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Query: UMLS:C0178874 (tumor progression)
 40,807 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Tumor angiogenesis is critically important for the growth of solid tumors as tumors remain in dormant phase for a long time in the absence of the initiation of blood vessel formation. Tumors can grow up to approximately 2mm size without requirement of blood supply as diffusion is sufficient at this level to support the removal of wastes from and supply of nutrients to tumor cells. Therefore, angiogenesis process could be an important target to suppress tumor growth and metastasis. Angiogenesis is required at almost every step of tumor progression and metastasis, and tumor vasculature has been identified as strong prognostic marker for tumor grading. Endothelial cells are the main players of angiogenesis process and could be peculiar target for antiangiogenic therapy because they are non-transformed and easily accessible to achievable concentrations of antiangiogenic agents, and also are unlikely to acquire drug resistance. Several antiangiogenic strategies have been developed to inhibit tumor growth by targeting different components of tumor angiogenesis. Chemopreventive agents have been shown to target and inhibit different aspects and components of angiogenesis process and can be used conveniently as they are mostly non-toxic natural compounds and could be part of our daily diet. However, a risk assessment for the use of antiangiogenic phytochemicals is needed as they can also disrupt normal physiologic angiogenesis such as wound healing and endometrium development processes. This review focuses on how different chemopreventive phytochemicals target various components of angiogenesis, including angiogenic signaling, which usually starts from tumor cells producing angiogenic factors and affecting endothelial cells growth, migration and capillary vessel organization for tumor angiogenesis.
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PMID:Tumor angiogenesis--a potential target in cancer chemoprevention. 1791 2

Although antiangiogenic strategies have proven highly promising in preclinical studies and some recent clinical trials, generally only combinations with cytotoxic therapies have shown clinical effectiveness. An ongoing question has been whether conventional therapies are enhanced or compromised by antiangiogenic agents. The present studies were designed to determine the pathophysiologic consequences of both single and combined treatments using fractionated radiotherapy plus AG-013736, a receptor tyrosine kinase inhibitor that preferentially inhibits vascular endothelial growth factor receptors. DU145 human prostate xenograft tumors were treated with (a) vehicle alone, (b) AG-013736, (c) 5x2 Gy/wk radiotherapy fractions, or (d) the combination. Automated image processing of immunohistochemical images was used to determine total and perfused blood vessel spacing, overall hypoxia, pericyte/collagen coverage, proliferation, and apoptosis. Combination therapy produced an increased tumor response compared with either monotherapy alone. Vascular density progressively declined in concert with slightly increased alpha-smooth muscle actin-positive pericyte coverage and increased overall tumor hypoxia (compared with controls). Although functional vessel endothelial apoptosis was selectively increased, reductions in total and perfused vessels were generally proportionate, suggesting that functional vasculature was not specifically targeted by combination therapy. These results argue against either an AG-013736- or a combination treatment-induced functional normalization of the tumor vasculature. Vascular ablation was mirrored by the increased appearance of dissociated pericytes and empty type IV collagen sleeves. Despite the progressive decrease in tumor oxygenation over 3 weeks of treatment, combination therapy remained effective and tumor progression was minimal.
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PMID:The addition of AG-013736 to fractionated radiation improves tumor response without functionally normalizing the tumor vasculature. 1794 24

Endosialin (Tem1) has been identified by two independent experimental approaches as an antigen of tumor-associated endothelial cells, and it has been claimed to be the most abundantly expressed tumor endothelial antigen, making it a prime candidate for vascular targeting purposes. Recent experiments have challenged the endothelial expression of endosialin and suggested an expression by activated fibroblasts and pericytes. Thus, clarification of the controversial cellular expression of endosialin is critically important for an understanding of its role during tumor progression and its validation as a potential therapeutic target. We have therefore performed extensive expression profiling analyses of endosialin. The experiments unambiguously demonstrate that endosialin is expressed by tumor-associated myofibroblasts and mural cells and not by endothelial cells. Endosialin expression is barely detectable in normal human tissues with moderate expression only detectable in the stroma of the colon and the prostate. Corresponding cellular experiments confirmed endosialin expression by mesenchymal cells and indicated that it may in fact be a marker of mesenchymal stem cells. Silencing endosialin expression in fibroblasts strongly inhibited migration and proliferation. Collectively, the experiments validate endosialin as a marker of tumor-associated myofibroblasts and tumor vessel-associated mural cells. The data warrant further functional analysis of endosialin during tumor progression and its exploitation as marker of tumor vessel-associated mural cells, expression of which may reflect the non-normalized phenotype of the tumor vasculature.
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PMID:Endosialin (Tem1) is a marker of tumor-associated myofibroblasts and tumor vessel-associated mural cells. 1818 65

