Broad targeting of angiogenesis for cancer prevention and therapy.

Semin Cancer Biol. 2015 Jan 16. pii: S1044-579X(15)00002-4. doi: 10.1016/j.semcancer.2015.01.001. [Epub ahead of print]
Broad targeting of angiogenesis 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 to growing tumors, and therefore considered an essential pathologic feature of cancer, while also playing a key role in enabling other aspects of tumor pathology such as metabolic deregulation and tumor dissemination/metastasis. Recently, inhibition of tumor angiogenesis has become a clinical anti-cancer strategy in line with chemotherapy, radiotherapy and surgery, which underscore the critical importance of the angiogenic switch during early tumor development. Unfortunately the clinically approved anti-angiogenic drugs in use today are only effective in a subset of the patients, and many who initially respond develop resistance over time. Also, some of the anti-angiogenic drugs are toxic and it would be of great importance to identify alternative compounds, which could overcome these drawbacks and limitations of the currently available therapy. Finding “the most important target” may, however, prove a very challenging approach as the tumor environment is highly 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. As an alternative approach to targeted therapy, options to broadly interfere with angiogenic signals by a mixture of non-toxic natural compound with pleiotropic actions were viewed by this team as an opportunity to develop a complementary anti-angiogenesis treatment option. As a part of the “Halifax Project” within the “Getting to know cancer” framework, we have here, based on a thorough review of the literature, identified 10 important aspects of tumor angiogenesis and the pathological tumor vasculature which would be well suited as targets for anti-angiogenic therapy: (1) endothelial cell migration/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 promoting inflammation, (9) tumor promoting fibroblasts and (10) tumor cell metabolism/acidosis. Following this analysis, we scrutinized the available literature on broadly acting anti-angiogenic natural products, with a focus on finding qualitative information on phytochemicals which could inhibit these targets and came up with 10 prototypical phytochemical compounds: (1) oleic acid, (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 be combined to constitute a broader acting and more effective inhibitory cocktail at doses that would not be likely to cause excessive toxicity. All the targets and phytochemical approaches were further cross-validated against their effects on 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 these other aspects of tumor biology. The aim is that this discussion could lead to the selection of combinations of such anti-angiogenic compounds which could be used in potent anti-tumor cocktails, for enhanced therapeutic efficacy, reduced toxicity 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.

Angiogenesis; Anti-angiogenic; Cancer; Phytochemicals; Treatment



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