scholarly journals Novel Iodine nanoparticles target vascular mimicry in intracerebral triple negative human MDA-MB-231 breast tumors

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Sharif M. Ridwan ◽  
James F. Hainfeld ◽  
Vanessa Ross ◽  
Yaroslav Stanishevskiy ◽  
Henry M. Smilowitz
Keyword(s):  
Tumor Cells ◽  
Triple Negative ◽  
Breast Cancers ◽  
Unique Form ◽  
X Ray ◽  
Fluorescence Confocal Microscopy ◽  
Tumor Periphery ◽  
Tumor Center ◽  
Tumor Homing ◽  
Vascular Mimicry

AbstractTriple negative breast cancer (TNBC), ~ 10–20% of diagnosed breast cancers, metastasizes to brain, lungs, liver. Iodine nanoparticle (INP) radioenhancers specifically localize to human TNBC MDA-MB-231 tumors growing in mouse brains after iv injection, significantly extending survival of mice after radiation therapy (RT). A prominent rim of INP contrast (MicroCT) previously seen in subcutaneous tumors but not intracerebral gliomas, provide calculated X-ray dose-enhancements up to > eightfold. Here, MDA-MB-231-cells, INPs, CD31 were examined by fluorescence confocal microscopy. Most INP staining co-localized with CD31 in the tumor center and periphery. Greatest INP/CD31 staining was in the tumor periphery, the region of increased MicroCT contrast. Tumor cells are seen to line irregularly-shaped spaces (ISS) with INP, CD31 staining very close to or on the tumor cell surface and PAS stain on their boundary and may represent a unique form of CD31-expressing vascular mimicry in intracerebral 231-tumors. INP/CD31 co-staining is also seen around ISS formed around tumor cells migrating on CD31+ blood-vessels. The significant radiation dose enhancement to the prolific collagen I containing, INP-binding ISS found throughout the tumor but concentrated in the tumor rim, may contribute significantly to the life extensions observed after INP-RT; VM could represent a new drug/NP, particularly INP, tumor-homing target.

scholarly journals EXTH-03. IODINE NANOPARTICLE RADIOTHERAPY OF HUMAN BREAST CANCER GROWING IN THE BRAINS OF ATHYMIC MICE

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii87-ii87
Author(s):  
James Hainfeld ◽  
Sharif M Ridwan ◽  
Yaroslav Stanishevsky ◽  
Henry Smilowitz
Keyword(s):  
Breast Cancer ◽  
Tumor Cells ◽  
X Rays ◽  
Breast Cancers ◽  
Dose Enhancement ◽  
Fluorescence Confocal Microscopy ◽  
Tumor Periphery ◽  
Tumor Center ◽  
Tumor Homing ◽  
Vascular Mimicry

Abstract About 30% of breast cancers metastasize to brain; those widely disseminated are fatal typically in 3–4 months, even with the best available surgery, drugs, and radiotherapy. To address this dire situation, we have developed iodine nanoparticles (INPs) that target brain tumors after intravenous (IV) injection. The iodine then absorbs X-rays during radiotherapy (RT), creating free radicals and local tumor damage, effectively boosting the local RT dose at the tumor. Efficacy was tested using the very aggressive human triple negative breast cancer (TNBC, MDA-MB-231 cells) growing in the brains of athymic nude mice. With a well-tolerated non-toxic IV dose of the INPs (7 g iodine/kg body weight), tumors showed a heavily iodinated rim surrounding the tumor having an average uptake of 2.9% iodine by weight (peaks at 4.5%), calculated to provide dose enhancement factors of ~5.5 (peaks at 8.0) -- the highest ever reported for any radio-sensitizing agents. With 15 Gy, single dose RT, all animals died by 72 days; INP pretreatment resulted in longer-term remissions with 40% of mice surviving 150 days and 30% surviving > 280 days. Fluorescence confocal microscopy revealed most INP staining co-localized with CD31in the tumor center and periphery. Greatest INP/CD31 staining was in the tumor periphery, the region of increased MicroCT contrast. Tumor cells line irregularly-shaped spaces (ISS) with INP, CD31 staining very close to or on the tumor cell surface and PAS stain on their boundary and may represent a unique form of CD31-expressing vascular mimicry in intracerebral 231-tumors. INP/CD31 co-staining is also seen around ISS formed around tumor cells migrating on CD31+blood-vessels. The significant radiation dose enhancement to the prolific INP-binding ISS found throughout the tumor but concentrated in the tumor rim, may contribute significantly to the life extensions observed after INP-RT; VM could represent a new NP, particularly INP, tumor-homing target.

