Melanin-like nanoparticles loaded with an angiotensin antagonist for an improved photothermal cancer therapy

2020 ◽  
Vol 8 (6) ◽  
pp. 1658-1668 ◽  
Author(s):  
Zhengjie Zhou ◽  
Yang Yan ◽  
Qiang Zhang ◽  
Yiyun Cheng
Keyword(s):  
Extracellular Matrix ◽  
Cancer Therapy ◽  
Blood Vessels ◽  
Tumor Cells ◽  
Tumor Blood Vessels

Losartan decompresses tumor blood vessels and degrades extracellular matrix in tumor to enhance nanoparticle penetration and accumulation in tumors, resulting in improved photothermal killing of tumor cells.

scholarly journals Three-dimensional relationships between tumor cells and microcirculation with double cyanine immunolabeling, laser scanning confocal microscopy, and computer-assisted reconstruction: an alternative to cast corrosion preparations.

1994 ◽  
Vol 42 (5) ◽  
pp. 681-686 ◽  
Author(s):  
V Rummelt ◽  
L M Gardner ◽  
R Folberg ◽  
S Beck ◽  
B Knosp ◽  
...  
Keyword(s):  
Electron Microscopy ◽  
Scanning Electron Microscopy ◽  
Blood Vessels ◽  
Tumor Cells ◽  
Laser Scanning ◽  
Three Dimensional ◽  
Melanoma Cells ◽  
Tumor Blood Vessels ◽  
The Relationship ◽  
Scanning Electron

The morphology of the microcirculation of uveal melanomas is a reliable market of tumor progression. Scanning electron microscopy of cast corrosion preparations can generate three-dimensional views of these vascular patterns, but this technique sacrifices the tumor parenchyma. Formalin-fixed wet tissue sections 100-150 microns thick from uveal melanomas were stained with the lectin Ulex europaeus agglutinin I (UEAI) and proliferating cell nuclear antigen (PCNA) to demonstrate simultaneously the tumor blood vessels and proliferating tumor cells. Indocarbocyanine (Cy3) was used as a fluorophore for UEAI and indodicarbocyanine (Cy5) was used for PCNA. Double labeled sections were examined with a laser scanning confocal microscope. Images of both stains were digitized at the same 5-microns intervals and each of the two images per interval was combined digitally to form one image. These combined images were visualized through voxel processing to study the relationship between melanoma cells expressing PCNA and various microcirculatory patterns. This technique produces images comparable to scanning electron microscopy of cast corrosion preparations while permitting simultaneous localization of melanoma cells expressing PCNA. The microcirculatory tree can be viewed from any perspective and the relationship between tumor cells and the tumor blood vessels can be studied concurrently in three dimensions. This technique is an alternative to cast corrosion preparations.

The Molecular and Cellular Processes of Tumor Cell-Mediated Tumor Angiogenesis and Vasculogenesis,

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 3267-3267
Author(s):  
Quansheng Zhou ◽  
Zhifei Cao ◽  
Meimei Bao ◽  
Graduate student ◽  
Bingxue Shang ◽  
...  
Keyword(s):  
Tumor Cell ◽  
Signaling Pathways ◽  
Blood Vessels ◽  
Tumor Cells ◽  
Erk Signaling ◽  
Tumor Cell Lines ◽  
Tumor Neovascularization ◽  
Tumor Blood Vessels

