Development Of Tumor Blood Vessels Research Articles

Frankincense myrrh attenuates hepatocellular carcinoma by regulating tumor blood vessel development through multiple epidermal growth factor receptor-mediated signaling pathways.

BACKGROUNDIn traditional Chinese medicine (TCM), frankincense and myrrh are the main components of the antitumor drug Xihuang Pill. These compounds show anticancer activity in other biological systems. However, whether frankincense and/or myrrh can inhibit the occurrence of hepatocellular carcinoma (HCC) is unknown, and the potential molecular mechanism(s) has not yet been determined.AIMTo predict and determine latent anti-HCC therapeutic targets and molecular mechanisms of frankincense and myrrh in vivo.METHODSIn the present study, which was based on the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (http://tcmspw.com/tcmsp.php), Universal Protein database (http://www.uniprot.org), GeneCards: The Human Gene Database (http://www.genecards.org/) and Comparative Toxicogenomics Database (http://www.ctdbase.org/), the efficacy of and mechanism by which frankincense and myrrh act as anti-HCC compounds were predicted. The core prediction targets were screened by molecular docking. In vivo, SMMC-7721 human liver cancer cells were transplanted as xenografts into nude mice to establish a subcutaneous tumor model, and two doses of frankincense plus myrrh or one dose of an EGFR inhibitor was administered to these mice continuously for 14 d. The tumors were collected and evaluated: the tumor volume and growth rate were gauged to evaluate tumor growth; hematoxylin-eosin staining was performed to estimate histopathological changes; immunofluorescence (IF) was performed to detect the expression of CD31, α-SMA and collagen IV; transmission electron microscopy (TEM) was conducted to observe the morphological structure of vascular cells; enzyme-linked immunosorbent assay (ELISA) was performed to measure the levels of secreted HIF-1α and TNF-α; reverse transcription-polymerase chain reaction (RT-qPCR) was performed to measure the mRNA expression of HIF-1α, TNF-α, VEGF and MMP-9; and Western blot (WB) was performed to determine the levels of proteins expressed in the EGFR-mediated PI3K/Akt and MAPK signaling pathways.RESULTSThe results of the network pharmacology analysis showed that there were 35 active components in the frankincense and myrrh extracts targeting 151 key targets. The molecular docking analysis showed that both boswellic acid and stigmasterol showed strong affinity for the targets, with the greatest affinity for EGFR. Frankincense and myrrh treatment may play a role in the treatment of HCC by regulating hypoxia responses and vascular system-related pathological processes, such as cytokine-receptor binding, and pathways, such as those involving serine/threonine protein kinase complexes and MAPK, HIF-1 and ErbB signaling cascades. The animal experiment results were verified. First, we found that, through frankincense and/or myrrh treatment, the volume of subcutaneously transplanted HCC tumors was significantly reduced, and the pathological morphology was attenuated. Then, IF and TEM showed that frankincense and/or myrrh treatment reduced CD31 and collagen IV expression, increased the coverage of perivascular cells, tightened the connection between cells, and improved the shape of blood vessels. In addition, ELISA, RT-qPCR and WB analyses showed that frankincense and/or myrrh treatment inhibited the levels of hypoxia-inducible factors, inflammatory factors and angiogenesis-related factors, namely, HIF-1α, TNF-α, VEGF and MMP-9. Furthermore, mechanistic experiments illustrated that the effect of frankincense plus myrrh treatment was similar to that of an EGFR inhibitor with regard to controlling EGFR activation, thereby inhibiting the phosphorylation activity of its downstream targets: the PI3K/Akt and MAPK (ERK, p38 and JNK) pathways.CONCLUSIONIn summary, frankincense and myrrh treatment targets tumor blood vessels to exert anti-HCC effects via EGFR-activated PI3K/Akt and MAPK signaling pathways, highlighting the potential of this dual TCM compound as an anti-HCC candidate.

Abstract A08: Investigating tumor vasculature development and the effects of OXi4503 by non-invasive photoacoustic imaging

Abstract Vasculature-targeted cancer therapies, such as vascular disrupting or anti-angiogenic agents, interact directly with tumor blood vessels. Direct longitudinal assessment of vascular response, as opposed to indirect measures of tumor volume, would aid clinical translation for these targeted therapies, but novel treatment strategies require adequate biomarkers of response. OXi4503 (Combretastatin-A1 phosphate, CA1P) is a vascular disrupting agent (VDA) known to have significant antitumor effects against a wide range of pre-clinical human tumor model systems, and in the clinic. OXi4503 causes disruption of the central tumor vasculature within an hour of administration, followed by thrombosis and vessel occlusion, resulting in massive central tumor necrosis 24 hours after treatment but leaving a thin viable rim of tumor cells. Photoacoustic imaging (PAI) is a novel non-ionising and non-invasive technique, that provides 3D images of the vascular microenvironment with high spatial resolution. Structural information of blood vessel location, and potentially functional data as well, can therefore be obtained in a longitudinal manner. It is thus ideally suited to assess preclinical models of subcutaneous tumors with regard to vascular targeted therapies. We have used PAI to investigate the development of tumor blood vessels, and the effects of OXi4503 (40mg/kg) on the vasculature of 2 human colorectal xenografts grown in nude mice. Results: The human colorectal tumor cell lines SW1222 and LS174T were established as subcutaneous models in nude mice, by the injection of 5X106 tumor cells. Using PAI we were able to: Determine the extent and pattern of tumor vascularization, non-invasively, over time Differentiate between the pathophysiologies of different tumor types Follow the response to vascular targeted therapy Determine the length of time to tumor regrowth following therapy Conclusion: The data suggest that PAI could prove invaluable in providing imaging biomarkers of response to treatment for vascular targeted therapies, with potential for clinical translation. Citation Format: Sean Peter Johnson, Ollie Ogunlade, Edward Zhang, Mark Lythgoe, Paul Beard, Rosamund Barbara Pedley. Investigating tumor vasculature development and the effects of OXi4503 by non-invasive photoacoustic imaging. [abstract]. In: Abstracts: AACR Special Conference on Cellular Heterogeneity in the Tumor Microenvironment; 2014 Feb 26-Mar 1; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2015;75(1 Suppl):Abstract nr A08. doi:10.1158/1538-7445.CHTME14-A08

