Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0596263 (carcinogenesis)
 64,820 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Radiation therapy has traditionally been the treatment of choice for locally or regionally advanced cancer, but its therapeutic efficacy is often hindered by limited tolerance of normal tissues and by tumor radioresistance. To improve therapeutic outcome, radiotherapy is frequently combined with chemotherapeutic drugs that are themselves cytotoxic and may sensitize cells to radiation. Solid evidence exists that administering standard chemotherapeutic agents during the course of radiotherapy (concurrent chemoradiotherapy) increases both local tumor control and patient survival in a number of cancer sites. These therapeutic improvements, however, have been achieved at the expense of considerable normal tissue toxicity. To improve chemoradiotherapy further, there have been extensive explorations of the potential of newer chemotherapeutic agents, including irinotecan (CPT-11, Camptosar) and other topoisomerase inhibitors. Preclinical studies have shown that these agents are potent radiosensitizers, providing a strong biologic rationale for using these drugs in combination with radiotherapy. These studies also generated information critical for designing effective treatment schedules in clinical settings. The therapeutic efficacy of topoisomerase inhibitor-radiation combinations is currently being tested clinically. Recent advances in molecular biology have discovered many cellular molecules, including the cyclooxygenase-2 (COX-2) enzyme, that promote tumor cell survival and are responsible for tumor resistance to cytotoxic agents, and hence may serve as potential targets for augmentation of radio (or chemo) response. COX-2 is often overexpressed in premalignant lesions and cancer, and is involved in carcinogenesis, tumor growth, and metastatic spread. Preclinical studies provided solid evidence that inhibition of this enzyme with selective COX-2 inhibitors prevents carcinogenesis, slows the growth of established tumors, and enhances tumor response to radiation without appreciably affecting normal tissue radioresponse. The mechanisms of enhancement of tumor radioresponse involve direct actions on tumor cells and indirect actions, primarily on tumor vasculature. COX-2 inhibitors also improve tumor response to chemotherapeutic agents, including irinotecan. Additional therapeutic benefit was observed for celecoxib (Celebrex), a selective COX-2 inhibitor, consisting of a strong reduction in irinotecan-induced diarrhea. Thus, selective targeting of COX-2 may potentially improve radiotherapy, chemotherapy, or chemoradiotherapy--a therapeutic strategy that is currently being tested in clinical trials.
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PMID:Improvement of radiotherapy or chemoradiotherapy by targeting COX-2 enzyme. 1280 Jun 1

Interleukin-6 (IL-6) is a proinflammatory cytokine associated with the disease status of gastric carcinoma (GC). Vascular endothelial growth factor (VEGF) is a potent tumor angiogenic factor in GC. In this study, we attempted to clarify whether IL-6 can regulate VEGF and angiogenesis in GC. GC samples from 54 surgical specimens were subjected to immunohistochemical examination of IL-6, VEGF, and tumor microvessels, and results showed that IL-6 was positively correlated with VEGF expression and tumor vasculature. We determined VEGF expression in four GC cell lines by ELISA, revealing that GC cells can produce significant amount of VEGF with increasing dose and duration of IL-6 stimulation. Next, a luciferase reporter gene assay was employed to determine the signaling pathway driving the VEGF promoter by IL-6, which showed that the JAK/STAT pathway is involved in the stimulation of VEGF gene expression. The effects of IL-6 on angiogenesis in vitro and in vivo were evaluated by HUVEC studies and the Matrigel plug assay, respectively. Results showed that IL-6 effectively promoted HUVEC proliferation and tube formation in vitro and Matrigel plug vascularization in vivo, primarily by inducing VEGF in GC. This study provides evidence that the multifunctional cytokine, IL-6, may induce VEGF expression which increases angiogenesis in gastric carcinogenesis.
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PMID:Interleukin-6 increases vascular endothelial growth factor and angiogenesis in gastric carcinoma. 1515 87

We identified regulator of G-protein signaling-5 (RGS-5) as an angiogenic pericyte marker at sites of physiologic and pathologic angiogenesis. In a mouse model of pancreatic islet cell carcinogenesis, RGS-5 is specifically induced in the vasculature of premalignant lesions during the "angiogenic switch" and further elevated in tumor vessels. Similarly, RGS-5 is overexpressed in highly angiogenic astrocytomas but not in hypoxia-inducible factor-1alpha (HIF-1alpha)-deficient tumors, which grow along preexisting brain capillaries without inducing neovessels. Elevated levels of RGS-5 in pericytes are also observed during wound healing and ovulation indicating a strong correlation between RGS-5 expression and active vessel remodeling beyond tumor angiogenesis. Moreover, antitumor therapy, which reverses tumor vasculature to an almost normal morphology, results in down-regulation of RGS-5 transcription. Taken together, these data demonstrate for the first time a factor that is specific for "activated" pericytes. This further supports the notion that pericytes, like endothelial cells, undergo molecular changes during neovascularization that makes them a novel target for antiangiogenic therapy.
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PMID:Regulator of G-protein signaling-5 induction in pericytes coincides with active vessel remodeling during neovascularization. 1545 6

