scholarly journals In vivo two-photon characterization of tumor-associated macrophages and microglia (TAM/M) and CX3CR1 during different steps of brain metastasis formation from lung cancer

Neoplasia ◽  
2021 ◽  
Vol 23 (11) ◽  
pp. 1089-1100
Author(s):  
Wenlong Zhang ◽  
Philipp Karschnia ◽  
Iven-Alex von Mücke-Heim ◽  
Matthias Mulazzani ◽  
Xiaolan Zhou ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Brain Metastasis ◽  
Metastasis Formation ◽  
Tumor Associated Macrophages ◽  
Two Photon

scholarly journals BSCI-08. In vivo two-photon characterization of tumor-associated macrophages and microglia (TAM/M) and CX3CR1 during different steps of brain metastasis formation from lung cancer

2021 ◽  
Vol 3 (Supplement_3) ◽  
pp. iii2-iii3
Author(s):  
Wenlong Zhang ◽  
Philipp Karschnia ◽  
Iven-Alex von Mücke-Heim ◽  
Matthias Mulazzani ◽  
Xiolan Zhou ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Brain Metastasis ◽  
Brain Metastases ◽  
Tumor Cells ◽  
Laser Scanning Microscopy ◽  
Metastasis Formation ◽  
Tumor Associated Macrophages ◽  
Two Photon ◽  
Cranial Window

Abstract Background Brain metastases represent a common complication of lung cancer and dramatically limit prognosis in affected patients. The influence of tumor-associated macrophages and microglia (TAM/M) and their receptor CX3CR1 on different steps of brain metastasis formation from lung cancer is poorly characterized, but might be of therapeutic relevance. Methods We established an orthotopic cerebral metastasis model using CX3CR1-proficient (CX3CR1GFP/wt) and -deficient (CX3CR1GFP/GFP) mice with green-fluorescent TAM/M. A cranial window was prepared, and intracarotid injection of red-fluorescent Lewis Lung Carcinoma-cells (tdtLLC) was performed two weeks later. Formation of brain metastases was followed by repetitive two-photon laser scanning microscopy. Results After intracarotid injection, intravascular tumor cells extravasated into the cerebral parenchyma and eventually formed micrometastases (≤50 cells) and mature macrometastases (>50 cells). We observed phagocytosis of extravasated tumor cells by TAM/M during early steps of metastatic growth. Notably, these anti-tumor effects of TAM/M diminished during later steps of metastasis formation and were accompanied by TAM/M accumulation and activation. CX3CR1-deficiency resulted in a lower number of extravasated tumor cells, and only a small number of TAM/M were visualized during early steps of metastasis formation (extravasation, formation of micrometastases) in such mice. In contrast, progression of extravasated tumor cells into micrometastases was more frequently found in CX3CR1-deficient mice. Overall, these mechanisms resulted in a comparable number of mature macrometastases between CX3CR1-deficient and -proficient mice. Conclusion Our findings indicate that unspecific inhibition of CX3CR1 might not be a suitable therapeutic approach to prevent cerebral dissemination of lung cancer cells. Given the close interaction between TAM/M and tumour cells during metastasis formation, other therapeutic approaches targeting TAM/M function warrant evaluation. Such concepts might be evaluated in vivo using the herein established orthotopic mouse model.

scholarly journals Characterization of Lung Cancer by Amide Proton Transfer (APT) Imaging: An In-Vivo Study in an Orthotopic Mouse Model

PLoS ONE ◽  
2013 ◽  
Vol 8 (10) ◽  
pp. e77019 ◽  
Author(s):  
Osamu Togao ◽  
Chase W. Kessinger ◽  
Gang Huang ◽  
Todd C. Soesbe ◽  
Koji Sagiyama ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Mouse Model ◽  
Proton Transfer ◽  
In Vivo Study ◽  
Amide Proton ◽  
Orthotopic Mouse Model ◽  
Amide Proton Transfer ◽  
Apt Imaging

Synergy of nanodiamond-doxorubicin conjugates and PD-L1 blockade effectively turns tumor associated macrophages against tumor cells

