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Brain sweet brain: importance of sugars for the cerebral microenvironment and tumor development
Quirico-Santos, Thereza;Fonseca, Clovis O;Lagrota-Candido, Jussara;
Arquivos de Neuro-Psiquiatria , 2010, DOI: 10.1590/S0004-282X2010000500024
Abstract: the extracellular matrix (ecm) in the brain tissue is a complex network of glycoproteins and proteoglycans that fills the intercellular space serving as scaffolding to provide structural framework for the tissue and regulate the behavior of cells via specific receptors - integrins. there is enormous structural diversity among proteoglycans due to variation in the core protein, the number of glycosaminoglycans chains, the extent and position of sulfation. the lectican family of proteoglycans interacts with growth factors, hyaluronan and tenascin forming a complex structure that regulates neuronal plasticity and ion homeostasis around highly active neurons. in this review, we will discuss the latest insights into the roles of brain glycoproteins as modulators of cell adhesion, migration, neurite outgrowth and glial tumor invasion.
Microenvironment Determinants of Brain Metastasis
Chenyu Zhang, Dihua Yu
Cell & Bioscience , 2011, DOI: 10.1186/2045-3701-1-8
Abstract: Brain metastasis is the major cancerous disease in the central nervous system (CNS), outnumbering primary brain tumor cases 10-fold [1]. Lung cancer, breast cancer and melanoma account for most clinical cases of brain metastasis from non-CNS primary tumors [2]. Brain metastasis often manifests at late stages of metastatic disease progression and causes rapid deterioration in patients' quality of life including neurocognitive impairment [3], although latency varies among different tumor types and many small cell lung cancer patients already exhibit metastatic lesions in the CNS at the time of primary tumor diagnosis. Distinct tumor cell properties from different primary organ sites are likely critical factors responsible for the discrepancy in brain metastasis latency, though the exact molecular mechanism remains elusive. With advances in cancer treatments that better control systemic metastatic diseases at other organ sites, more brain metastasis has emerged in the clinic as exemplified in the cases of HER2-positive breast cancer patients treated by the monoclonal antibody trastuzumab (Herceptin). More than one-third of trastuzumab-treated patients developed brain metastasis in clinical trials [4-6]. Brain metastatic tumors are generally refractory to conventional chemotherapy and the recently developed targeted therapeutic regimens, presumably due to the inability of these therapeutic agents to penetrate the blood-brain barrier (BBB). Current standard treatments for brain metastasis include surgical resection, whole brain radiation therapy (WBRT) or more focused radio-surgical procedures for small numbers of tumor lesions in the CNS [7]. Brain metastasis presents an emerging and urgent unmet medical need and that has been historically understudied. Recently, there has been a steady increase of reports in the literature studying brain metastasis from various primary tumor sites of origin. The current review will emphasize the unique challenges posed by brain metasta
The role of the microenvironment in tumor immune surveillance  [cached]
Oluwadayo Oluwadara,Luca Giacomelli,Xenia Brant,Russell Christensen4
Bioinformation , 2011,
Abstract: The evidence appears compelling that the microenvironment, and associated biological cellular and molecular factors, may contribute to the progression of a variety of tumors. The effects of the microenvironment may directly influence the plasticity of T cell lineages, which was recently discussed (O’Shea & Paul, 2010 ). To review the putative role of the microenvironment in modulating the commitment of tumor immune surveillance, we use the model of oral premalignant lesions.
