Tumor Microenvironment and Angiogenic Blood Vessels Dual-Targeting for Enhanced Anti-Glioma Therapy

2016 ◽  
Vol 8 (36) ◽  
pp. 23568-23579 ◽  
Author(s):  
Quanyin Hu ◽  
Ting Kang ◽  
Jingxian Feng ◽  
Qianqian Zhu ◽  
Tianze Jiang ◽  
...  
Keyword(s):  
Tumor Microenvironment ◽  
Blood Vessels ◽  
Dual Targeting

scholarly journals Tumor Microenvironment as A “Game Changer” in Cancer Radiotherapy

2019 ◽  
Vol 20 (13) ◽  
pp. 3212 ◽  
Author(s):  
Magdalena Jarosz-Biej ◽  
Ryszard Smolarczyk ◽  
Tomasz Cichoń ◽  
Natalia Kułach
Keyword(s):  
Immune System ◽  
Tumor Microenvironment ◽  
Blood Vessels ◽  
Tumor Hypoxia ◽  
Suppressor Cells ◽  
Anticancer Efficacy ◽  
Anti Cancer ◽  
Radiation Induced ◽  
Game Changer

Radiotherapy (RT), besides cancer cells, also affects the tumor microenvironment (TME): tumor blood vessels and cells of the immune system. It damages endothelial cells and causes radiation-induced inflammation. Damaged vessels inhibit the infiltration of CD8+ T lymphocytes into tumors, and immunosuppressive pathways are activated. They lead to the accumulation of radioresistant suppressor cells, including tumor-associated macrophages (TAMs) with the M2 phenotype, myeloid-derived suppressor cells (MDSCs), and regulatory T cells (Tregs). The area of tumor hypoxia increases. Hypoxia reduces oxygen-dependent DNA damage and weakens the anti-cancer RT effect. It activates the formation of new blood vessels and leads to cancer relapse after irradiation. Irradiation may also activate the immune response through immunogenic cell death induction. This leads to the “in situ” vaccination effect. In this article, we review how changes in the TME affect radiation-induced anticancer efficacy. There is a very delicate balance between the activation of the immune system and the immunosuppression induced by RT. The effects of RT doses on immune system reactions and also on tumor vascularization remain unclear. A better understanding of these interactions will contribute to the optimization of RT treatment, which may prevent the recurrence of cancer.

Cellular Composition of the Tumor Microenvironment

2013 ◽  
pp. e91-e97 ◽  
Author(s):  
Stephen M. Ansell ◽  
Robert H. Vonderheide
Keyword(s):  
Tumor Microenvironment ◽  
B Cell ◽  
Blood Vessels ◽  
Tumor Cells ◽  
Hematologic Malignancies ◽  
Secreted Proteins ◽  
Malignant Cells ◽  
Cellular Composition ◽  
Different Types ◽  
And Function

In addition to malignant cells, the tumor microenvironment also includes nonmalignant cells, secreted proteins, and blood vessels that surround and support the growth of the tumor. Interactions between the various components of the tumor microenvironment are significant; tumor cells can change the nature of the microenvironment, and conversely, the microenvironment can affect how a tumor grows and spreads. The structure and composition of the tumor microenvironment varies among different types of cancers and between patients. This paper focuses on the composition and function of the tumor microenvironment in hematologic malignancies with a specific focus on B-cell lymphomas.

scholarly journals STIM-Orai Channels and Reactive Oxygen Species in the Tumor Microenvironment

Cancers ◽  
2019 ◽  
Vol 11 (4) ◽  
pp. 457 ◽  
Author(s):  
Janina Frisch ◽  
Adrian Angenendt ◽  
Markus Hoth ◽  
Leticia Prates Roma ◽  
Annette Lis
Keyword(s):  
Reactive Oxygen Species ◽  
Tumor Microenvironment ◽  
Tumor Growth ◽  
Cancer Cells ◽  
Blood Vessels ◽  
Cancer Cell ◽  
Reactive Oxygen ◽  
Oxygen Species ◽  
Soluble Factors ◽  
Orai Channels

The tumor microenvironment (TME) is shaped by cancer and noncancerous cells, the extracellular matrix, soluble factors, and blood vessels. Interactions between the cells, matrix, soluble factors, and blood vessels generate this complex heterogeneous microenvironment. The TME may be metabolically beneficial or unbeneficial for tumor growth, it may favor or not favor a productive immune response against tumor cells, or it may even favor conditions suited to hijacking the immune system for benefitting tumor growth. Soluble factors relevant for TME include oxygen, reactive oxygen species (ROS), ATP, Ca2+, H+, growth factors, or cytokines. Ca2+ plays a prominent role in the TME because its concentration is directly linked to cancer cell proliferation, apoptosis, or migration but also to immune cell function. Stromal-interaction molecules (STIM)-activated Orai channels are major Ca2+ entry channels in cancer cells and immune cells, they are upregulated in many tumors, and they are strongly regulated by ROS. Thus, STIM and Orai are interesting candidates to regulate cancer cell fate in the TME. In this review, we summarize the current knowledge about the function of ROS and STIM/Orai in cancer cells; discuss their interdependencies; and propose new hypotheses how TME, ROS, and Orai channels influence each other.