Plasminogen activator inhibitor-1 (PAI-1) is an important endogenous inhibitor of urokinase-type plasminogen activator. Its action in tumor angiogenesis is complicated, varying with experimental setting and its cellular origin. To further understand the mechanism of the effect of PAI-1 on tumor angiogenesis, especially newly established tumor vasculature in early tumor progression, stable transfectants (TO-PAI-1) of the human prostate adenocarcinoma, PC3, were generated in which PAI-1 expression is under the control of the tetracycline-responsive promoter (Tet-On system). The TO-PAI-1 transfectants exhibit tight inducibility of expression of biologically active PAI-1 in vitro. Induction of PAI-1 expression in nude mice resulted in significant inhibition of tumor growth. This inhibition appears to be due to the effect of PAI-1 on angiogenesis, because it is manifested by an initial wave of tumor endothelial apoptosis accompanied by induction of tumor cell apoptosis and inhibition of tumor cell proliferation. Similar endothelial apoptosis is observed in vitro when human microvascular endothelial cells are physically cocultivated with TO-PAI-1 cells on vitronectin-coated plate. Taken together, these data show for the first time that PAI-1 induces endothelial apoptosis in the newly established tumor vasculature.
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PMID:Plasminogen activator inhibitor-1 inhibits prostate tumor growth through endothelial apoptosis. 1848 10

Blood vessels inside tumors are crucial for cancer survival and progression but equally contribute to the tumor's intrinsic resistance to therapy. Abnormal blood flow in the local tumor environment acts as a physiological barrier to the delivery of chemotherapeutic agents. Furthermore, tumor vasculature can also act as a barrier for immune cell migration into the tumor parenchyma. Much has been made of anti-angiogenic therapies that specifically inhibit vessel growth. However, recent findings demonstrate that the chaotic architecture of tumor blood vessels can be reversed which in turn normalizes blood flow and physical parameters in the tumor environment. Importantly, vessel normalization also improves lymphocyte migration into tumor tissue and immune destruction. Identification of regulator of G protein signaling 5 (RGS5) as a key modulator of the vascular barrier in tumor progression and regression has brought new insights into the molecular basis of vessel normalization and opens new therapeutic opportunities.
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PMID:Modulation of the "blood-tumor" barrier improves immunotherapy. 1871 82

Cancer, with more than 10 million new cases a year worldwide, is the third leading cause of death in developed countries. One critical requirement during cancer progression is angiogenesis, the formation of new blood vessels. Structural and functional imaging of tumor vasculature has been studied using various imaging modalities such as magnetic resonance imaging (MRI), computed tomography (CT), and ultrasound. Molecular imaging, a key component of the 21st-century cancer-patient management strategy, takes advantage of these traditional imaging techniques and introduces molecular probes to determine the expression of indicative molecular markers at different stages of cancer development. In this chapter, we will focus on two tumor vasculature-related targets: integrin alpha(v)beta(3) and vascular endothelial growth factor receptor (VEGFR). For imaging of integrin alpha(v)beta(3) on the tumor vasculature, only nanoparticle-based probes will be discussed. VEGFR imaging will be discussed in depth, and we will give a detailed example of positron emission tomography (PET) imaging of VEGFR expression using radio-labeled VEGF(121) protein. Future clinical translation will be critical for maximum patient benefit from these agents. To achieve this goal, multidisciplinary approaches and cooperative efforts from many individuals, institutions, industries, and organizations are needed to quickly translate multimodality tumor vasculature imaging into multiple facets of cancer patient management.
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PMID:Chapter 7. Molecular imaging of tumor vasculature. 1902 59

The inhibition of key receptor tyrosine kinases (RTKs) that are implicated in tumor vasculature formation and maintenance, as well as tumor progression and metastasis, has been a major focus in oncology research over the last several years. Many potent small molecule inhibitors of vascular endothelial growth factor receptor (VEGFR) and platelet-derived growth factor receptor (PDGFR) kinases have been evaluated. More recently, compounds that act through the complex inhibition of multiple kinase targets have been reported and may exhibit improved clinical efficacy. We report herein a series of potent, orally efficacious 4-amino-3-benzimidazol-2-ylhydroquinolin-2-one analogues as inhibitors of VEGF, PDGF, and fibroblast growth factor (FGF) receptor tyrosine kinases. Compounds in this class, such as 5 (TKI258), are reversible ATP-competitive inhibitors of VEGFR-2, FGFR-1, and PDGFRbeta with IC(50) values <0.1 microM. On the basis of its favorable in vitro and in vivo properties, compound 5 was selected for clinical evaluation and is currently in phase I clinical trials.
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PMID:Design, structure-activity relationships and in vivo characterization of 4-amino-3-benzimidazol-2-ylhydroquinolin-2-ones: a novel class of receptor tyrosine kinase inhibitors. 1911 66