Interaction of tumor cells with the microenvironment
Hendrik Ungefroren, Susanne Sebens, Daniel Seidl, Hendrik Lehnert, Ralf Hass
Cell Communication and Signaling , 2011, DOI: 10.1186/1478-811x-9-18
Abstract: The complex process of metastasis formation can be divided into several stages: emigration from the primary tumor, invasion of the surrounding tissue and its extracellular matrix (ECM), intravasation into the circulation or the lymphatic system via transmigration through the endothelial lining and the basement membrane, and finally extravasation and metastasis formation at target sites. During each stage, tumor cells have to detach, migrate, invade, adapt and re-attach by involving matrix degrading enzymes and mechanical processes such as cell adhesion, changes of cell fate, cell movements and motility, and the generation of forces. Indeed, an understanding of the invasion process is only possible in the context of detailed insights into the cancer cell's interactions with the microenvironment. These interactions are determined by structural and biochemical properties of the ECM as well as by communication with surrounding non-neoplastic cells such as endothelial cells (ECs, during the process of transendothelial migration), cancer-associated fibroblasts (CAFs), mesenchymal stem cells (MSC), and a variety of different immune cells including lymphocytes and tumor-associated macrophages (TAMs). Since these multiple interactions with the tumor stroma determine not only cancer growth and metastasis but may also develop protective effects with respect to the tumor cells' drug sensitivity/resistance, the tumor stroma also has to be considered as a potential therapeutic target. Specifically, a deeper understanding of these interactions will elucidate the mechanisms of action of classical drugs that have been discovered by empirical approaches and, even more appealing, will facilitate the design and development of novel mechanistically-acting or even individually-designed drugs. This particularly applies for tumors exhibiting a pronounced stromal compartment such as invasive mammary adenocarcinoma (MaCa) and the highly malignant pancreatic ductal adenocarcinoma (PDAC), the
Targeting the Tumor Microenvironment: Focus on Angiogenesis
Fengjuan Fan,Alexander Schimming,Dirk Jaeger,Klaus Podar
Journal of Oncology , 2012, DOI: 10.1155/2012/281261
Abstract: Tumorigenesis is a complex multistep process involving not only genetic and epigenetic changes in the tumor cell but also selective supportive conditions of the deregulated tumor microenvironment. One key compartment of the microenvironment is the vascular niche. The role of angiogenesis in solid tumors but also in hematologic malignancies is now well established. Research on angiogenesis in general, and vascular endothelial growth factor in particular, is a major focus in biomedicine and has led to the clinical approval of several antiangiogenic agents including thalidomide, bevacizumab, sorafenib, sunitinib, pazopanib, temesirolimus, and everolimus. Indeed, antiangiogenic agents have significantly changed treatment strategies in solid tumors (colorectal cancer, renal cell carcinoma, and breast cancer) and multiple myeloma. Here we illustrate important aspects in the interrelationship between tumor cells and the microenvironment leading to tumor progression, with focus on angiogenesis, and summarize derived targeted therapies.
Brain Metastases from Colorectal Cancer: Microenvironment and Molecular Mechanisms  [PDF]
Yi-Wen Zang,Xiao-Dong Gu,Jian-Bin Xiang,Zong-You Chen
International Journal of Molecular Sciences , 2012, DOI: 10.3390/ijms131215784
Abstract: Colorectal cancer is one of the most common digestive tract malignancies in the world. Owing to the newer and more effective systemic therapies, the life of colorectal cancer patients can be remarkably prolonged, and the incidence of brain metastases is increasing. However, little is known about the underlying mechanisms of brain metastasis from colorectal cancer. Here we review the tumor microenvironment and metastasis associated molecules in brain metastases from colorectal cancer. A further understanding of these mechanisms will help us to propose better strategies for colorectal cancer patients with brain metastasis and improve their life quality.
In silico Experimentation of Glioma Microenvironment Development and Anti-tumor Therapy  [PDF]
Yu Wu,Yao Lu,Weiqiang Chen,Jianping Fu,Rong Fan
PLOS Computational Biology , 2012, DOI: 10.1371/journal.pcbi.1002355
Abstract: Tumor cells do not develop in isolation, but co-evolve with stromal cells and tumor-associated immune cells in a tumor microenvironment mediated by an array of soluble factors, forming a complex intercellular signaling network. Herein, we report an unbiased, generic model to integrate prior biochemical data and the constructed brain tumor microenvironment in silico as characterized by an intercellular signaling network comprising 5 types of cells, 15 cytokines, and 69 signaling pathways. The results show that glioma develops through three distinct phases: pre-tumor, rapid expansion, and saturation. We designed a microglia depletion therapy and observed significant benefit for virtual patients treated at the early stages but strikingly no therapeutic efficacy at all when therapy was given at a slightly later stage. Cytokine combination therapy exhibits more focused and enhanced therapeutic response even when microglia depletion therapy already fails. It was further revealed that the optimal combination depends on the molecular profile of individual patients, suggesting the need for patient stratification and personalized treatment. These results, obtained solely by observing the in silico dynamics of the glioma microenvironment with no fitting to experimental/clinical data, reflect many characteristics of human glioma development and imply new venues for treating tumors via selective targeting of microenvironmental components.
