Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0699790 (colon cancer)
 28,837 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We previously reported that upregulation of angiogenesis, i.e. angiogenic switch (AS), may occur simultaneously to initiation of invasion in the early development of human colon cancer. We also showed that mRNA upregulation of the gene of vascular endothelial growth factor (VEGF) occurs immediately prior to metastasis in human colon cancer in an orthotopic nude mouse model of colon cancer liver metastasis. In this paper, we studied whether the antibody against VEGF inhibits AS and liver metastasis in an orthotopic xenograft model with site-dependent expression of VEGF. We examined levels of vessel density, VEGF mRNA by in situ hybridization (ISH) method and liver metastasis in pre-AS (on days 8 and 11) and post-AS (on days 15 and 18) treatment groups. The mean vessel density and the intensity of VEGF mRNA by ISH in the pre-AS treatment group were significantly lower than those for the post-AS treatment and the control group. Liver metastases were completely inhibited (0/10) in the pre-AS treatment, while they occurred in 4 out of 10 and 5 out of 10 mice in the post-AS treatment and the control groups, respectively (p<0.01). These results suggest that VEGF antibody treatment performed before AS could efficiently inhibit AS and liver metastasis, which may indicate that VEGF antibody has another potential as a drug for chemoprevention of colon cancer.
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PMID:Antibody against vascular endothelial growth factor (VEGF) inhibits angiogenic switch and liver metastasis in orthotopic xenograft model with site-dependent expression of VEGF. 1611 Jul 57

Hypoxia inducible factor-1 (HIF-1) is considered a crucial mediator of the cellular response to hypoxia through its regulation of genes that control angiogenesis. It represents an attractive therapeutic target in colon cancer, one of the few tumor types that shows a clinical response to antiangiogenic therapy. But it is unclear whether inhibition of HIF-1 alone is sufficient to block tumor angiogenesis. In HIF-1alpha knockdown DLD-1 colon cancer cells (DLD-1(HIF-kd)), the hypoxic induction of vascular endothelial growth factor (VEGF) was only partially blocked. Xenografts remained highly vascularized with microvessel densities identical to DLD-1 tumors that had wild-type HIF-1alpha (DLD-1(HIF-wt)). In addition to the preserved expression of VEGF, the proangiogenic cytokine interleukin (IL)-8 was induced by hypoxia in DLD-1(HIF-kd) but not DLD-1(HIF-wt) cells. This induction was mediated by the production of hydrogen peroxide and subsequent activation of NF-kappaB. Furthermore, the KRAS oncogene, which is commonly mutated in colon cancer, enhanced the hypoxic induction of IL-8. A neutralizing antibody to IL-8 substantially inhibited angiogenesis and tumor growth in DLD-1(HIF-kd) but not DLD-1(HIF-wt) xenografts, verifying the functional significance of this IL-8 response. Thus, compensatory pathways can be activated to preserve the tumor angiogenic response, and strategies that inhibit HIF-1alpha may be most effective when IL-8 is simultaneously targeted.
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PMID:Induction of interleukin-8 preserves the angiogenic response in HIF-1alpha-deficient colon cancer cells. 1614 72

Colon cancer remains a major cause of death; however, in the last 3 years a number of trials have been published that have led to changes in the treatment of patients with this disease. Initially, the adjuvant treatment of patients following curative resection was based on their Dukes staging; this is now being refined by consideration of other pathological factors, as well as the investigation of newer prognostic markers such as p53, Ki67 and a number of genes on chromosome 18. Tumours generally develop from the progressive accumulation of genetic events, although some develop through mutation or inactivation of DNA mismatch repair proteins leading to microsatellite instability; this is particularly important in Lynch's syndrome. The loss of gene expression can occur by deletion or mutation of genes or by aberrant methylation of CpG islands. In patients with Dukes C colon cancer the standard of care for adjuvant chemotherapy was previously based on bolus fluorouracil (5-fluorouracil) and folinic acid (leucovorin) administered 5 days per month or weekly for 6 months. Recent studies with a combination of infusional fluorouracil, folinic acid and oxaliplatin have been found to be superior. A further study replacing fluorouracil with oral capecitabine has also demonstrated equivalent disease-free survival. Although some debate remains regarding the benefit of adjuvant treatment for patients with Dukes B colon cancer, the emerging consensus is that, for those patients who are younger and have high-risk features, chemotherapy should be discussed. A number of large vaccine trials have also been conducted in the adjuvant setting and, overall, these have been disappointing. This is a rapidly advancing area of therapy and the results of new trials are awaited to determine whether additional benefits can be achieved with biological therapies such as anti-vascular endothelial growth factor and anti-epithelial growth factor receptor monoclonal antibodies, which have already been shown to be effective in setting of metastatic colon cancer.
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PMID:Adjuvant treatment strategies for early colon cancer. 1616 19