Tumor neovasculature substantially derives from sprouting of existing vessels, whereas the functional contribution of bone marrow-derived progenitors to neovessels remains controversial. We used transgenic mouse models of multistep carcinogenesis to monitor incorporation of bone marrow-derived cells into the neovasculature and to elucidate mechanisms of endothelial precursor cell (EPC) recruitment into the tumor microenvironment. We unequivocally demonstrate integration of bone marrow cells into the tumor vasculature as a late event in carcinogenesis that temporally correlates with VEGF release by the tumor and mobilization of circulating EPC in the periphery. Moreover, we demonstrate a chemokine-dependent mechanism of EPC homing into tumor, whereby neovessels of late-stage tumors release a battery of CC chemokines, which direct CCR2(+) and CCR5(+) progenitors into the vasculature. Thus, we show that tumor vessels promote their own growth and development in a self-amplifying fashion.
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PMID:Chemokines direct endothelial progenitors into tumor neovessels. 1632 6

Interferon (IFN)-alpha is a cytokine with marked therapeutic activity in transplantable tumor models, that is in part due to angiogenesis inhibition. Aim of this study was to investigate the effects of IFN-alpha during the early phases of tumor development in the transgenic adenocarcinoma of the mouse prostate (TRAMP) model. To provide sustained IFN-alpha production, TRAMP mice were injected intraperitoneally with lentiviral vectors. IFN-alpha administration resulted in rapid and protracted upregulation of IFN-alpha-regulated genes associated with antiangiogenic and antiproliferative functions in the prostate of TRAMP mice, including guanylate-binding protein 1 (GBP-1), IFI204 and CXCL10-11. These transcriptional changes were accompanied by effects on the tumor vasculature, including significant reduction of intraductal microvessel density and increased pericyte coverage, and marked reduction of tumor cell proliferation, without induction of tumor necrosis. Intriguingly, GBP-1 and myxovirus resistance A, two IFN-regulated proteins, were found expressed in approximately 40% of human prostate cancer samples analyzed, suggesting expression of endogenous IFN-alpha. Overall, these findings demonstrate that IFN-alpha is able to counteract the angiogenic switch and impairs tumor cell proliferation in preinvasive lesions. Since the angiogenic switch also marks progression of human prostatic cancer, these results highlight the potential of angiogenesis inhibitors for the development of chemoprevention strategies in high-risk individuals.
Carcinogenesis 2009 May
PMID:Interferon-alpha counteracts the angiogenic switch and reduces tumor cell proliferation in a spontaneous model of prostatic cancer. 1923 8

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

Accessibility of tumors for highly effective local treatment represents a major challenge for anticancer therapy. Immunostimulatory oligodeoxynucleotides (ODN) with CpG motifs are ligands of TLR9, which prime spontaneous antitumor immunity, but are less effective when applied systemically. We therefore developed a liposome-based agent for selective delivery of CpG-ODN into the tumor environment. A peptide that specifically targets angiogenic endothelial cells in a transgenic tumor model for islet cell carcinogenesis was engrafted into CpG-ODN containing liposomes. Intravenous injection of these liposomes resulted in specific accumulation around tumor vessels, increased uptake by tumor-resident macrophages, and retention over time. In contrast, nontargeted liposomes did not localize to the tumor vasculature. Consequently, only vascular targeting of CpG-ODN liposomes provoked a marked inflammatory response at vessel walls with enhanced CD8(+) and CD4(+) T cell infiltration and, importantly, activation of spontaneous, tumor-specific cytotoxicity. In a therapeutic setting, 40% of tumor-bearing, transgenic mice survived beyond week 45 after systemic administration of vascular-directed CpG-ODN liposomes. In contrast, control mice survived up to 30 wk. Therapeutic efficacy was further improved by increasing the frequency of tumor-specific effector cells through adoptive transfers. NK cells and CD8(+) T cells were major effectors which induced tumor cell death and acted in conjunction with antivascular effects. Thus, tumor homing with CpG-ODN-loaded liposomes is as potent as direct injection of free CpG-ODN and has the potential to overcome some major limitations of conventional CpG-ODN monotherapy.
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PMID:Targeted liposomal delivery of TLR9 ligands activates spontaneous antitumor immunity in an autochthonous cancer model. 1956 Nov 11

