scholarly journals TAMI-02. ALTERATIONS IN C-X3-C MOTIF CHEMOKINE RECEPTOR 1 (CX3CR1) EXPRESSION INFLUENCE MICROGLIAL AND MACROPHAGE RESPONSE IN DIFFERENT STEPS OF CEREBRAL METASTASIS FORMATION

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii213-ii213
Author(s):  
Wenlong Zhang ◽  
Iven-Alex von Mücke-Heim ◽  
Matthias Mulazzani ◽  
Philipp Karschnia ◽  
Andreas Straube ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Tumor Microenvironment ◽  
Tumor Cells ◽  
Laser Scanning Microscopy ◽  
Cerebral Metastasis ◽  
Body Volume ◽  
Metastasis Formation ◽  
Cranial Window ◽  
Deficient Mice

Abstract Metastasis to the brain is a frequent complication in lung cancer and is still associated with a dismal prognosis. Current treatment strategies not only target tumor cells but also focus on cells of the tumor microenvironment like tumor associated microglia/macrophages (TAMs). The interactions between tumor cells and TAMs during different steps of cerebral metastasis formation of lung cancer brain metastasis are poorly characterized. Moreover, the role of CX3CR1 in this process remains unclear. We established a syngeneic cerebral metastasis mouse model by combining a chronic cranial window and two-photon laser scanning microscopy (TPLSM), which allows the tracking of single fluorescent metastasizing tumor cells and the tumor microenvironment on a cellular resolution in vivoover time for a period of weeks. Transgenic CX3CR1 proficient and deficient mice (CX3CRGFP/wt and CX3CR1GFP/GFP) were injected with red fluorescent Lewis lung carcinoma cells. During different steps of metastasis formation (extravasation, formation of micro- and macrometastasis) the density and cell body volume of TAMs, their interaction with tumor cells and possible influence on the fate of single metastatic tumor cells were investigated using serial TPLSM. We found that during metastasis formation TAM density was significantly lower in CX3CR1 deficient mice. However, activation as assessed by TAM morphology did not differ in the absence of CX3CR1. Strikingly, CX3CR1 deficiency was associated with a significant increase of tumor cells successfully extravasating the cerebral vasculature. However, subsequent steps (mirco- and macrometastasis formation) were observed less frequent in CX3CR1 deficient mice. In summary, our results highlight a complex role of CX3CR1 for TAMs during cerebral metastasis formation, indicating anti-tumorous properties of CX3CR1 at early steps and possible pro-tumorous effects at later stages (micro- and macrometastasis formation).

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.

The prognostic role of circulating tumor cells in lung cancer

2016 ◽  
Vol 16 (8) ◽  
pp. 859-867 ◽  
Author(s):  
Nicola Normanno ◽  
Antonella De Luca ◽  
Marianna Gallo ◽  
Nicoletta Chicchinelli ◽  
Antonio Rossi
Keyword(s):  
Lung Cancer ◽  
Tumor Cells ◽  
Circulating Tumor Cells ◽  
Prognostic Role

scholarly journals Prognostic role of circulating tumor cells in patients with EGFR -mutated or ALK -rearranged non-small cell lung cancer

2018 ◽  
Vol 9 (5) ◽  
pp. 640-645 ◽  
Author(s):  
Bing Tong ◽  
Yan Xu ◽  
Jing Zhao ◽  
Minjiang Chen ◽  
Wei Zhong ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Tumor Cells ◽  
Circulating Tumor Cells ◽  
Cell Lung Cancer ◽  
Small Cell ◽  
Small Cell Lung ◽  
Prognostic Role ◽  
Egfr Mutated

P10.02 Combined methods of a micropump system and a chronic cranial window allows tumor observation with multi photon laser scanning microscopy under continuous treatment

2021 ◽  
Vol 23 (Supplement_2) ◽  
pp. ii28-ii28
Author(s):  
S Weil ◽  
E Jung ◽  
D Domínguez Azorín ◽  
J Higgins ◽  
J Reckless ◽  
...  
Keyword(s):  
Drug Delivery ◽  
Tumor Cells ◽  
Blood Brain Barrier ◽  
Laser Scanning ◽  
Laser Scanning Microscopy ◽  
New Drugs ◽  
Brain Barrier ◽  
Cranial Window ◽  
Blood Brain ◽  
The Brain