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 VEGFR-2 Expression in Glioblastoma Multiforme Depends on Inflammatory Tumor Microenvironment

2015 ◽  
Vol 2015 ◽  
pp. 1-7 ◽  
Author(s):  
Jana Jaal ◽  
Marju Kase ◽  
Ave Minajeva ◽  
Mikk Saretok ◽  
Aidi Adamson ◽  
...  
Keyword(s):  
Glioblastoma Multiforme ◽  
Tumor Microenvironment ◽  
Blood Vessels ◽  
Optical Density ◽  
Antiangiogenic Therapy ◽  
Growth Factor Receptor ◽  
Positive Association ◽  
Staining Intensity ◽  
Tissue Expression ◽  
The Impact

Glioblastoma multiforme (GBM) is one of the most angiogenic tumors. However, antiangiogenic therapy has not shown significant clinical efficacy. The aim of our study was to evaluate the impact of inflammatory tumor microenvironment on the expression of vascular endothelial growth factor receptor 2 (VEGFR-2). Surgically excised primary GBM tissues were histologically examined for overall extent of inflammation (score 1–3). After immunohistochemistry, the tissue expression of ICAM-1 (optical density), the number of VEGFR-2 positive (VEGFR-2+) blood vessels (per microscopic field), and the endothelial staining intensity of VEGFR-2 (score 0–3) were determined. In GBM, the extent of inflammation was 1.9 ± 0.7 (group mean ± SD). Mean optical density of inflammatory mediator ICAM-1 was 57.0 ± 27.1 (pixel values). The number of VEGFR-2+ blood vessels and endothelial VEGFR-2 staining intensity were 6.2 ± 2.4 and 1.2 ± 0.8, respectively. A positive association was found between endothelial VEGFR-2 staining intensity and the extent of inflammation (p=0.005). Moreover, VEGFR-2 staining intensity correlated with the expression level of ICAM-1 (p=0.026). The expression of VEGFR-2, one of the main targets of antiangiogenic therapy, depends on GBM microenvironment. Higher endothelial VEGFR-2 levels were seen in the presence of more pronounced inflammation. Target dependence on inflammatory tumor microenvironment has to be taken into consideration when treatment approaches that block VEGFR-2 signaling are designed.

scholarly journals Crosstalk between Blood Vessels and Tumor Microenvironment

2010 ◽  
Vol 7 (1) ◽  
pp. 1-10 ◽  
Author(s):  
Kyoko Hida ◽  
Noritaka Ohga ◽  
Takuro Kurosu ◽  
Yasunori Totsuka ◽  
Masanobu Shindoh
Keyword(s):  
Tumor Microenvironment ◽  
Blood Vessels

scholarly journals Dual-targeting biomimetic delivery for anti-glioma activityviaremodeling the tumor microenvironment and directing macrophage-mediated immunotherapy

2018 ◽  
Vol 9 (10) ◽  
pp. 2674-2689 ◽  
Author(s):  
Pengfei Zhao ◽  
Yonghui Wang ◽  
Xuejia Kang ◽  
Aihua Wu ◽  
Weimin Yin ◽  
...  
Keyword(s):  
Tumor Microenvironment ◽  
Treatment Strategy ◽  
Dual Targeting

A dual-targeting biomimetic codelivery and treatment strategy was developed for anti-glioma activity.

scholarly journals Potential Strategies to Improve the Effectiveness of Drug Therapy by Changing Factors Related to Tumor Microenvironment

2021 ◽  
Vol 9 ◽  
Author(s):  
Dehong Cao ◽  
Xiaokaiti Naiyila ◽  
Jinze Li ◽  
Yin Huang ◽  
Zeyu Chen ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Drug Therapy ◽  
Tumor Microenvironment ◽  
Blood Vessels ◽  
Tumor Cells ◽  
Significant Role ◽  
Cell Types ◽  
Related Factors ◽  
Continuous Interaction ◽  
Cellular Components

A tumor microenvironment (TME) is composed of various cell types and extracellular components. It contains tumor cells and is nourished by a network of blood vessels. The TME not only plays a significant role in the occurrence, development, and metastasis of tumors but also has a far-reaching impact on the effect of therapeutics. Continuous interaction between tumor cells and the environment, which is mediated by their environment, may lead to drug resistance. In this review, we focus on the key cellular components of the TME and the potential strategies to improve the effectiveness of drug therapy by changing their related factors.

