Hypoxia inducible factor-1 independent pathways in tumor angiogenesis.

Among the factors that can stimulate angiogenesis, vascular endothelial growth factor has emerged as one of the most important, and inhibition of vascular endothelial growth factor has recently shown efficacy in the treatment of advanced colorectal cancer. Hypoxia develops within solid tumors and is one of the most potent stimuli of vascular endothelial growth factor expression. This effect is mediated primarily by hypoxia inducible factor-1 (HIF-1), often considered a master regulator of angiogenesis in hypoxia. Consequently, inhibition of HIF-1 has been proposed as a strategy to block tumor angiogenesis therapeutically. However, accumulating evidence indicates that HIF-independent pathways can also control angiogenesis. This review highlights some of the key signaling pathways independent of HIF-1 that can stimulate angiogenesis in hypoxia. Understanding the full spectrum of molecular pathways that control tumor angiogenesis is critical for the optimal design of targeted therapies.     

血管内皮生长因子和Notch信号通路与肿瘤血管生成

血管内皮生长因子(VEGF)和Notch信号通路是血管发育及肿瘤血管生成的重要机制.阻断VEGF可抑制肿瘤生长和血管生成.Notch能抑制内皮形成尖端细胞,减少血管生成.实验证明,两条通路相互作用,联合阻断VEGF和Notch信号通路可协同抑制肿瘤生长.对VEGF和Notch通路的研究,将为肿瘤临床治疗提供新的方法.     

Signaling pathways governing tumor angiogenesis

Angiogenesis is regulated by the highly coordinated function of various proteins with pro- and antiangiogenic functions. Proangiogenic factors include vascular endothelial growth factor (VEGF), fibroblast growth factor, platelet-derived growth factor, insulin-like growth factor, transforming growth factor, angiopoietins, and several chemokines; antiangiogenic factors include thrombospondin-1, angiostatin, and endostatin. Matrix metalloproteinases display a dual role in vascular development. Notch signaling affects remodeling of the primary vascular network of uniformly sized vessels into functionally and morphologically distinct arteries, veins, and capillaries. Tumors, described as 'wounds that never heal', lose the appropriate balance among these factors. Although VEGF-targeted therapies are showing promise, new angiogenesis targets are needed to make additional gains. Here, we highlight recent advances in our understanding of the regulation of tumor angiogenesis and discuss the potential of molecular targeting as a new therapeutic approach.     

Notch regulation of tumor angiogenesis

The growth of new blood vessels (angiogenesis) is critical for tumor growth and progression. The highly conserved Notch signaling pathway is involved in a variety of cell fate decisions and regulates many cellular biological processes, including angiogenesis. Aberrant Notch signaling has also been implicated in tumorigenesis. Notch ligands and receptors are expressed on many different cell types present within the tumor, including tumor cells and the stromal compartment. This article highlights in particular the various mechanisms by which Notch signaling can mediate tumor angiogenesis. The most studied Notch ligands, Delta-like 4 and Jagged1, competitively regulate tumor angiogenesis. Studies have demonstrated that Delta-like 4 functions as a negative regulator of tumor angiogenesis, whereas Jagged1 promotes angiogenesis. Understanding the implications of Notch signaling in various tumor backgrounds will enable the effects of specific Notch signaling inhibition on tumor angiogenesis and growth to be evaluated as a potential for a novel antiangiogenic therapy in the clinic.     

Role of angiogenic factors of herbal origin in regulation of molecular pathways that control tumor angiogenesis

The formation of blood capillaries to sustain development and growth of new tissues is referred to as angiogenesis. Angiogenesis is pivotal in both carcinogenesis and metastasis since capillaries are the sole source of supplying nutrients and oxygen to the proliferating tumor cells; therefore, this dependency of tumor growth on angiogenesis challenges researchers to halt tumor growth by targeting angiogenesis with the help of either synthetic or natural inhibitors. Many synthetic inhibitors of angiogenesis have not only come into force but also resulted in some severe adverse effects. Natural compounds may effectively fit into this condition and possibly decrease the time of treatment. In the recent past, literature is replete with evidences advocating the usefulness of natural compounds that target multiple biochemical pathways. The additional advantage of natural compounds is that their active principles interact with one another and work synergistically to give more meaningful and reliable effects than individual principle. Hence, if we are somehow able to combine more than two natural compounds, then it may be possible to enhance their potential by many folds, which shall prove to be very effective in combating tumor angiogenesis. This review shall discuss the concept of angiogenesis, molecular pathways, and angiogenic inhibitors and their specific targets and potential of natural compounds to greatly enhance the current knowledge of angiogenesis-inhibiting factors.     