scholarly journals Increased lysosomal biomass is responsible for the resistance of triple-negative breast cancers to CDK4/6 inhibition

2020 ◽  
Vol 6 (25) ◽  
pp. eabb2210 ◽  
Author(s):  
Anne Fassl ◽  
Christopher Brain ◽  
Monther Abu-Remaileh ◽  
Iga Stukan ◽  
Deborah Butter ◽  
...  
Keyword(s):  
Tumor Cell ◽  
Tumor Cells ◽  
Hormone Receptor ◽  
Triple Negative ◽  
Breast Cancers ◽  
Cyclin Dependent Kinases ◽  
Hormone Receptor Positive ◽  
Inhibitor Compounds ◽  
Resistant Cells

Inhibitors of cyclin-dependent kinases CDK4 and CDK6 have been approved for treatment of hormone receptor–positive breast cancers. In contrast, triple-negative breast cancers (TNBCs) are resistant to CDK4/6 inhibition. Here, we demonstrate that a subset of TNBC critically requires CDK4/6 for proliferation, and yet, these TNBC are resistant to CDK4/6 inhibition due to sequestration of CDK4/6 inhibitors into tumor cell lysosomes. This sequestration is caused by enhanced lysosomal biogenesis and increased lysosomal numbers in TNBC cells. We developed new CDK4/6 inhibitor compounds that evade the lysosomal sequestration and are efficacious against resistant TNBC. We also show that coadministration of lysosomotropic or lysosome-destabilizing compounds (an antibiotic azithromycin, an antidepressant siramesine, an antimalaria compound chloroquine) renders resistant tumor cells sensitive to currently used CDK4/6 inhibitors. Lastly, coinhibition of CDK2 arrested proliferation of CDK4/6 inhibitor-resistant cells. These observations may extend the use of CDK4/6 inhibitors to TNBCs that are refractory to current anti-CDK4/6 therapies.

Preclinical efficacy of the combination of olaparib plus carboplatin with vandetanib in triple-negative breast cancer.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. e13579-e13579 ◽  
Author(s):  
Nandini Dey ◽  
Hui Wu ◽  
Yuliang Sun ◽  
Pradip De ◽  
Brian Leyland-Jones
Keyword(s):  
Breast Cancer ◽  
Tumor Cells ◽  
Triple Negative ◽  
Clonogenic Assay ◽  
Directed Migration ◽  
Tnbc Cell ◽  
Huvec Cells ◽  
Vascular Mimicry

e13579 Background: BRCA1-deficiency confers sensitivity to PARP1 inhibition (alone or in combination with platinum compounds) in triple-negative breast cancer (TNBC). Recent understanding of the biology of TNBC tumor cells has recognized molecular targets suitable for treatment with targeted therapeutics including cell surface RTK(s), such as EGFR. Methods: We studied the effect of combination of PARP inhibitor, (olaparib) plus carboplatin with a dual EGFR/VEGFR inhibitor, vandetanib in a TNBC model in both in vitro and in vivo settings. We tested the effects of drug combinations on (a) cell signaling marker(s) of survival/proliferation/apoptosis, (b) adhesion-dependent and clonogenic survival, and (c) different phenotypes (migration, invasion, vascular mimicry, and cord formation) using TNBC cell and HUVEC cells. The combination of PARP1 inhibition and EGFR/VEGFR inhibition was evaluated in tumor-bearing athymic mice treated with olaparib plus carboplatin and vandetanib. Results: Data showed that, (1) EC50s for vandetanib ranged from 5-15 µM, (2) vandetanib (10 µM) inhibited phosphorylation of AKT (S473 & T308), S6RP, 4EBP1 and ERK, (3) effect of olaparib on TNBC cell survival can be effectively studied in vitro by clonogenic assay, (4) TNBC cell lines exhibited higher sensitivity to vandetanib in clonogenic assay when combined with 10 µM fixed dose of olaparib, and (5) a combination of vandetanib with olaparib plus carboplatin time dependently increased caspase-3 and PARP cleavage, inhibited vascular mimicry, blocked fibronectin-directed migration, and suppressed clonogenic growth in TNBC cells.Vandetanib blocked (a) cord formation, (b) vitronectin-directed migration, and (c) HIF-1alpha accumulation and phosphorylation of proliferation markers (AKT, 4EBP1, and ERK) in HUVEC cells. Conclusions: Anti-proliferative/pro-apoptotic, and anti-migratory/invasive effects of vandetanib (alone or in combination with carboplatin plus olaparib) were observed both in tumor cells and in endothelial cells. We are currently studying in vivo the effect of combining olaparib plus carboplatin with vandetanib, in xenograft model the results of which will be presented in the meeting.