Can selenium levels act as a marker of colorectal cancer risk?

BackgroundSelenium has attracted attention because of its antioxidant properties. Antioxidants protects cells from damage. Certain breakdown products of selenium are believed to prevent tumor growth by enhancing the immune cell activity and suppressing the development of tumor blood vessels. In this observational study, selenium level was measured in a series of patients from Poland and Estonia to determine a correlation between levels of this microelement and colorectal cancer risk.MethodsA total of 169 colorectal cancer patients and 169 healthy controls were enrolled in the study after obtaining their informed consent. Selenium level in the blood serum was measured using Graphite Furnace Atomic Absorption Spectrometry (GFAAS). The statistical analysis was performed by Fisher’s exact test.ResultsThe threshold point of selenium level was 55 μg/l and 65 μg/l for Poland and Estonia respectively, for an increase in cancer risk. The lower levels of selenium were associated with greater risk of colorectal cancer.ConclusionsThe result reveals a significant strong association between low selenium level and the colorectal cancer risk in both Estonian and Polish populations.

Selenium and gastrointestinal cancers risk

Research suggests that selenium may influence the behavior of the cancer risk in two ways. As an antioxidant, selenium helps to protect the body against free radicals. Selenium may also prevent or slow tumor growth, as some breakdown products of selenium can inhibit tumor growth by enhancing immune cell activity and inhibition of tumor blood vessel development.

Selenium and the risk of cancers of the colon, pancreas and stomach

Research suggests that selenium may influence the behavior of the cancer risk in two ways. As an antioxidant, selenium helps to protect the body against free radicals. Selenium may also prevent or slow tumor growth, as some breakdown products of selenium can inhibit tumor growth by enhancing immune cell activity and inhibition of tumor blood vessel development.

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Retinoblastoma Tumor Vessel Maturation Impacts Efficacy of Vessel Targeting in the LHBETATAGMouse Model

The aim of this study was to quantify tumor cell proliferation and growth, analyze tumor blood vessel development, and determine the efficacy of antiangiogenic and angiostatic therapy in targeting mature vessels in retinal tumors of the LH(BETA)T(AG) mouse model for retinoblastoma. LH(BETA)T(AG) mouse retinas were analyzed at 4, 8, 12, and 16 weeks of age. Tumor burden was analyzed by histology; cell proliferation, vessel density, angiogenesis, and vessel maturation were detected by immunofluorescence. To assess the efficacy of mature vessel targeting, 16-week-old mice were treated with single subconjunctival injections of the selective vascular-targeting drug combretastatin A4 prodrug (CA4P) or anecortave acetate, and eyes were analyzed 1 day and 1 week after injection to determine microvessel density and the number of angiogenic and mature vessels. Increased cell proliferation and angiogenesis were detected in the retinal inner nuclear layer (INL) before morphologic neoplastic changes were evident. As tumor size increased, angiogenesis diminished concomitantly with the appearance of mature vessels. Treatment with CA4P and anecortave acetate resulted in significant reductions in total vessel density. However, neither drug reduced the amount of alpha-smooth muscle actin (SMA)-positive, mature vessels. Results of this study provide new insight into the relationship between tumor growth and blood vessel development in the LH(BETA)T(AG) mouse and establish the framework for defining the selective action of two vessel-targeting drugs against new blood vessels compared with mature blood vessels. These findings suggest a high potential value in targeting the process of angiogenesis in the treatment of children with retinoblastoma.

Bone Marrow-Derived lin−c-kit+Sca-1+ Stem Cells Do Not Contribute to Vasculogenesis in Lewis Lung Carcinoma

The development of tumor vasculature is thought to occur through two complementary processes: sprouting angiogenesis from preexisting blood vessels of the host, vasculogenesis, which involves the spontaneous development of vessels through specific recruitment, differentiation, vascular incorporation of circulating endothelial cells (EC), endothelial progenitor cells (EPC), or potentially bone marrow-derived cells. Recent reports, however, have challenged the belief that bone marrow-derived cells contribute to tumor neovascularization, claiming an exclusive role for sprouting angiogenesis in tumor blood vessel development. In the present study, we explored the recruitment behavior of bone marrow-derived lin− c-kit+Sca-1+ stem cells to subcutaneously implanted Lewis lung carcinoma in a syngeneic bone marrow transplantation model. We observed that although lin− c-kit+Sca-1+ and their derived cells demonstrate significant recruitment to carcinomas in vivo, they do not appear to functionally contribute to tumor neovascularization. Furthermore, our results support the hypothesis that new vessel formation in carcinomas occurs primarily through endothelialization from adjacent and preexisting vasculature.