Signalling pathways in UHRF1-dependent regulation of tumor suppressor genes in cancer

Epigenetic silencing of tumor suppressor genes (TSGs) through DNA methylation and histone changes is a main hallmark of cancer. Ubiquitin-like with PHD and RING Finger domains 1 (UHRF1) is a potent oncogene overexpressed in various solid and haematological tumors and its high expression levels are associated with decreased expression of several TSGs including p16 ^INK4A , BRCA1, PPARG and KiSS1. Using its several functional domains, UHRF1 creates a strong coordinated dialogue between DNA methylation and histone post-translation modification changes causing the epigenetic silencing of TSGs which allows cancer cells to escape apoptosis. To ensure the silencing of TSGs during cell division, UHRF1 recruits several enzymes including histone deacetylase 1 (HDAC1), DNA methyltransferase 1 (DNMT1) and histone lysine methyltransferases G9a and Suv39H1 to the right place at the right moment. Several in vitro and in vivo works have reported the direct implication of the epigenetic player UHRF1 in tumorigenesis through the repression of TSGs expression and suggested UHRF1 as a promising target for cancer treatment. This review describes the molecular mechanisms underlying UHRF1 regulation in cancer and discusses its importance as a therapeutic target to induce the reactivation of TSGs and subsequent apoptosis.     

Endothelial Robo4 suppresses breast cancer growth and metastasis through regulation of tumor angiogenesis

Targeting tumor angiogenesis is a promising alternative strategy for improvement of breast cancer therapy. Robo4 (roundabout homolog 4) signaling has been shown to protect endothelial integrity during sepsis shock and arthritis, and inhibit Vascular Endothelial Growth Factor (VEGF) signaling during pathological angiogenesis of retinopathy, which indicates that Robo4 might be a potential target for angiogenesis in breast cancer. In this study, we used immune competent Robo4 knockout mouse model to show that endothelial Robo4 is important for suppressing breast cancer growth and metastasis. And this effect does not involve the function of Robo4 on hematopoietic stem cells. Robo4 inhibits breast cancer growth and metastasis by regulating tumor angiogenesis, endothelial leakage and tight junction protein zonula occludens protein‐1 (ZO‐1) downregulation. Treatment with SecinH3, a small molecule drug which deactivates ARF6 downstream of Robo4, can enhance Robo4 signaling and thus inhibit breast cancer growth and metastasis. SecinH3 mediated its effect by reducing tumor angiogenesis rather than directly affecting cancer cell proliferation. In conclusion, endothelial Robo4 signaling is important for suppressing breast cancer growth and metastasis, and it can be targeted (enhanced) by administrating a small molecular drug.     

Postradiotherapy quality of life for head-and-neck cancer patients is independent of xerostomia

PURPOSE: To determine the relationship between quality of life (QOL) and xerostomia over time for patients undergoing radiotherapy (RT) for head-and-neck cancer in a prospective clinical trial. METHODS AND MATERIALS: Patients with head-and-neck cancer were randomized to pilocarpine (n = 65) vs. placebo (n = 65) during RT. QOL was measured using the McMaster Head and Neck Radiotherapy Questionnaire (HNRQ). Xerostomia was measured on a linear analog scale. No statistically significant differences were observed between arms; all 130 patients were analyzed together. RESULTS: Baseline QOL data were obtained for 98.5% of participants. The baseline HNRQ score of 5.7 declined significantly to 4.0 (p <0.0001) by RT Week 6 and returned to baseline (5.8) by 6 months after treatment. This represents a large, clinically important change of 1.7 of 7 (24%; effect size 1.34). The decline in HNRQ score during RT paralleled the onset of xerostomia on the linear analog scale (r = 0.36 at 1 month). After treatment, the QOL scores recovered without improvement in xerostomia. The trajectory of the linear analog scale score resembled that of the HNRQ's single xerostomia question (r = 0.75 at 1 month). CONCLUSION: Quality of life recovers to baseline after RT, despite persistent xerostomia. Either a response shift occurs or xerostomia in the absence of acute mucositis has a relatively small influence on overall QOL.     