Abstract BACKGROUND Glioblastomas are notoriously therapy resistant tumors. As opposed to other tumor entities, no major advances in therapeutic success have been made in the past decades. This has been calling for a deeper biological understanding of the tumor, its growth and resistance patterns. We have been using a xenograft glioma model, where human glioblastoma cells are implanted under chronic cranial windows and studied longitudinally over many weeks and months using multi photon laser scanning microscopy (MPLSM). To test the effect of (new) drugs, a stable and direct delivery system avoiding the blood-brain-barrier has come into our interest. MATERIAL AND METHODS We implanted cranial windows and fluorescently labeled human glioblastoma stem-like cells into NMRI nude mice to follow up on the tumor development in our MPLSM model. After tumor establishment, an Alzet® micropump was implanted to directly deliver agents via a catheter system continuously over 28 days directly under the cranial window onto the brain surface. Using the MPLSM technique, the continuous delivery and infusion of drugs onto the brain and into the tumor was measured over many weeks in detail using MPLSM. RESULTS The establishment of the combined methods allowed reliable concurrent drug delivery over 28 days bypassing the blood-brain-barrier. Individual regions and tumor cells could be measured and followed up before, and after the beginning of the treatment, as well as after the end of the pump activity. Fluorescently labelled drugs were detectable in the MPLSM and its distribution into the brain parenchyma could be quantified. After the end of the micropump activity, further MPLSM measurements offer the possibility to observe long term effects of the applied drug on the tumor. CONCLUSION The combination of tumor observation in the MPSLM and concurrent continuous drug delivery is a feasible and reliable method for the investigation of (novel) anti-tumor agents, especially drugs that are not blood-brain-barrier penetrant. Morphological or even functional changes of individual tumor cells can be measured under and after treatment. These techniques can be used to test new drugs targeting the tumor, its tumor microtubes and tumor cells networks, and measure the effects longitudinally.

scholarly journals Hypoxia-inducible factor (HIF): fuel for cancer progression

2021 ◽  
Vol 14 ◽  
Author(s):  
Saurabh Satija ◽  
Harpreet Kaur ◽  
Murtaza M. Tambuwala ◽  
Prabal Sharma ◽  
Manish Vyas ◽  
...  
Keyword(s):  
Biological Sciences ◽  
Tumor Microenvironment ◽  
Tumor Cells ◽  
Cancer Progression ◽  
Oxygen Deficiency ◽  
Hypoxia Inducible Factor ◽  
Transcription Factor Activation ◽  
Underlying Mechanisms ◽  
Adaptive Reactions

Hypoxia is an integral part of tumor microenvironment, caused primarily due to rapidly multiplying tumor cells and a lack of proper blood supply. Among the major hypoxic pathways, HIF-1 transcription factor activation is one of the widely investigated pathways in the hypoxic tumor microenvironment (TME). HIF-1 is known to activate several adaptive reactions in response to oxygen deficiency in tumor cells. HIF-1 has two subunits, HIF-1β (constitutive) and HIF-1α (inducible). The HIF-1α expression is largely regulated via various cytokines (through PI3K-ACT-mTOR signals), which involves the cascading of several growth factors and oncogenic cascades. These events lead to the loss of cellular tumor suppressant activity through changes in the level of oxygen via oxygen-dependent and oxygen-independent pathways. The significant and crucial role of HIF in cancer progression and its underlying mechanisms have gained much attention lately among the translational researchers in the fields of cancer and biological sciences, which have enabled them to correlate these mchanisms with various other disease modalities. In the present review, we have summarized the key findings related to the role of HIF in the progression of tumors.

scholarly journals Inflammatory Cells in Diffuse Large B Cell Lymphoma

2020 ◽  
Vol 9 (8) ◽  
pp. 2418
Author(s):  
Roberto Tamma ◽  
Girolamo Ranieri ◽  
Giuseppe Ingravallo ◽  
Tiziana Annese ◽  
Angela Oranger ◽  
...  
Keyword(s):  
Tumor Microenvironment ◽  
B Cell ◽  
Tumor Cells ◽  
Immune Cells ◽  
Tumor Antigens ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Large B Cell Lymphoma ◽  
Large B Cell