Abstract Abstract 3267 It is well known that tumors make blood vessels through endothelial cell-mediated angiogenesis; whereas, increasing data have shown that tumor cell-mediated vasculogenesis plays an important role in tumor neovascularization in a variety of high metastatic malignant tumors, but the mechanisms are largely unknown. We previously established new models for studying the mechanisms of tumor angiogenesis and vasculogenesis (Zhou Q. et al. Method 44(2):190–195, 2008; Zhou Q, et al. Nature: Structure and Molecular Biology 2010, 17:57–62). Using in vitro tube formation system and in vivo mouse tumor xenografts, we have recently tested the vasculogenic capability of 85 tumor cell lines and studied the molecular and cellular processes of tumor cell-mediated tumor neovascularization. Among 62 human tumor cell lines tested, 25 of them were able to directly form capillary-like tubes in vitro and tumor blood vessels in vivo tumor xenografts, while 10 out of 23 mouse tumor cell lines displayed tube-forming and vasculogenic capabilities. Notably, these vasculogenic tumor cells were mostly derived from high metastatic and aggressive tumors, including pre-cancerous stem cells, cancer stem cells, high metastatic tumor cells, and tumor endothelial cells. Utilizing DNA microarray, tumor tissue array, RT-PCR, western blotting, and immunofluorescient staining, we observed that 15 genes were highly expressed in vasculogenic cancer stem cells and various tumor cells; among them, 4 genes did not expressed in all of the 15 normal human tissues while other 11 genes were only expressed in the testis, but absent in other normal tissues. Additionally, many embryonic angiogenic and vasculogenic genes were overexpressed in the vasculogenic tumor cells, implying that these genes may play an important role in tumor vasculogenesis. Accordingly, we raise a hypothetic model that endogenous and exogenous factors induce tumor cells to express a variety of angiogenic and vasculogenic genes which drive the vasculogenic tumor cells to connect each other and to interact with endothelial cells and various blood cells, resulting in generation of tumor blood vessels. Furthermore, we explored the role and mechanism of human ovarian cancer Hey1B cell-mediated tumor neovascularization. Herein, for the first time we found that Hey1B cells directly formed capillary tubular structure in vitro independent of any growth factors and functional tumor blood vessels in vivo tumor xenografts. Moreover, we observed that more than 30 angiogenic and vasculogenic genes were overexpressed in the cells and the tumor tissues, including VE-cadherin, FGFR1, VEGFA, HIF1A, Sema4D, plexinB1, EphB2, NOTCH1, ROBO4, Ephrin B2, SFRP1, MAFB, SOX17, WIPF2, MAGEF1, MAGED1, New3, ZFP106, RUNX1, and other 16 poorly annotated genes, while Akt and ERK signaling pathways were found to be over activated in Hey1B cells and the tumor tissues. This valuable information gets new insight into the mechanisms of tumor cell-predominant neovascularization. Using Hey1B cells as tumor vasculogenic model, we screened anti-tumor vasculogenic small molecules in the traditional Chinese herbal medicinal library and found that lycorine hydrochloride (LH) effectively inhibited Hey1B cell-mediated tube formation in vitro, blood vessel generation and tumor growth in vivo. Molecular mechanism analysis showed that LH markedly inhibited the expression of VE-cadherin, Sema4D, FGFR1, VEGFA, NOTCH1 and SFRP1 genes, and it also blocked Akt and ERK signaling pathways. Taken together, a varieties of angiogenic and vasculogenic genes are overexpressed in angiogenic and vasculogenic tumor cells, meanwhile, Akt and ERK signaling pathways were activated in the vasculogenic tumor cells tested; and that LH effectively suppresses ovarian cancer neovascularization and tumor growth through inhibition of several key genes and signaling pathways. Therefore, angiogenic and vasculogenic genes and tumor cells are good targets for novel anti-tumor vasculogenesis and anti-tumor drug discovery. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Tumor Endothelial Heterogeneity in Cancer Progression

Cancers ◽  
2019 ◽  
Vol 11 (10) ◽  
pp. 1511 ◽  
Author(s):  
Nako Maishi ◽  
Dorcas A. Annan ◽  
Hiroshi Kikuchi ◽  
Yasuhiro Hida ◽  
Kyoko Hida
Keyword(s):  
Tumor Microenvironment ◽  
Blood Vessels ◽  
Tumor Cells ◽  
Cancer Progression ◽  
Phenotypic Diversity ◽  
Expression Patterns ◽  
Specific Gene ◽  
Endothelial Heterogeneity ◽  
Tumor Blood Vessels ◽  
And Migration