Hypoxia-activated cytotoxicity of benznidazole against clonogenic tumor cells

Solid tumors contain numerous regions with insufficient oxygen concentrations, a condition termed hypoxia. Tumor hypoxia is significantly associated with metastasis, refractory to conventional cancer therapies, and poor patient survival. Therefore, eradication of hypoxic tumor cells will likely have significant impact on the overall progression-free patient survival. This article reports a new discovery that Benznidazole, a bioreductive drug currently used to treat Chagas disease caused by the parasitic protozoan Trypanosoma cruzi, is activated by hypoxia and can kill clonogenic tumor cells especially those under severe hypoxic conditions (≤0.1 % O₂). This type of hypoxia selectivity is important in that severely hypoxic tumor microenvironment is where tumor cells exhibit the strongest resistance to therapy. Mechanistically, activation of Benznidazole coincides with the stabilization of the Hypoxia-Inducible Factor 1α (HIF-1α), suggesting that Benznidazole is activated after tumor cells have entered into a fully hypoxic state. Under such hypoxic conditions, Benznidazole induces the formation of 53BP1 foci, a hallmark of DNA double-stranded breaks that can cause clonogenic inhibition or cell death. These results demonstrate that Benznidazole is a hypoxia-activated cytotoxin with the potential to specifically eliminate hypoxic tumor cells.     

尿激酶纤溶酶原激活物系统与肿瘤血管形成

恶性肿瘤合成分泌大量胞外蛋白水解酶 ,降解细胞外基质及基底膜 ,是恶性肿瘤侵袭转移及新生血管形成的重要基础。尿激酶纤溶酶原激活物 (uPA)系统作为主要的蛋白水解酶在其中发挥重要作用。就uPA系统的结构、功能及其在肿瘤新生血管形成的作用作简单介绍     

血管内皮生长因子和Dll4-Notch信号通路在肿瘤血管发生中的作用

抗肿瘤血管发生是一种全新的抗肿瘤治疗策略,目前研究最多的是寻找有效抗血管内皮生长因子(VEGF)信号通路的药物.然而VEGF抑制剂并不是对所有肿瘤有效,因此,有必要进一步探索血管发生的其他信号通路.目前,Dll4-Notch信号通路被认为是抗肿瘤血管发生的新靶点,而且VEGF和Dll4-Notch信号通路在多方面相互作...     

血管内皮生长因子和D114-Notch信号通路在肿瘤血管发生中的作用

抗肿瘤血管发生是一种全新的抗肿瘤治疗策略,目前研究最多的是寻找有效抗血管内皮生长因子（VEGF）信号通路的药物。然而VEGF抑制剂并不是对所有肿瘤有效,因此,有必要进一步探索血管发生的其他信号通路。目前,DH4-Nmch信号通路被认为是抗肿瘤血管发生的新靶点,而且VEGF和DH4-N0tch信号通路在多方面相互作用,在调控血管发生过程中发挥重要作用,对这两条通路的探索和研究,将会使治疗肿瘤的手段更为丰富。     

Phosphoinositide 3-kinase signalling pathways in tumor progression, invasion and angiogenesis

AIMS AND BACKGROUND: The PI3 kinase signalling pathway is now accepted as being at least as important as the ras-MAP kinase pathway in cell survival and proliferation, and hence its potential role in cancer is of great interest. The purpose of this review is briefly to examine evidence for an involvement of PI3K in human cancers, discuss the mechanisms by which its activation promotes tumor progression, and consider its utility as a novel target for anticancer therapy. METHODS AND STUDY DESIGN: A Medline review of recent literature concerning the role of PI3 kinase in tumor progression--mechanisms of action and clinical implications. RESULTS: Evidence is presented that misregulation of the PI3 kinase pathway is a feature of many common cancers, either by loss of the suppressor protein PTEN, or by constitutive activation of PI3 kinase isoforms or downstream elements such as AKT and mTOR. This activation potentiates not only cell survival and proliferation, but also cytoskeletal deformability and motility; key elements in tumor invasion. In addition the PI3K pathway is implicated in many aspects of angiogenesis, including upregulation of angiogenic cytokines due to tumor hypoxia or oncogene activation and endothelial cell responses to them. These cytokines signal though receptors such as VEGF-R, FGF-R and Tie-2 and potentiate processes essential for neoangiogenesis including cell proliferation, migration, differentiation into tubules and "invasion" of these capillary sprouts into extracellular matrix (ECM). CONCLUSIONS: A more complete understanding of the role of the PI3 kinase pathway in cancer will lead the way to the development of more potent and selective inhibitors which should be a useful adjunct to conventional therapies, potentially interfering with tumor progression at several pivotal points; in particular cell survival, invasion and angiogenesis.     