Discussion of the correlation between phlegm and tumor microenvironment
Zhong Xi Yi Jie He Xue Bao , 2010,
Abstract: : An abnormal microenvironment which is not fit for the living of normal cells is induced and maintained due to rapid growth, abnormal energy metabolism and self-regulation of specific proteins of the tumor cells. At the same time, the abnormal microenvironment is the guarantee of the neoplastic transformation, proliferation, invasion and metastasis of tumor cells. The microenvironment mainly consists of interstitial cells and their components. There are correlations between the physiological role of body fluid and the physiological functions of microenvironment. Phlegm is the product of abnormal body fluid metabolism. So to discuss the correlations of them may contribute to clarifying the material base of phlegm and will further give new insight for integrated traditional Chinese and Western medicine in cancer research.
Immune Microenvironment in Tumor Progression: Characteristics and Challenges for Therapy  [PDF]
Valerie Chew,Han Chong Toh,Jean-Pierre Abastado
Journal of Oncology , 2012, DOI: 10.1155/2012/608406
Abstract: The tumor microenvironment plays a critical role in cancer development, progression, and control. The molecular and cellular nature of the tumor immune microenvironment influences disease outcome by altering the balance of suppressive versus cytotoxic responses in the vicinity of the tumor. Recent developments in systems biology have improved our understanding of the complex interactions between tumors and their immunological microenvironment in various human cancers. Effective tumor surveillance by the host immune system protects against disease, but chronic inflammation and tumor “immunoediting” have also been implicated in disease development and progression. Accordingly, reactivation and maintenance of appropriate antitumor responses within the tumor microenvironment correlate with a good prognosis in cancer patients. Improved understanding of the factors that shape the tumor microenvironment will be critical for the development of effective future strategies for disease management. The manipulation of these microenvironmental factors is already emerging as a promising tool for novel cancer treatments. In this paper, we summarize the various roles of the tumor microenvironment in cancer, focusing on immunological mediators of tumor progression and control, as well as the significant challenges for future therapies. 1. Introduction The tumor microenvironment consists of cancer cells, stromal tissue, and extracellular matrix. The immune system is an important determinant of the tumor microenvironment. Indeed, the complex interplay between cancer cells and the host immune response has been extensively investigated in the past few decades. Several immunological deficiencies have been linked with enhanced tumor development in mouse models as well as in humans [1, 2]. The higher incidence of cancers in transplant patients receiving long-term immunosuppressive treatment is well documented [3–5]. Similarly, mice with compromised immune functions due to genetic modifications develop more tumors [6–9]. It is now well recognized that effective tumor surveillance by the immune system is critical to maintain homeostasis in the host. Despite exerting a key role in host protection, tumor surveillance by the immune system may eventually fail. As described in the three “Es” of cancer immunoediting, tumor cells are initially eliminated by the immune system before becoming clinically detectable. This is then followed by an equilibrium phase, where a selection process for less immunogenic tumor variants take place until the tumors finally “escape” the immune
Molecular targeting of liposomal nanoparticles to tumor microenvironment  [cached]
Zhao G,Rodriguez BL
International Journal of Nanomedicine , 2012,
Abstract: Gang Zhao,1,2 B Leticia Rodriguez21Institute of Materia Medica, Shandong Academy of Medical Science, Shandong, China; 2Pharmaceutics Division, College of Pharmacy, The University of Texas at Austin, Austin, TX, USAAbstract: Liposomes are biodegradable and can be used to deliver drugs at a much higher concentration in tumor tissues than in normal tissues. Both passive and active drug delivery by liposomal nanoparticles can significantly reduce the toxic side effects of anticancer drugs and enhance the therapeutic efficacy of the drugs delivered. Active liposomal targeting to tumors is achieved by recognizing specific tumor receptors through tumor-specific ligands or antibodies coupled onto the surface of the liposomes, or by stimulus-sensitive drug carriers such as acid-triggered release or enzyme-triggered drug release. Tumors are often composed of tumor cells and nontumor cells, which include endothelial cells, pericytes, fibroblasts, stromal, mesenchymal cells, innate, and adaptive immune cells. These nontumor cells thus form the tumor microenvironment, which could be targeted and modified so that it is unfavorable for tumor cells to grow. In this review, we briefly summarized articles that had taken advantage of liposomal nanoparticles as a carrier to deliver anticancer drugs to the tumor microenvironment, and how they overcame obstacles such as nonspecific uptake, interaction with components in blood, and toxicity. Special attention is devoted to the liposomal targeting of anticancer drugs to the endothelium of tumor neovasculature, tumor associated macrophages, fibroblasts, and pericytes within the tumor microenvironment.Keywords: tumor microenvironment, endothelium, neovasculature, tumor-associated macrophages, cationic liposomes, ligand- or antibody-mediated targeting

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