Tumor blood vessels supply nutrients and oxygen to tumor cells for their growth and provide routes for them to enter circulation. Thus, angiogenesis, the formation of new blood vessels, is essential for tumor progression and metastasis. Tumor endothelial cells (TECs) that cover the inner surfaces of tumor blood vessels reportedly show phenotypes distinct from those of their normal counterparts. As examples, TECs show cytogenetic abnormalities, resistance to anticancer drugs, activated proliferation and migration, and specific gene expression patterns. TECs contain stem-like cell populations, which means that the origin of TECs is heterogeneous. In addition, since some abnormal phenotypes in TECs are induced by factors in the tumor microenvironment, such as hypoxia and tumor cell-derived factors, phenotypic diversity in TECs may be caused in part by intratumoral heterogeneity. Recent studies have identified that the interaction of tumor cells and TECs by juxtacrine and paracrine signaling contributes to tumor malignancy. Understanding TEC abnormality and heterogeneity is important for treatment of cancers. This review provides an overview of the diversity of TECs and discusses the interaction between TECs and tumor cells in the tumor microenvironment.

scholarly journals In vitro modeling of solid tumor interactions with perfused blood vessels

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Tae Joon Kwak ◽  
Esak Lee
Keyword(s):  
Extracellular Matrix ◽  
Blood Vessels ◽  
Tumor Cells ◽  
Solid Tumor ◽  
Cancer Metastasis ◽  
Structural Integrity ◽  
Umbilical Vein ◽  
Lung Fibroblasts ◽  
Microfluidic Channels ◽  
Tumor Spheroids

AbstractMolecular crosstalk between intra-tumor blood vessels and tumor cells plays many critical roles in tumorigenesis and cancer metastasis. However, it has been very difficult to investigate the biochemical mechanisms underlying the overlapping, multifactorial processes that occur at the tumor-vascular interface using conventional murine models alone. Moreover, traditional two-dimensional (2D) culture models used in cancer research do not recapitulate aspects of the 3D tumor microenvironment. In the present study, we introduce a microfluidic model of the solid tumor-vascular interface composed of a human umbilical vein endothelial cell (HUVEC)-lined, perfusable, bioengineered blood vessel and tumor spheroids embedded in an extracellular matrix (ECM). We sought to optimize our model by varying the composition of the tumor spheroids (MDA-MB-231 breast tumor cells + mesenchymal stem cells (MSCs)/human lung fibroblasts (HLFs)/HUVECs) and the extracellular matrix (ECM: collagen, Matrigel, and fibrin gels with or without free HLFs) that we used. Our results indicate that culturing tumor spheroids containing MDA-MB-231 cells + HUVECs in an HLF-laden, fibrin-based ECM within our microfluidic device optimally (1) enhances the sprouting and migration of tumor spheroids, (2) promotes angiogenesis, (3) facilitates vascular invasion, and (4) preserves the structural integrity and functionality of HUVEC-lined microfluidic channels. This model may provide a platform for drug screening and mechanism studies on solid tumor interactions with functional blood vessels.

Analysis of multidrug resistant transporter expression in tumor blood vessels of urothelial carcinoma during chemotherapy.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. e23004-e23004
Author(s):  
Hiroshi Kikuchi ◽  
Nako Maishi ◽  
Kosuke Akiyama ◽  
Masahiro Morimoto ◽  
Misa Yanagiya ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Endothelial Cells ◽  
Blood Vessels ◽  
Tumor Cells ◽  
Cancer Drug ◽  
Cancer Drug Resistance ◽  
Before And After ◽  
Mdr1 Mrna ◽  
Tumor Blood Vessels ◽  
Line Chemotherapy