Diffuse large B cell lymphoma (DLBCL), known as the most common non-Hodgkin lymphoma (NHL) subtype, is characterized by high clinical and biological heterogeneity. The tumor microenvironment (TME), in which the tumor cells reside, is crucial in the regulation of tumor initiation, progression, and metastasis, but it also has profound effects on therapeutic efficacy. The role of immune cells during DLBCL development is complex and involves reciprocal interactions between tumor cells, adaptive and innate immune cells, their soluble mediators and structural components present in the tumor microenvironment. Different immune cells are recruited into the tumor microenvironment and exert distinct effects on tumor progression and therapeutic outcomes. In this review, we focused on the role of macrophages, Neutrophils, T cells, natural killer cells and dendritic cells in the DLBCL microenvironment and their implication as target for DLBCL treatment. These new therapies, carried out by the induction of adaptive immunity through vaccination or passive of immunologic effectors delivery, enhance the ability of the immune system to react against the tumor antigens inducing the destruction of tumor cells.

scholarly journals Biological mechanisms linked to inflammation in cancer: Discovery of tumor microenvironment-related biomarkers and their clinical application in solid tumors

2020 ◽  
Vol 35 (1_suppl) ◽  
pp. 8-11 ◽  
Author(s):  
Paola Nisticò ◽  
Gennaro Ciliberto
Keyword(s):  
Tumor Microenvironment ◽  
Tumor Cells ◽  
Cancer Progression ◽  
Cancer Biology ◽  
Tumor Development ◽  
Short Paper ◽  
Great Relevance ◽  
Cellular Components ◽  
The Relationship

Our view of cancer biology radically shifted from a “cancer-cell-centric” vision to a view of cancer as an organ disease. The concept that genetic and/or epigenetic alterations, at the basis of cancerogenesis, are the main if not the exclusive drivers of cancer development and the principal targets of therapy, has now evolved to include the tumor microenvironment in which tumor cells can grow, proliferate, survive, and metastasize only within a favorable environment. The interplay between cancer cells and the non-cellular and cellular components of the tumor microenvironment plays a fundamental role in tumor development and evolution both at the primary site and at the level of metastasis. The shape of the tumor cells and tumor mass is the resultant of several contrasting forces either pro-tumoral or anti-tumoral which have at the level of the tumor microenvironment their battle field. This crucial role of tumor microenvironment composition in cancer progression also dictates whether immunotherapy with immune checkpoint inhibitor antibodies is going to be efficacious. Hence, tumor microenvironment deconvolution has become of great relevance in order to identify biomarkers predictive of efficacy of immunotherapy. In this short paper we will briefly review the relationship between inflammation and cancer, and will summarize in 10 short points the key concepts learned so far and the open challenges to be solved.

scholarly journals The Role of Extracellular Vesicles in Cancer: Cargo, Function, and Therapeutic Implications

Cells ◽  
2018 ◽  
Vol 7 (8) ◽  
pp. 93 ◽  
Author(s):  
James Jabalee ◽  
Rebecca Towle ◽  
Cathie Garnis
Keyword(s):  
Tumor Microenvironment ◽  
Tumor Cells ◽  
Extracellular Vesicles ◽  
Tumor Stroma ◽  
Therapeutic Implications ◽  
Membrane Bound ◽  
Immune Destruction ◽  
And Function ◽  
Cargo Molecule

Extracellular vesicles (EVs) are a heterogeneous collection of membrane-bound structures that play key roles in intercellular communication. EVs are potent regulators of tumorigenesis and function largely via the shuttling of cargo molecules (RNA, DNA, protein, etc.) among cancer cells and the cells of the tumor stroma. EV-based crosstalk can promote proliferation, shape the tumor microenvironment, enhance metastasis, and allow tumor cells to evade immune destruction. In many cases these functions have been linked to the presence of specific cargo molecules. Herein we will review various types of EV cargo molecule and their functional impacts in the context of oncology.

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