Targeted biologic therapy remains a very active and evolving field since the US Food and Drug Administration approved cetuximab, a recombinant, human/mouse chimeric monoclonal antibody against the endothelial growth factor receptor, and bevacizumab, a humanized monoclonal antibody directed against vascular endothelial growth factor, for the treatment of colorectal cancer. Benefits of these reagents in diverse clinic settings combined with different chemotherapeutic agents are being defined. Current research is focused on defining which patients will benefit from these treatments and how best to use them in the clinic. Additional preclinical and clinical studies will enable better usage of these biologic agents and lead to the development of new targeted therapies for the treatment of colon cancer.
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PMID:Biologic therapy for colon cancer. 1616 38

The induction of new blood vessels is critical to the pathogenesis of colon cancer, and inhibition of vascular endothelial growth factor (VEGF) has proven to be an effective approach to the treatment of this malignancy. Another potential therapeutic strategy would utilize endogenous anti-angiogenic molecules such as thrombospondin-1 (TSP-1). However, the regulation of TSP-1 expression in colon cancer is poorly understood. Our results demonstrate that TSP-1 is strongly expressed in normal colonic epithelial cells. However, loss of TSP-1 was observed in early colonic adenomas and it became undetectable in invasive colon cancers. Activation of the Wnt signaling pathway in intestinal epithelial cells repressed TSP-1 gene expression, and inhibition of Wnt signaling in colon cancer cells reversed this repression. Although mutant K-ras also inhibited the TSP-1 promoter in intestinal epithelial cells, silencing of mutant K-ras in colon cancer cells with an activated Wnt pathway did not upregulate TSP-1 expression. Collectively, these findings suggest that activation of the Wnt pathway rather than K-ras plays a more important role in the downregulation of TSP-1 observed in colon cancer.
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PMID:Wnt signaling can repress thrombospondin-1 expression in colonic tumorigenesis. 1625 61

With recent Food and Drug Administration approval of the anti-vascular endothelial growth factor (VEGF) antibody for the treatment of colon cancer, it may be possible to achieve similar progress in the treatment of locally advanced lung cancer. Antiangiogenic therapies in the clinic are a reality, and it is important to demonstrate that they can be used safely with conventional modalities, including radiation therapy (RT). Strategies under scrutiny in preclinical and clinical studies include the use of endogenous inhibitors of angiogenesis, use of agents that target VEGF and VEGF receptor signaling, targeting endothelial-related integrins during angiogenesis, and targeting the preexisting immature vessels growing within tumors (ie, vascular targeting). Regardless of the approach, it is necessary to address whether angiogenesis is a consistent phenomenon within the lung parenchyma around a cancer and a relevant target and whether inhibiting angiogenesis will improve current lung cancer therapies without increasing toxicity. Vascular-targeting agents (VTAs) are an interesting class of agents that have the potential to enhance RT, but their clinical promise has yet to be realized. In preclinical models, these agents selectively destroy the tumor vasculature, initiating a rapid centralized necrosis within established tumors. Characteristically, after treatment with VTAs, a rim of viable tumor cells remains at the periphery of the tumor, which remains well perfused and should therefore be relatively sensitive to radiation-induced cytotoxicity. This review will focus on VTAs in the treatment of lung cancer and includes a discussion of combination studies with RT in the laboratory and some of the hurdles in the clinical application of these agents.
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PMID:Vascular-targeting agents and radiation therapy in lung cancer: where do we stand in 2005? 1635 11