e23004 Background: ABCB1, a multidrug transporter, is encoded by multidrug resistance (MDR) 1 gene and plays a major role in drug resistance. Recently, we have reported that not only tumor cells, tumor vascular endothelial cells (TECs) also confer cancer drug resistance. We isolated TECs and found that they have various abnormalities such as aneuploidy or stemness characteristics. TECs showed resistance to Paclitaxel (PTX) with ABCB1 up-regulation. Furthermore, their resistance to PTX was abrogated by ABCB1 inhibition of TECs in vivo. In clinical urology, gemcitabine / cisplatin (GC) is standard 1st line chemotherapy for metastatic urothelial carcinoma (mUC). PTX is often selected in 2nd line chemotherapy for GC resistant cases, however the therapeutic outcomes are limited. We hypothesized that ABCB1 inhibitor/PTX combination would be more effective strategy for mUC, if TEC ABCB1 expression is upregulated. In this study, we investigated ABCB1 expression in tumor blood vessels of UC during 1st line chemotherapy. Methods: Paraffin-embedded samples were corrected from 50 patients who were performed tumor resection before and after 1st line chemotherapy. ABCB1 expressions were analyzed by immunohistochemical staining and the ratio of ABCB1 positive (+) vessels in total vessels were quantified. In vitro assays were performed to address how endothelial cells (ECs) are affected by change of tumor microenvironment during chemotherapy. Results: The ABCB1 (+) vessels were 0.00 – 16.80% (Median 0.00%) and 0.00-58.94% (Median 4.49%), before and after chemotherapy, respectively. In 32 of 50 cases (64%), the ratio of ABCB1 (+) vessels increased after 1st line chemotherapy. Additionally, gemcitabine induced MDR1 mRNA expression in ECs via NF-kB activation. Furthermore, gemcitabine and cisplatin induced IL-8 secretion from tumor cells, and MDR1 mRNA expression level was elevated in ECs. Conclusions: It was suggested that conventional chemotherapy may cause inflammatory change in tumor tissues, which causes in ABC transporter induction in tumor blood vessels. It was suggested that inhibition of ABC transporter in TECs is one of important new strategy to overcome cancer drug resistance.

scholarly journals Distribution of vascular permeability factor (vascular endothelial growth factor) in tumors: concentration in tumor blood vessels.

1991 ◽  
Vol 174 (5) ◽  
pp. 1275-1278 ◽  
Author(s):  
H F Dvorak ◽  
T M Sioussat ◽  
L F Brown ◽  
B Berse ◽  
J A Nagy ◽  
...  
Keyword(s):  
Endothelial Cell ◽  
Blood Vessels ◽  
Vascular Permeability ◽  
Tumor Cells ◽  
Vascular Endothelial Cell ◽  
Vascular Endothelial ◽  
Vascular Permeability Factor ◽  
Tumor Vessels ◽  
Tumor Blood Vessels

Vascular permeability factor (VPF) is a highly conserved 34-42-kD protein secreted by many tumor cells. Among the most potent vascular permeability-enhancing factors known, VPF is also a selective vascular endothelial cell mitogen, and therefore has been called vascular endothelial cell growth factor (VEGF). Our goal was to define the cellular sites of VPF (VEGF) synthesis and accumulation in tumors in vivo. Immunohistochemical studies were performed on solid and ascites guinea pig line 1 and line 10 bile duct carcinomas using antibodies directed against peptides synthesized to represent the NH2-terminal and internal sequences of VPF. These antibodies stained tumor cells and, uniformly and most intensely, the endothelium of immediately adjacent blood vessels, both preexisting and those newly induced by tumor angiogenesis. A similar pattern of VPF staining was observed in autochthonous human lymphoma. In situ hybridization demonstrated VPF mRNA in nearly all line 10 tumor cells but not in tumor blood vessels, indicating that immunohistochemical labeling of tumor vessels with antibodies to VPF peptides reflects uptake of VPF, not endogenous synthesis. VPF protein staining was evident in adjacent preexisting venules and small veins as early as 5 h after tumor transplant and plateaued at maximally intense levels in newly induced tumor vessels by approximately 5 d. VPF-stained vessels were also hyperpermeable to macromolecules as judged by their capacity to accumulate circulating colloidal carbon. In contrast, vessels more than approximately 0.5 mm distant from tumors were not hyperpermeable and did not exhibit immunohistochemical staining for VPF. Vessel staining disappeared within 24-48 h of tumor rejection. These studies indicate that VPF is synthesized by tumor cells in vivo and accumulates in nearby blood vessels, its target of action. Because leaky tumor vessels initiate a cascade of events, which include plasma extravasation and which lead ultimately to angiogenesis and tumor stroma formation, VPF may have a pivotal role in promoting tumor growth. Also, VPF immunostaining provides a new marker for tumor blood vessels that may be exploitable for tumor imaging or therapy.