Cancer associated fibroblasts: the major player in pancreatic cancer

2021 ◽  
Author(s):  
Débora B. Vendramini Costa
Keyword(s):  
Tumor Microenvironment ◽  
Pancreatic Ductal Adenocarcinoma ◽  
Blood Vessels ◽  
Cancer Cell ◽  
Immune Cells ◽  
Tissue Injury ◽  
Ductal Adenocarcinoma ◽  
Cancer Associated Fibroblasts ◽  
Tumor Mass ◽  
Major Player

Tumor cells are not alone in the tumor mass; in fact they are surrounded by a complex and active microenvironment, composed by fibroblasts and their extracellular matrix (ECM), immune cells, nerves, blood vessels, and secreted factors. It is now well recognized that the microenvironment plays an important role in tumor development and thus it is imperative for the comprehensive understanding of the interplay between cancer and its microenviroment for the development of better preventative and therapeutic strategies. Pancreatic ductal adenocarcinoma (PDAC) is a devastating disease with a 5 year survival rate of only 10% after diagnosis[1]. One of the main reasons for this outcome is the poor understanding of the unique microenvironment of PDAC, where up to 90% of the tumor mass can be composed by the stroma, with most of it being the expansion of activated fibroblasts and their ECM[2]. Even though CAFs represent an important component of PDAC (and other types of cancers), they are still incompletely understood. This can be partially explained by the fact that there are no specific markers to discriminate CAFs, and researchers need to rely on negative selections, absence of mutations that characterize the transformed epithelial cells plus the presence of mesenchymal markers, all together with the assessment of fibroblastic function2. There are still controversies about the pro- and anti-tumor effects of CAFs and their origin. Recently, a consensus was published2, where authors suggest that CAFs are mostly originated by the local activation and proliferation of resident fibroblasts, stimulated by tissue injury, reactive oxidative species, growth factors and more. These CAFs are characterized by their plasticity, as they can interchange between functions according to the signals of the environment. Many are the functions attributed to these cells; CAFs produce a very dense ECM, which can lead to the collapse of blood vessels, thus affecting nutrient supply and the delivery of therapies to this environment[3]. Moreover, CAFs can be immunusuppressive, producing a millieu of cytokines and chemokines that can turn off anti-tumor immune cells and recruit pro-tumor ones[4]. Interestingly, CAFs can also contribute to the metabolic signature of the environment, as they produce and modify a large range of metabolites, often supporting cancer cell survival[5]. Recently, our research group uncovered the pro-tumor roles of the synaptic protein Netrin G1 in CAFs[6]. The expression of Netrin G1 in CAFs from PDAC patients inversely correlated with overall survival. Moreover, the loss of Netrin G1 in CAFs led to decreased production of immunosuppressive factors, allowing NK cells to kill PDAC cells in vitro. Netrin G1 expression was also important for the production of metabolites (mainly glutamine and glutamate) by CAFs and for the support of nutrient deprived PDAC cells. It is important to mention that the Netrin G1 related studies were perfomed using 3D co-cultures, and that its expression can only be detected in CAFs growing in their 3D environment, further reinforcing the need for better strategies to study and understand the tumor microenvironment in PDAC. Therefore, CAFs can be seen as the major intermediaries of PDAC microenvironment and to target these cells in an attempt to normalize them rather than eliminate them, might be an effective strategy for PDAC therapy. References: [1] Siegel RL, Miller KD, Jemal A. Cancer statistics, 2020. CA Cancer J Clin, 2020; 70: 7-30. [2] Sahai E et al. A framework for advancing our understanding of cancer-associated fibroblasts. Nat Rev Cancer, 2020; 20:174-186 [3] Provenzano et al. Enzymatic targeting of the stroma ablates physical barriers to treatment of pancreatic ductal adenocarcinoma. Cancer Cell, 2012; 21:418-29. [4] Ziani L, Chouaib S, Thiery J. Alteration of the Antitumor Immune Response by Cancer-Associated Fibroblasts. Front Immunol, 2018; 9:414. [5] Lyssiotis CA and Kimmelman AC. Metabolic interactions in the tumor microenvironment. Trends Cell Biol, 2017; 27: 863-875. [6] Francescone et al. Netrin G1 promotes pancreatic tumorigenesis through cancer associated fibroblast driven nutritional support and immunosuppression. Cancer Discov. 2020 Oct 30:CD-20-0775. Epub ahead of print.

CGKRK-modified nanoparticles for dual-targeting drug delivery to tumor cells and angiogenic blood vessels

Biomaterials ◽  
2013 ◽  
Vol 34 (37) ◽  
pp. 9496-9508 ◽  
Author(s):  
Quanyin Hu ◽  
Xiaoling Gao ◽  
Ting Kang ◽  
Xingye Feng ◽  
Di Jiang ◽  
...  
Keyword(s):  
Drug Delivery ◽  
Blood Vessels ◽  
Tumor Cells ◽  
Dual Targeting
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