment. When in the tumors, these bone marrow-derived cells contribute to an inflammatory reaction and to the formation of the tumor vasculature. Third, bone marrow-derived cells can home in distant organs, where they form niches that attract circulating tumor cells. Our understanding of the contribution of the bone marrow microenvironment to cancer progression has therefore dramatically improved over the last few years. The importance of this new knowledge cannot be underestimated considering that the vast majority of cancer treatments such as cytotoxic and myeloablative chemotherapy, bone marrow transplantation and radiation therapy inflict a trauma to the bone marrow microenvironment. How such trauma affects the influence that the bone marrow microenvironment exerts on cancer is still poorly understood. In this article, the reciprocal relationship between the bone marrow microenvironment and tumor cells is reviewed, and its potential impact on cancer therapy is discussed.
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Project description:Active targeting of nanoscale drug carriers can improve tumor-specific delivery; however, cellular heterogeneity both within and among tumor sites is a fundamental barrier to their success. Here, we describe a tumor microenvironment-responsive layer-by-layer (LbL) polymer drug carrier that actively targets tumors based on two independent mechanisms: pH-dependent cellular uptake at hypoxic tumor pH and hyaluronan-directed targeting of cell-surface CD44 receptor, a well-characterized biomarker for breast and ovarian cancer stem cells. Hypoxic pH-induced structural reorganization of hyaluronan-LbL nanoparticles was a direct result of the nature of the LbL electrostatic complex, and led to targeted cellular delivery in vitro and in vivo, with effective tumor penetration and uptake. The nanoscale drug carriers selectively bound CD44 and diminished cancer cell migration in vitro, while co-localizing with the CD44 receptor in vivo. Multimodal targeting of LbL nanoparticles is a powerful strategy for tumor-specific cancer diagnostics and therapy that can be accomplished using a single bilayer of polyamine and hyaluronan that, when assembled, produce a dynamic and responsive cell-particle interface.
| S-EPMC4148172 | biostudies-literature
Project description:Goodpasture antigen-binding protein (GPBP) is an exportable1 Ser/Thr kinase that induces collagen IV expansion and has been associated with chemoresistance following epithelial-to-mesenchymal transition (EMT). Here we demonstrate that cancer EMT phenotypes secrete GPBP (mesenchymal GPBP) which displays a predominant multimeric oligomerization and directs the formation of previously unrecognized mesh collagen IV networks (mesenchymal collagen IV). Yeast two-hybrid (YTH) system was used to identify a 260SHCIE264 motif critical for multimeric GPBP assembly which then facilitated design of a series of potential peptidomimetics. The compound 3-[4''-methoxy-3,2'-dimethyl-(1,1';4',1'')terphenyl-2''-yl]propionic acid, or T12, specifically targets mesenchymal GPBP and disturbs its multimerization without affecting kinase catalytic site. Importantly, T12 reduces growth and metastases of tumors populated by EMT phenotypes. Moreover, low-dose doxorubicin sensitizes epithelial cancer precursor cells to T12, thereby further reducing tumor load. Given that T12 targets the pathogenic mesenchymal GPBP, it does not bind significantly to normal tissues and therapeutic dosing was not associated with toxicity. T12 is a first-in-class drug candidate to treat cancer by selectively targeting the collagen IV of the tumor cell microenvironment.
| S-EPMC5834258 | biostudies-literature