scholarly journals Enhancing the Effectiveness of Drug-based Cancer Therapy by Electroporation (Electropermeabilization)

2002 ◽  
Vol 1 (1) ◽  
pp. 71-82 ◽  
Author(s):  
Dietmar P. Rabussay ◽  
Gurvinder S. Nanda ◽  
Paul M. Goldfarb
Keyword(s):  
Cancer Therapy ◽  
Cell Membrane ◽  
Field Strength ◽  
Head And Neck ◽  
Blood Vessels ◽  
Tumor Cells ◽  
Tumor Tissue ◽  
Tumor Response ◽  
Efficient Access

Many conventional chemotherapeutic drugs, as well as DNA for cancer gene therapy, require efficient access to the cells' interior to be effective. The cell membrane is a formidable barrier to many of these drugs, including therapeutic DNA constructs. Electropermeabilization (EP, often used synonymously with “electroporation”) has become a useful method to temporarily increase the permeability of the cell membrane, allowing a broad variety of molecules efficient access to the cell interior. EP is achieved by the application of short electrical pulses of relatively high local field strength to the target tissue of choice. In cancer therapy, EP can be applied in vivo directly to the tumor to be treated, in order to enhance intracellular uptake of drugs or DNA. Alternatively, EP can be used to deliver DNA into cells of healthy tissue to achieve longer-lasting expression of cancer-suppressing genes. In addition, EP has been used in ex vivo therapeutic approaches for the transfection of a variety of cells in suspension. In this paper, we communicate results related to the development of a treatment for squamous cell carcinomas of the head and neck, using electropermeabilization to deliver the drug bleomycin in vivo directly into the tumor cells. This drug, which is not particularly effective as a conventional therapeutic, becomes highly potent when the intracellular concentration is enhanced by EP treatment. In animal model experiments we found a drug dose of 1 U/cm3 tumor tissue (delivered in 0.25 mL of an aqueous solution/cm3 tumor tissue) and an electrical field strength of 750 V/cm or higher to be optimal for the treatment of human squamous cell tumors grown subcutaneously in mice. Within 24–48 hours, the majority of tumor cells are rapidly destroyed by this bleomycin-electroporation therapy (B-EPT). This raises the concern that healthy tissue may be similarly affected. In studies with large animals we showed that normal muscle and skin tissue, normal tissue surrounding major blood vessels and nerves, as well as healthy blood vessels and nerves themselves, are much less affected than tumor tissue. Normal tissues did show acute, focal, and transitory effects after treatment, but these effects are relatively minor under standard treatment conditions. The severity of these effects increases with the number of electric pulse cycles and applied voltage. The observed histological changes resolved 20 to 40 days after treatment or sooner, even after excessive EP treatment. Thus, B-EPT is distinct from other ablative therapies, such as thermal, cryo, or photodynamic ablation, which equally affect healthy and tumor tissue. In comparison to surgical or radiation therapy, B-EPT also has potential as a tissue-sparing and function-preserving therapy. In clinical studies with over 50 late stage head and neck cancer patients, objective tumor response rates of 55–58%, and complete tumor response rates of 19–30% have been achieved.

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