scholarly journals ARF6–JIP3/4 regulate endosomal tubules for MT1-MMP exocytosis in cancer invasion

2015 ◽  
Vol 211 (2) ◽  
pp. 339-358 ◽  
Author(s):  
Valentina Marchesin ◽  
Antonio Castro-Castro ◽  
Catalina Lodillinsky ◽  
Alessia Castagnino ◽  
Joanna Cyrta ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Tumor Cells ◽  
Cell Biology ◽  
Breast Cancer Cells ◽  
Triple Negative ◽  
Breast Cancers ◽  
Interacting Protein ◽  
Membrane Type ◽  
Syndrome Protein

Invasion of cancer cells into collagen-rich extracellular matrix requires membrane-tethered membrane type 1–matrix metalloproteinase (MT1-MMP) as the key protease for collagen breakdown. Understanding how MT1-MMP is delivered to the surface of tumor cells is essential for cancer cell biology. In this study, we identify ARF6 together with c-Jun NH2-terminal kinase–interacting protein 3 and 4 (JIP3 and JIP4) effectors as critical regulators of this process. Silencing ARF6 or JIP3/JIP4 in breast tumor cells results in MT1-MMP endosome mispositioning and reduces MT1-MMP exocytosis and tumor cell invasion. JIPs are recruited by Wiskott-Aldrich syndrome protein and scar homologue (WASH) on MT1-MMP endosomes on which they recruit dynein–dynactin and kinesin-1. The interaction of plasma membrane ARF6 with endosomal JIPs coordinates dynactin–dynein and kinesin-1 activity in a tug-of-war mechanism, leading to MT1-MMP endosome tubulation and exocytosis. In addition, we find that ARF6, MT1-MMP, and kinesin-1 are up-regulated in high-grade triple-negative breast cancers. These data identify a critical ARF6–JIP–MT1-MMP–dynein–dynactin–kinesin-1 axis promoting an invasive phenotype of breast cancer cells.

scholarly journals The Periphery of Salivary Gland Carcinoma Tumors Reveals a PD-L1/PD-1 Biomarker Niche for the Evaluation of Disease Severity and Tumor—Immune System Interplay

Biomedicines ◽  
2021 ◽  
Vol 9 (2) ◽  
pp. 97
Author(s):  
Martin Kuchar ◽  
Zuzana Strizova ◽  
Linda Capkova ◽  
Martin Komarc ◽  
Jiri Skrivan ◽  
...  
Keyword(s):  
Cell Death ◽  
Salivary Gland ◽  
Tumor Cells ◽  
Disease Severity ◽  
Immune Cell ◽  
Checkpoint Inhibitors ◽  
Tumor Periphery ◽  
Tumor Center ◽  
Programed Cell Death ◽  
Cell Death Protein

The treatment options for patients with advanced salivary gland cancers (SGCs) are limited. Immune checkpoint inhibitors (ICIs) have revolutionized cancer treatment. However, the response to ICI immunotherapy is largely driven by the immune cell signatures within the tumor tissue and the para-tumoral tissue compartments. To date, there are no data on the expression of programed cell death protein-1/programed cell death protein-ligand 1 (PD-1/PD-L1) in SGC, which may enable the implementation of ICI immunotherapy for this disease. Thus, we performed an immunohistochemical analysis of PD-1 and PD-L1 expression in tumor cells and tumor-infiltrating immune cells (TIICs) in the tumor center and periphery of 62 SGC patients. The tumor periphery showed significantly higher expression of PD-L1 in tumor cells than in TIICs. Moreover, peripheral TIICs had significantly higher PD-1 expression than peripheral tumor cells. PD-1-positive tumor cells were detected exclusively in the tumor center of high-grade tumors, and most importantly, the presence of lymph node (LN) metastases and primary tumor stage significantly correlated with the presence of PD-L1-positive tumor cells in the tumor periphery. The PD-1/PD-L1 molecular signatures in SGC are clustered predominantly in the tumor periphery, reflect disease severity, and may predict the response to ICI immunotherapy in SGC patients.

scholarly journals CD95 expression in triple negative breast cancer blocks induction of an inflammatory state through differential regulation of NF-kB Signaling

