Broad targeting of angiogenesis for cancer prevention and therapy.

SeminCancer Biol.2015 Jan 16. pii: S1044-579X(15)00002-4. doi: 10.1016/j.semcancer.2015.01.001.[Epub ahead of print]
Broad targeting ofangiogenesis for cancer prevention and therapy.
Wang Z1, Dabrosin C2, Yin X3, Fuster MM3, Arreola A4, Rathmell WK4, Generali D5, Nagaraju GP6, El-Rayes B6, Ribatti D7, Chen YC8, Honoki K9, Fujii H9, Georgakilas AG10, Nowsheen S11, Amedei A12, Niccolai E12, Amin A13, Ashraf SS14, Helferich B15, Yang X15, Guha G16, Bhakta D16, Ciriolo MR17, Aquilano K17, Chen S18, Halicka D19, Mohammed SI20, Azmi AS21, Bilsland A22, Keith WN22, Jensen LD23.
Author information

1Department of Urology, Massachusetts General Hospital,     Harvard Medical School, Boston, MA, USA. Electronic address:

2Department of Oncology, Linköping University,     Linköping, Sweden; Department of Clinical and Experimental Medicine,     Linköping University, Linköping, Sweden.

3Medicine and Research Services, Veterans Affairs San     Diego Healthcare System & University of California, San Diego, San     Diego, CA, USA.

4Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC,     USA.

5Molecular Therapy and Pharmacogenomics Unit, AO Isituti     Ospitalieri di Cremona, Cremona, Italy.

6Department of Hematology and Medical Oncology, Emory     University, Atlanta, GA, USA.

7Department of Basic Medical Sciences, Neurosciences and     Sensory Organs, University of Bari Medical School, Bari, Italy; National Cancer Institute Giovanni Paolo II, Bari, Italy.

8Department of Biology, Alderson Broaddus University,     Philippi, WV, USA.

9Department of Orthopedic Surgery, Arthroplasty and     Regenerative Medicine, Nara Medical University, Nara, Japan.

10Physics Department, School of Applied Mathematics and     Physical Sciences, National Technical University of Athens, Athens,     Greece.

11Mayo Graduate School, Mayo Clinic College of Medicine,     Rochester, MN, USA.

12Department of Experimental and Clinical Medicine,     University of Florence, Florence, Italy.

13Department of Biology, College of Science, United Arab     Emirate University, United Arab Emirates; Faculty of Science, Cairo     University, Cairo, Egypt.

14Department of Chemistry, College of Science, United     Arab Emirate University, United Arab Emirates.

15University of Illinois at Urbana Champaign, Urbana, IL,     USA.

16School of Chemical and Bio Technology, SASTRA     University, Thanjavur, India.

17Department of Biology, University of Rome “Tor     Vergata”, Rome, Italy.

18Ovarian and Prostate Cancer Research Trust Laboratory, Guilford, Surrey, UK.

19New York Medical College, New York City, NY, USA.

20Department of Comparative Pathobiology, Purdue     University Center for Cancer Research, West Lafayette, IN, USA.

21School of Medicine, Wayne State University, Detroit,     MI, USA.

22Institute of Cancer Sciences,     University of Glasgow, Glasgow, UK.

23Department of Medical, and Health Sciences, Linköping     University, Linköping, Sweden; Department of Microbiology, Tumor and Cell     Biology, Karolinska Institutet, Stockholm, Sweden. Electronic address:

Deregulation of angiogenesis – the growth of new blood vessels from an existing vasculature -is a main driving force in many severe human diseases including cancer.As such, tumor angiogenesis is important for delivering oxygen and nutrients togrowing tumors, and therefore considered an essential pathologic feature of cancer, while also playing a key role in enabling other aspects of tumor pathology suchas metabolic deregulation and tumor dissemination/metastasis. Recently,inhibition of tumor angiogenesis has become a clinical anti-cancerstrategy in line with chemotherapy, radiotherapy and surgery,which underscore the critical importance of the angiogenic switch during earlytumor development. Unfortunately the clinically approved anti-angiogenic drugsin use today are only effective in a subset of the patients, and many whoinitially respond develop resistance over time. Also, some of theanti-angiogenic drugs are toxic and it would be of great importance to identifyalternative compounds, which could overcome these drawbacks and limitations ofthe currently available therapy. Finding “the most important target”may, however, prove a very challenging approach as the tumor environment ishighly diverse, consisting of many different cell types, all of which may contribute to tumor angiogenesis. Furthermore, the tumor cells themselves are genetically unstable, leading to a progressive increase in the number of different angiogenic factors produced as the cancer progresses to advanced stages. Asan alternative approach to targeted therapy, options to broadly interfere withangiogenic signals by a mixture of non-toxic natural compound with pleiotropicactions were viewed by this team as an opportunity to develop a complementaryanti-angiogenesis treatment option. As a part of the “HalifaxProject” within the “Getting to know cancer” framework, we have here,based on a thorough review of the literature, identified 10 important aspectsof tumor angiogenesis and the pathological tumor vasculature which would bewell suited as targets for anti-angiogenic therapy: (1) endothelial cellmigration/tip cell formation, (2) structural abnormalities of tumor vessels,(3) hypoxia, (4) lymphangiogenesis, (5) elevated interstitial fluid pressure,(6) poor perfusion, (7) disrupted circadian rhythms, (8) tumor promotinginflammation, (9) tumor promoting fibroblasts and (10) tumor cellmetabolism/acidosis. Following this analysis, we scrutinized the availableliterature on broadly acting anti-angiogenic natural products, with a focus onfinding qualitative information on phytochemicals which could inhibit thesetargets and came up with 10 prototypical phytochemical compounds: (1) oleicacid, (2) tripterine, (3) silibinin, (4) curcumin, (5)epigallocatechin-gallate, (6) kaempferol, (7) melatonin, (8) enterolactone, (9)withaferin A and (10) resveratrol. We suggest that these plant-derived compounds could becombined to constitute a broader acting and more effective inhibitory cocktailat doses that would not be likely to cause excessive toxicity. All the targetsand phytochemical approaches were further cross-validated against their effectson other essential tumorigenic pathways (based on the “hallmarks” of cancer) in order to discover possible synergies or potentially harmful interactions,and were found to generally also have positive involvement in/effects on theseother aspects of tumor biology. The aim is that this discussion could lead tothe selection of combinations of such anti-angiogenic compounds which could beused in potent anti-tumor cocktails, for enhanced therapeutic efficacy, reducedtoxicity and circumvention of single-agent anti-angiogenic resistance, as well as for possible use in primary or secondary cancer prevention strategies.
Copyright ©2015 The Authors. Published by Elsevier Ltd.. All rights reserved.

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One thought on “Broad targeting of angiogenesis for cancer prevention and therapy.

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