2021 ◽  
Author(s):  
Huazhen Xu ◽  
Tongfei Li ◽  
Chao Wang ◽  
Yan Ma ◽  
Yan Liu ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Tumor Cell ◽  
Cancer Cells ◽  
Tumor Cells ◽  
Lung Cancer Cells ◽  
Dependent Manner ◽  
Tumor Associated Macrophages ◽  
M1 Type

Abstract Background: Tumor-associated macrophages (TAM) are the most abundant stromal cells in the tumor microenvironment. Turning the TAM against their host tumor cells is an intriguing therapeutic strategy particularly attractive for patients with immunologically “cold” tumors. This concept was mechanistically demonstrated on in vitro human and murine lung cancer cells and their corresponding TAM models through combinatorial use of nanodiamond-doxorubicin conjugates (Nano-DOX) and a PD-L1 blocking agent BMS-1. Nano-DOX are an agent previously proved to be able to stimulate tumor cells’ immunogenicity and thereby reactivate the TAM into the anti-tumor M1 phenotype. Results: Nano-DOX were first shown to stimulate the tumor cells and the TAM to release the cytokine HMGB1 which, regardless of its source, acted through the RAGE/NF-κB pathway to induce PD-L1 in the tumor cells and PD-L1/PD-1 in the TAM. Interestingly, Nano-DOX also induced NF-κB-dependent RAGE expression in the tumor cells and thus reinforced HMGB1’s action thereon. Then, BMS-1 was shown to enhance Nano-DOX-stimulated M1-type activation of TAM both by blocking Nano-DOX-induced PD-L1 in the TAM and by blocking tumor cell PD-L1 ligation with TAM PD-1. The TAM with enhanced M1-type repolarization both killed the tumor cells and suppressed their growth. BMS-1 could also potentiate Nano-DOX’s action to suppress tumor cell growth via blocking of Nano-DOX-induced PD-L1 therein. Finally, Nano-DOX and BMS-1 achieved synergistic therapeutic efficacy against in vivo tumor grafts in a TAM-dependent manner. Conclusions: PD-L1/PD-1 upregulation mediated by autocrine and paracrine activation of the HMGB1/RAGE/NF-κB signaling is a key response of lung cancer cells and their TAM to stress, which can be induced by Nano-DOX. Blockade of Nano-DOX-induced PD-L1, both in the cancer cells and the TAM, achieves enhanced activation of TAM-mediated anti-tumor response.

P-318 Characterization of a human small-cell lung cancer cell line from in vivo multidrug resistant tumour

Lung Cancer ◽  
2003 ◽  
Vol 41 ◽  
pp. S172
Author(s):  
M.J. Valladares-Ayerbes ◽  
Antolin S. Novoa ◽  
P. Iglesias Diaz ◽  
Haz Mar ◽  
Brandon Inmaculada ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Cancer Cell Line ◽  
Multidrug Resistant ◽  
Lung Cancer Cell Line ◽  
Small Cell ◽  
Lung Cancer Cell ◽  
Small Cell Lung

TMOD-01. AN IN VIVO FUNCTIONAL GENOMICS SCREEN TO IDENTIFY NOVEL DRIVERS OF LUNG-TO-BRAIN METASTASIS

2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi215-vi215
Author(s):  
Nikoo Aghaei ◽  
Fred C Lam ◽  
Ekkhard Kasper ◽  
Chitra Venugopal ◽  
Sheila K Singh
Keyword(s):  
Lung Cancer ◽  
Brain Metastasis ◽  
Brain Metastases ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Small Cell ◽  
Small Cell Lung ◽  
Genome Wide ◽  
Crispr Activation