2021 ◽  
Author(s):  
Jean-Philippe Guegan ◽  
Justine Pollet ◽  
Christophe Ginestier ◽  
Emmanuelle Charafe-Jauffret ◽  
Marcus E Peter ◽  
...  
Keyword(s):  
Tumor Cells ◽  
Triple Negative ◽  
Tumor Infiltrating Lymphocytes ◽  
Breast Cancers ◽  
Immune Effector ◽  
Effector Cells ◽  
Proteomic Approach ◽  
Inflammatory State ◽  
Innate Immune Effector ◽  
Partial Degradation

CD95L is expressed by tumor-infiltrating lymphocytes to eliminate CD95-expressing tumor cells and thereby CD95 loss by tumor cells is often considered as a consequence of an immunoediting process. Nonetheless CD95 expression is maintained in most triple negative breast cancers (TNBCs), and we recently reported that CD95 loss in TNBC cells triggers the induction of a pro-inflammatory program promoting the recruitment of cytotoxic NK and CD8+ T-cells and impairing tumor growth. Using a comprehensive proteomic approach, we have identified two yet unknown CD95 interaction partners, Kip1 ubiquitination-promoting complex protein 2 (KPC2) and p65. KPC2 contributes to the partial degradation of p105 (NFκB1) and the subsequent generation of p50 homodimers, which transcriptionally represses pro-inflammatory NF-κB-driven gene expression. Mechanistically, KPC2 directly interacts with the C-terminal region of CD95 and links the receptor to RelA (p65) and KPC1, the catalytic subunit of the KPC complex that acts as E3 ubiquitin-protein ligase promoting the partial degradation of p105 into p50. Loss of CD95 in TNBC cells releases KPC2, limiting the formation of the NF-κB inhibitory homodimer complex (p50/p50), promoting NF-κB activation and the production of pro-inflammatory cytokines including CSF1, CSF2, CXCL1 and IL1 members, known to promote recruitment and differentiation of certain adaptive and innate immune effector cells.

scholarly journals Comparison of PD-L1 protein expression between primary tumors and metastatic lesions in triple negative breast cancers

2020 ◽  
Vol 8 (2) ◽  
pp. e001558
Author(s):  
Mariya Rozenblit ◽  
Richard Huang ◽  
Natalie Danziger ◽  
Priti Hegde ◽  
Brian Alexander ◽  
...  
Keyword(s):  
Tumor Cells ◽  
Immune Cells ◽  
Soft Tissues ◽  
Triple Negative ◽  
Breast Cancers ◽  
Primary Tumors ◽  
Metastatic Lesions ◽  
Programmed Death ◽  
Metastatic Sites ◽  
L1 Protein

Programmed Death Ligand 1 (PD-L1) positivity rates differ between different metastatic sites and the primary tumor. Understanding PD-L1 expression characteristics could guide biopsy procedures and motivate research to better understand site-specific differences in the tumor microenvironment. The purpose of this study was to compare PD-L1 positivity on immune cells and tumor cells in primary and metastatic triple negative breast cancer (TNBC) tumors. Retrospective study utilizing the PD-L1 database of Foundation Medicine containing the SP142 companion diagnostic immunohistochemistry assay (SP142 CDx) and Food and Drug Administration guidelines for scoring. 340 TNBC cases (179 primary tumors and 161 unmatched metastatic lesions) were evaluated. The primary outcome measures were PD-L1 positivity rates in immune cells and tumor cells. χ2 test was used for comparisons. Spearman’s correlation coefficient was used for correlations. More primary tumors were positive for PD-L1 expression on immune cells than metastatic lesions (114 (63.7%) vs 68 (42.2%), p<0.0001). This was driven by the lower PD-L1 positivity rates in skin (23.8%, 95% CI: 8.22% to 47.2%), liver (17.4%, 95% CI: 5.00% to 38.8%) and bone (16.7%, 95% CI: 2.10% to 48.4%) metastases. Lung (68.8%, 95% CI: 41.3% to 90.0%), soft tissues (65.2%, 95% CI: 42.7% to 83.6%) and lymph nodes (51.1%, 95% CI: 35.8% to 66.3%) had PD-L1 % positivity rates similar to primary tumors. PD-L1 expression was rare on tumor cells in both the breast and metastatic sites (8.3% vs 4.3%, p=0.13). The rate of PD-L1 positivity varies by metastatic location with substantially lower positivity rates in liver, skin and bone metastases compared with primary breast lesions or lung, soft tissue or lymph node metastases. This difference in PD-L1 positivity rates between primary tumors and different metastatic sites should inform physicians when choosing sites to biopsy and suggests a difference in the immune microenvironment across metastatic sites.

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