Hypoxia-inducible factor-1alpha (HIF-1alpha) is a transcription factor that directly transactivates genes important for the growth and metabolism of solid tumors. HIF-1alpha is overexpressed in cancer, and its level of expression is correlated with patient mortality. Increased synthesis or stability of HIF-1alpha can be induced by hypoxia-dependent or hypoxia-independent factors. Thus, HIF-1alpha is expressed in both nonhypoxic and hypoxic cancer cells. The role of HIF-1alpha in nonhypoxia-mediated cancer cell proliferation remains speculative. We have disrupted HIF-1alpha by targeted homologous recombination in HCT116 and RKO human colon cancer cells. Loss of HIF-1alpha significantly reduced nonhypoxia-mediated cell proliferation in vitro and in vivo. Paradoxically, loss of HIF-1alpha expression did not grossly affect the hypoxic compartments within tumor xenografts in vivo, although HIF-1alpha promoted cell proliferation and survival under hypoxia in vitro. To further test the role of HIF-1alpha within tumor compartments, we generated cells with combined disruptions of both HIF-1alpha and vascular endothelial growth factor (VEGF). In all xenografts, disruption of VEGF led to marked expansion of the hypoxic compartments and growth delay. Nonetheless, the presence or absence of HIF-1alpha did not grossly affect these expanded hypoxic compartments. These data provide compelling evidence that, in a subset of colon cancers, (a) HIF-1alpha is a positive factor for nonhypoxia-mediated cell proliferation in vitro and in vivo and (b) HIF-1alpha is a positive factor for cell proliferation and survival under hypoxic conditions in vitro, but does not grossly contribute to the tumor hypoxic compartments in vivo.
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PMID:Hypoxia-inducible factor-1alpha promotes nonhypoxia-mediated proliferation in colon cancer cells and xenografts. 1645 28

The induction of vascular endothelial growth factor (VEGF) is an essential feature of tumor angiogenesis. Hypoxia is a potent stimulator of VEGF expression, and hypoxia-inducible factor-1 (HIF-1) is considered to be critical for this induction. However, we have previously demonstrated that induction of VEGF by hypoxia was preserved when HIF-1alpha was silenced. We sought to better define the molecular basis of this HIF-1-independent regulation. In colon cancer cells, hypoxia stimulated multiple K-ras effector pathways including phosphatidylinositol 3-kinase. VEGF promoter deletion studies identified a novel promoter region between -418 and -223 bp that was responsive to hypoxia in a PI3K/Rho/ROCK-dependent manner. Electrophoretic mobility shift assays identified a fragment between -300 and -251 bp that demonstrated a unique shift only in hypoxic conditions. Inhibition of PI3K or ROCK blocked the formation of this complex. A binding site for c-Myc, a target of ROCK, was identified at -271 bp. A role for c-Myc in the hypoxic induction of VEGF was demonstrated by site-directed mutagenesis of the VEGF promoter and silencing of c-Myc by small interfering RNA. Collectively, these findings suggest an alternative mechanism for the hypoxic induction of VEGF in colon cancer that does not depend upon HIF-1alpha but instead requires the activation of PI3K/Rho/ROCK and c-Myc.
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PMID:Hypoxic regulation of vascular endothelial growth factor through the induction of phosphatidylinositol 3-kinase/Rho/ROCK and c-Myc. 1654 45

The usefulness of a synchrotron microangiography system for depicting, quantitating and therapeutically evaluating angiogenic vessels in cancer is illustrated. In 20 mice transplanted with murine colon cancer, sequential changes in the angiogenic vessels were determined by using synchrotron microangiography, using changes in tumor volume for reference. This system allowed the depiction and quantification of angiogenic vessels in the period from one to four weeks after transplantation. The effects of antiangiogenic therapy were evaluated by using a neutralizing antibody against vascular endothelial growth factor. The neutralizing antibody partially suppressed angiogenesis and tumor growth. Synchrotron microangiography is shown to be useful for the depiction, quantification and evaluation of angiogenic vessels in cancer.
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PMID:Visualization, quantification and therapeutic evaluation of angiogenic vessels in cancer by synchrotron microangiography. 1660 22

Colorectal cancer is the second leading cause of cancer death in Switzerland. The nihilism that dominated the treatment of these patients for decades has been replaced by a measure of enthusiasm, given recent therapeutic advances. New anticancer drugs such as irinotecan and oxaliplatin have changed the standard chemotherapy treatment of metastatic colorectal cancer. However, the real hype has come from molecular targeted therapy. Identification of cellular processes characteristic of colon cancer has permitted therapeutic targeting with favorable therapeutic index. Inhibition of the epidermal growth factor receptor in the clinic has provided proof of principle that interruption of signal transduction cascades in patients has therapeutic potential. Angiogenesis, especially the vascular endothelial growth factor pathway, has been proven to be another highly successful molecular target. In this article, we will review molecular targets, which are under active clinical investigation in colon cancer.
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PMID:[Molecular targets in colon cancer]. 1668 54


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