Abstract INTRODUCTION Brain metastases, the most common tumors of the central nervous system, occur in approximately 20% of primary adult cancers. In particular, 40% of patients with non-small cell lung cancer develop brain metastasis. As systemic therapies for the treatment of non-small cell lung cancer become increasingly effective at controlling primary disease, patients are ironically succumbing to their brain metastases. This highlights a large unmet need to develop novel targeted therapies for the treatment of lung-to-brain metastases (LBM). We hypothesize that an in vivo functional genomic screen can identify novel genes that drive LBM. METHODS To do this, we developed a patient-derived xenograft (PDX) mouse model of LBM using patient lung cancer cell lines. This PDX model of LBM enables the use of fluorescent and bioluminescent in vivo imaging to track the progression of lung tumor and brain metastases. RESULTS We have performed an in vivo genome-wide CRISPR activation screening to identify novel drivers of LBM. We will derive candidate genes through mouse brain and lung tissue sequencing after mice reach endpoint. EXPECTED AREA OF FINDINGS This platform will lead to potential therapeutic targets to prevent the formation of LBM and prolong the survival of patients with non-small cell lung cancer. LIMITATIONS There may be limitations in getting candidate hits that overlap in all mice in our first replicate. This can be remedied by conducting the in vivo screen in at least three biological replicates. CONCLUSION To the best of our knowledge, this is the first genome-wide in vivo CRISPR activation screen searching for drivers of LBM using a PDX animal model. This study can provide a framework to gain a deeper understanding of the regulators of BM formation which will hopefully lead to targeted drug discovery.

Enumeration and Molecular Characterization of Tumor Cells in Lung Cancer Patients Using a Novel In Vivo Device for Capturing Circulating Tumor Cells

2015 ◽  
Vol 22 (9) ◽  
pp. 2197-2206 ◽  
Author(s):  
Tobias M. Gorges ◽  
Nicole Penkalla ◽  
Thomas Schalk ◽  
Simon A. Joosse ◽  
Sabine Riethdorf ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Cancer Patients ◽  
Tumor Cells ◽  
Molecular Characterization ◽  
Circulating Tumor Cells ◽  
Lung Cancer Patients

scholarly journals BSCI-15. METASTATIC BRAIN TUMOR TARGETING PEPTIDES ISOLATED THROUGH PHAGE DISPLAY BIOPANNING AGAINST BRAIN METASTASIS-INITIATING CELLS

2019 ◽  
Vol 1 (Supplement_1) ◽  
pp. i4-i4
Author(s):  
JongMyung Kim ◽  
James Liu
Keyword(s):  
Lung Cancer ◽  
Brain Metastasis ◽  
Phage Display ◽  
Metastatic Brain Tumors ◽  
Serum Free ◽  
Phage Display Biopanning ◽  
Free Media ◽  
In Vivo Phage Display

Abstract To effectively target metastatic brain tumors (MBTs), the paradigm of treating MBTs after visualization on clinical imaging needs to be shifted to an understanding of the mechanisms that drive the formation and maintenance of brain metastasis-initiating cells (BMICs). Targeting this tumor sub-population, which may form as a result from activation of epithelial-mesenchymal transition, may allow for more effective means of isolating and targeting brain metastasis. In order to isolate BMICs, we have harvested cells from patient derived MBTs originating from lung cancer and cultured the cells using serum-free media conditions. In vivo phage display biopanning was used to isolate 12-amino acid length peptides that specifically target BMICs. Of the peptides recovered, one peptide, LBM4, was tested for specificity of binding to MBTs through in vitro and in vivo binding assays. When comparing patient derived metastatic brain tumors cells against brain metastasis cell lines, we found that both types of cells demonstrated similar morphology when grown in serum media conditions, but when grown in serum-free media, both demonstrated a tumor sphere morphology, similar to a stem cell-like state. LBM4 demonstrated specific binding to MBT cells over primary lung cancer cells in vitro through flow cytometry analysis and immunocytochemistry. Fluorescent tagged LBM4 intravenously injected into mice harboring intracranial BM demonstrated peptide localization to the tumor within the intracranial cavity visualized with live animal imaging. In vivo phage display biopanning is an effective tool that is able to isolate cell specific targeting peptides. MBT targeting peptides can potentially result in a shifting of the clinical treatment paradigm of brain metastases, through the development of more effective targeted therapeutics aimed at BMICs, as well as improving detection of MBT cells which may result in earlier tumor visualization as well as delineation of tumor recurrence versus radiation effects.

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