Tag Archives: angiogenesis and cancer

Broad targeting of angiogenesis for cancer prevention and therapy

Semin Cancer Biol. 2015 Dec;35 Suppl:S224-S243. doi: 10.1016/j.semcancer.2015.01.001. Epub  2015 Jan 16.
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.

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Abstract

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) oleanolic 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.

KEYWORDS:
Angiogenesis; Anti-angiogenic; Cancer; Phytochemicals; Treatment

PMID:   25600295
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PMCID:   PMC4737670

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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: zwang0@partners.org.
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: lasse.jensen@liu.se.

Abstract

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.

KEYWORDS:
Angiogenesis; Anti-angiogenic; Cancer; Phytochemicals; Treatment

PMID:

25600295

[PubMed – as supplied by publisher]

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Fatty Acid Metabolite Shows Promise Against Cancer in Mice

Fatty Acid Metabolite Shows Promise Against Cancer in Mice

Apr. 2, 2013 — A team of UC Davis scientists has found that a product resulting from a metabolized omega-3 fatty acid helps combat cancer by cutting off the supply of oxygen and nutrients that fuel tumor growth and spread of the disease.

The scientists report their discovery in the Proceedings of the National Academy of Sciences (PNAS). The groundbreaking study was a collaboration among multiple UC Davis laboratories and Harvard University.
The metabolite is epoxy docosapentaenoic acid (EDP), an endogenous compound produced by the human body from the omega-3 fatty acid named docosahexaenoic acid (DHA), which is found in fish oil and breast milk. In animal studies, the UC Davis scientists found that EDP inhibits angiogenesis, the formation of new blood vessels in the body.
Tumors grow and spread by hijacking the normal biological process of angiogenesis, which plays a role in wound repair as well in growth and development. The UC Davis researchers determined that by inhibiting angiogenesis, EDP reduces the growth and spread (metastasis) of tumors in mice. The research provides the first scientific evidence about EDP’s potent anti-cancer, anti-metastatic effects.
EDP works by a different mechanism than many current anti-cancer drugs that block angiogenesis. “Our investigation opens up a new understanding of the pathways by which omega-3 fatty acids exert their biologic effects,” said Guodong Zhang, the lead author of the article and a postdoctoral researcher in the laboratory of Bruce Hammock in the Department of Entomology and the UC Davis Comprehensive Cancer Center.
The researchers said that future studies hopefully will determine that stabilized EDP can be safely and effectively combined with other current anti-angiogenesis drugs in the treatment of cancer.
“As far as we know, EDPs are the first signaling lipids that have been discovered to have such potent anti-cancer effects. Researchers may be able to use EDPs as structural targets to develop stable analogs that mimic their anti-cancer agents,” Zhang said.
“The study by Zhang and colleagues has uncovered a previously unrecognized anti-cancer effect of omega-3 fatty acids, which are an important lipid component of diets that have been developed to prevent heart disease and cancer,” said Jonathan R. Lindner, professor of medicine at Oregon Health & Sciences University.
“The authors have demonstrated that metabolites of these lipids can act to suppress the growth of new blood vessels that are necessary to feed tumor growth,” added Lindner, who was not involved in the study. “By shutting off a tumor’s blood supply, these compounds can act to dramatically slow tumor growth and prevent spread.  The results from this study suggest that new drug strategies for fighting cancer could emerge from knowledge of how the body uses nutrition to promote health.”
The EDPs are broken down in the body by inhibiting the enzyme soluble epoxide hydrolase (sHI). In previous research, Hammock’s lab showed that inhibitors of the sEHI enzyme help to normalize physiological activity. In the current study, UC Davis researchers determined that the addition of sEHI stabilized EDP in circulating blood thereby producing EDPs’ anti-tumor effects.  The anti-cancer drugs sorafenib and regorafenib are FDA-approved sEHIs.
“It may be possible to improve the efficacy of these anti-cancer drugs by combining them with a diet high in omega-3 and low in omega-6 fatty acids,” Hammock said.
The researchers also found that a metabolite of arachidonic acid (ARA), an omega-6 fatty acid, has the opposite effect of EDP. The ARA metabolite, epoxyeicosatrienoic acids (EETs), slightly increases angiogenesis and tumor progression in mice.
“There is no free lunch,” said Katherine W. Ferrara, professor in the UC Davis Department of Biomedical Engineering. “The EETs encourage wound healing, while the EDPs block the growth and metastasis of solid tumors.
“Our results designate EDPs and EETs as unique mediators of an angiogenic switch to regulate tumorigenesis,” Ferrara said. “They also implicate a novel mechanistic linkage between omega-3 and omega-6 fatty acids and cancers.”
UC Davis scientists determined that EDP starves tumors by inhibiting vascular endothelial growth factor (VEGF) and fibroblast growth factor-2 (FGF-2)-induced angiogenesis in mice. In laboratory cultures, EDP also suppresses the endothelial cell migration needed for new blood vessels.
Thus, EDP-based angiogenesis inhibitors offer an advantage over angiogenesis inhibitors that target the VEGF-VEGFR2 pathway, which increase patients’ risk for developing high blood pressure.
Because EDPs widen the blood vessels, a medication based on the UC Davis researchers’ discovery should not increase the patient’s risk for high blood pressure.
Harvard researchers Mark Kieran and Dipak Panigrahy conducted the metastasis studies. The in vivo imaging work that allowed the scientists to monitor tumors in living mice was done in Ferrara’s UC Davis laboratory.