Comparison of CT- and FDG-PET-defined gross tumor volume in intensity-modulated radiotherapy for head-and-neck cancer

PURPOSE: To compare the gross tumor volume (GTV) identified on CT to that obtained from fluorodeoxyglucose (FDG) positron emission tomography (PET) and determine the differences in volume and dose coverage of the PET-GTV when the CT-GTV is used for radiotherapy planning. METHODS AND MATERIALS: A total of 40 patients with intact squamous cell carcinoma arising in the head-and-neck region underwent intensity-modulated radiotherapy (IMRT) at one department. All patients underwent CT simulation for treatment planning followed by PET-CT in the treatment position. CT simulation images were fused to the CT component of the PET-CT images. The GTV using the CT simulation images was contoured (CT-GTV), as was the GTV based on the PET scan (PET-GTV). The IMRT plans were obtained using the CT-GTV. RESULTS: The PET-GTV was smaller, the same size, and larger than the CT-GTV in 30 (75%), 3 (8%), and 7 (18%) cases respectively. The median PET-GTV and CT-GTV volume was 20.3 cm(3) (range, 0.2-294) and 37.2 cm(3) (range, 2-456), respectively. The volume of PET-GTV receiving at least 95% of the prescribed dose was 100% in 20 (50%), 95-99% in 10 (25%), 90-94% in 3 (8%), 85-89% in 1 (3%), 80-84% in 2 (5%), 75-79% in 1 (3%), and <75% in 3 (8%) cases. The minimal dose received by 95% of the PET-GTV was >/=100% in 19 (48%), 95-99% in 11 (28%), 90-94% in 5 (13%), 85-89% in 2 (5%), and <75% in 3 (8%) cases. CONCLUSION: The PET-GTV was larger than the CT-GTV in 18% of cases. In approximately 25% of patients with intact head-and-neck cancer treated using IMRT, the volume of PET-GTV receiving at least 95% of the prescribed dose and minimal dose received by 95% of the PET-GTV were less than optimal.     

肿瘤干细胞在肿瘤血管生成中的作用

 肿瘤干细胞（CSC）在肿瘤血管生成中有重要作用,血管生成因子、乏氧等介导了这一过程。CSC能分化成血管内皮细胞,并且参与血管生成拟态的形成,这可能是肿瘤启动和进展的关键因素之一。深入研究CSC在肿瘤血管生成中的作用对肿瘤的靶向治疗有重大意义。     

Improving tumor response to radiotherapy by targeting angiogenesis signaling pathways

Radiotherapy is one of the most widely used treatments for cancer; however, the development of tumor radioresistance is an ongoing problem. Agents that target tumor angiogenesis are being used in combination with radiotherapy to improve the therapeutic index without a clear understanding of how these agents may affect radiosensitization. This article discusses recently published studies that may shed some light on the underlying signaling mechanisms that are involved in the interactions of antiangiogenic agents with ionizing radiation.     

MicroRNA regulation of core apoptosis pathways in cancer

Recent research has demonstrated that microRNAs (miRNAs) are key regulators of many cell processes often deregulated in cancer, including apoptosis. Indeed, it is becoming clear that many miRNAs are anti-apoptotic and mediate this effect by targeting pro-apoptotic mRNAs or positive regulators of pro-apoptotic mRNAs. Conversely, many pro-apoptotic miRNAs target anti-apoptotic mRNAs or their positive regulators. We have reviewed the current knowledge in this area including evidence of miRNA involvement in cancer drug resistance.