Tumor growth and progression rely upon angiogenesis, which is regulated by pro- and antiangiogenic factors, including members of the semaphorin family. By analyzing 3 different mouse models of multistep carcinogenesis, we show here that during angiogenesis, semaphorin 3A (Sema3A) is expressed in ECs, where it serves as an endogenous inhibitor of angiogenesis that is present in premalignant lesions and lost during tumor progression. Pharmacologic inhibition of endogenous Sema3A during the angiogenic switch, the point when pretumoral lesions initiate an angiogenic phase that persists throughout tumor growth, enhanced angiogenesis and accelerated tumor progression. By contrast, when, during the later stages of carcinogenesis following endogenous Sema3A downmodulation, Sema3A was ectopically reintroduced into islet cell tumors by somatic gene transfer, successive waves of apoptosis ensued, first in ECs and then in tumor cells, resulting in reduced vascular density and branching and inhibition of tumor growth and substantially extended survival. Further, long-term reexpression of Sema3A markedly improved pericyte coverage of tumor blood vessels, something that is thought to be a key property of tumor vessel normalization, and restored tissue normoxia. We conclude, therefore, that Sema3A is an endogenous and effective antiangiogenic agent that stably normalizes the tumor vasculature.
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PMID:Semaphorin 3A is an endogenous angiogenesis inhibitor that blocks tumor growth and normalizes tumor vasculature in transgenic mouse models. 1980 58

Hepatocellular carcinoma develops in a multistep process. Previous studies have revealed changes in blood supply in hepatocellular carcinoma during its carcinogenesis. However, little is known about the relationship between tumor vasculature and the biological behavior of moderately differentiated hepatocellular carcinoma which demonstrates varied degrees of biological behavior. We immunohistochemically assessed intratumoral arterial vessel density (by high-molecular-weight caldesmon and calponin) and microvessel density (by CD34) in 123 cases of moderately differentiated hepatocellular carcinomas, and compared these densities with clinicopathological findings. Arterial vessel density and microvessel density of 19 well-differentiated and 37 poorly differentiated hepatocellular carcinomas were also evaluated. The arterial vessel density of moderately differentiated hepatocellular carcinomas with capsule formation, infiltration to the capsule, portal venous invasion, and high Ki-67 labeling index was lower than that of moderately differentiated hepatocellular carcinomas without these pathological findings (high-molecular-weight caldesmon: P < .0001, P = .0074, P = .0009, P = .0244, calponin: P < .0001, P = .0695, P = .0033, and P = .0155, respectively). The low arterial vessel density group (<10) of moderately differentiated hepatocellular carcinomas tended to show poorer overall survival than the high arterial vessel density group (>or=10) (high-molecular-weight caldesmon: P = .0347, calponin: P = .0404). The arterial vessel density and microvessel density of moderately differentiated hepatocellular carcinomas were significantly higher than those of well-differentiated hepatocellular carcinomas (high-molecular-weight caldesmon: P = .022, calponin: P = .027, CD34: P = .036) and poorly differentiated hepatocellular carcinomas (high-molecular-weight caldesmon, calponin and CD34: P < .0001). The moderately differentiated hepatocellular carcinomas with lower arterial vessel density had more malignant potential than those with higher arterial vessel density. The changes of arterial vessel density in moderately differentiated hepatocellular carcinomas were suggested.
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PMID:Down-regulation of artery in moderately differentiated hepatocellular carcinoma related to tumor development. 2018 61

Global increase in incidence and mortality as well as poor prognosis of oral cancer (OC) has intensified efforts towards early detection and prevention of this disfiguring disease. Several studies have been conducted using experimental animal models to understand the pathophysiology and molecular events involved in OC. Lack of identification of specific biomarkers during the multifaceted steps of oral carcinogenesis has hindered its diagnosis and treatment. Solid stress generated by growing tumors as well as abnormalities in tumor vasculature lead to increased interstitial fluid pressure, which could obstruct therapeutic drug delivery to tumors. Furthermore, the sympathetic nervous system is known to affect angiogenesis, vessel permeability, immune responses and carcinogenesis. Recent findings indicate that, in addition to angiogenic and lymphangiogenic factors, tumor cells release neurotrophic factors that initiate innervation. Interactions between cytokines and sympathetic neurotransmitters, and their respective receptors expressed by the nerve, immune and tumor cells appear to influence tumor growth. Thus, understanding the complex signaling processes and interrelationships between vascular, nervous and immune systems during oral carcinogenesis may prove vital for successful prevention and treatment of OC. This review aims at outlining the available knowledge on pathophysiology of OC in experimental animal models including evidence from our own findings.
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PMID:Pathophysiology of oral cancer in experimental animal models: a review with focus on the role of sympathetic nerves. 2081 30


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