Pancreatic cancer is a devastating disease with no cure. Therapies that target the tumor vasculature are promising new treatment strategies. Magnetic resonance imaging (MRI) can non-invasively determine a vessel size index and a blood volume fraction to characterize the vascular compartment in a tumor. The changes in the T2 and T2* relaxation rate constants after the administration of superparamagnetic iron oxide (SPIO) particles are dependent on the size and morphology of tissue blood vessels. In this study, MRI was used to investigate changes in the tumor vasculature in an orthotopic primary human pancreatic cancer xenograft model during tumor progression. The SPIO contrast agent Feridex I.V. was first validated as an intravascular contrast agent over the course of the imaging session, and shown to remain in the blood for at least 1.5 h. The average vessel size index was not correlated to the tumor area within an image slice, but the average blood volume fraction was significantly and negatively correlated to the tumor area (p<0.05). Blood volume fraction may serve as a non-invasive biomarker for changes in the tumor vasculature due to tumor growth Further investigation is needed to evaluate this promising technique as a tool to monitor tumor vascular changes in response to antiangiogenic therapies in pancreatic cancer.
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PMID:Assessment of vessel size by MRI in an orthotopic model of human pancreatic cancer. 1916 90

The bone marrow constitutes an unique microenvironment for cancer cells in three specific aspects. First, the bone marrow actively recruits circulating tumor cells where they find a sanctuary rich in growth factors and cytokines that promote their proliferation and survival. When in the bone marrow, tumor cells profoundly affect the homeostasis of the bone and the balance between osteogenesis and osteolysis. As a consequence, growth and survival factors normally sequestered into the bone matrix are released, further fueling cancer progression. Second, tumor cells actively recruit bone marrow-derived precursor cells into their own microenvironment. When in the tumors, these bone marrow-derived cells contribute to an inflammatory reaction and to the formation of the tumor vasculature. Third, bone marrow-derived cells can home in distant organs, where they form niches that attract circulating tumor cells. Our understanding of the contribution of the bone marrow microenvironment to cancer progression has therefore dramatically improved over the last few years. The importance of this new knowledge cannot be underestimated considering that the vast majority of cancer treatments such as cytotoxic and myeloablative chemotherapy, bone marrow transplantation and radiation therapy inflict a trauma to the bone marrow microenvironment. How such trauma affects the influence that the bone marrow microenvironment exerts on cancer is still poorly understood. In this article, the reciprocal relationship between the bone marrow microenvironment and tumor cells is reviewed, and its potential impact on cancer therapy is discussed.
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PMID:Bone marrow microenvironment and tumor progression. 1930 82

Transgenic mouse models offer an excellent opportunity for studying the molecular basis of cancer development and progression. Here we applied flat-panel volume computed tomography (fpVCT) to monitor tumor progression as well as the development of tumor vasculature in vivo in a transgenic mouse model for oncogene-induced mammary carcinogenesis (WAP-T mice). WAP-T mice develop multiple mammary carcinomas on oncogene induction within 3 to 5 months. Following induction, 3-dimensional fpVCT data sets were obtained by serial single scans of entire mice in combination with iodine containing contrast agents and served as basis for precise measurements of tumor volumes. Thereby, we were able to depict tumors within the mammary glands at a very early stage of the development. Tumors of small sizes (0.001 cm(3)) were detected by fpVCT before being palpable or visible by inspection. The capability to determine early tumor onset combined with longitudinal noninvasive imaging identified diverse time points of tumor onset for each mammary carcinoma and different tumor growth kinetics for multiple breast carcinomas that developed in single mice. Furthermore, blood supply to the breast tumors, as well as blood vessels around and within the tumors, were clearly visible over time by fpVCT. Three-dimensional visualization of tumor vessels in high resolution was enhanced by the use of a novel blood pool contrast agent. Here, we demonstrate by longitudinal fpVCT imaging that mammary carcinomas develop at different time points in each WAP-T mouse, and thereafter show divergent growth rates and distinct vascularization patterns.
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PMID:Detection of different tumor growth kinetics in single transgenic mice with oncogene-induced mammary carcinomas by flat-panel volume computed tomography. 1938 54


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