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Dr Nina Fuller-Shavel 2021 Systems approach to cancer angiogenesis, invasion, metastasis and CSCs
SYSTEMS APPROACH TO CANCER - MONTH 4
DR NINA FULLER-SHAVEL
MA HONS (CANTAB) MB BCHIR IFMCP DIPIM PG CERT DIPION RYT200 Disclaimer
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Dr Nina Fuller-Shavel Ltd provides healthcare information to registered healthcare practitioners and offers the opportunity to hear the views, recommendations and experiences of other practitioners. Research discussed in this course on cancer and the application of nutrients, herbs and other health-related information regarding cancer is not a substitute for medical advice and standard of care treatment.
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Dr Nina Fuller-Shavel Ltd has not evaluated the legal status of herbs, products, services or recommendations with respect to individual scope of practice. Practitioners are advised to consult their professional association for further guidance. Dr Nina Fuller-Shavel Ltd does not and cannot accept responsibility for errors or omissions or for any consequences from applications of the information provided and makes no warranty, expressed or implied, with respect to the information provided.
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This education programme is not intended to diagnose, treat or cure any disease.
> Dr Nina Fuller-Shavel 2021
## Dr Ninas systems approach to cancer
Dr Nina Fuller-Shavel 2021
Systems approach to cancer
Healthy microbiome balance and GI function
Balanced immune function
Effective detoxification
Healthy circulation and tissue architecture
Mitochondrial and metabolic health
Hormone balance
Balanced methylation and genomic stability
Mental/ emotional/ spiritual health and biorhythms Healthy circulation and tissue architecture
Healthy circulation and tissue architecture
Promote normal blood flow, tissue perfusion and healthy coagulation
Support inhibition of angiogenesis and metastasis
> Dr Nina Fuller-Shavel 2021
Importance of normal circulation and coagulation
Cancer is a hypercoaguable state high risk of DVT/PE, be on alert and advise clients to seek immediate medical input
Important to test and target fibrinogen where possible, e.g. systemic proteolytic enzymes like nattokinase
Some patients will be on prophylaxis or treatment with anticoagulants, e.g. warfarin, oral anticoagulants or injectable LMWH
Impact of treatment on circulation, e.g. lymphoedema, and poor healing post-surgery if circulation is impaired
Consider appropriate interventions, e.g. regular movement, MLD (under lymphoedema nurse guidance)
> Dr Nina Fuller-Shavel 2021
## Hallmarks of cancer original 6
> Dr Nina Fuller-Shavel 2021
## Inducing angiogenesis
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Growth of new blood vessels to supply the tumour with oxygen and nutrients needed for survival
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Tumour angiogenesis is controlled by the balance between angiogenesis promoters and inhibitors.
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The molecular basis of the angiogenic switch involves increased production of angiogenic factors and/or loss of angiogenic inhibitors. These factors may be produced directly by the tumour cells themselves or by inflammatory cells (e.g., macrophages) or other stromal cells associated with the tumours
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Most common pro-angiogenic factors are VEGF and bFGF
> Dr Nina Fuller-Shavel 2021
# Molecular pathways in angiogenesis
> Dr Nina Fuller-Shavel 2021
## Key activators of angiogenesis
Hypoxia increases VEGF production via HIF-1
Local hypoxia within the central areas of solid tumours promotes angiogenesis (survival) and is one of the major issues contributing to treatment resistance
> Dr Nina Fuller-Shavel 2021
Key activators of angiogenesis
Inflammation in TME
Note that meta-inflammation also plays a role
> Dr Nina Fuller-Shavel 2021
## Obesity and cancer
Dr Nina Fuller-Shavel 2021 Important natural compounds that may play a role as angiogenesis inhibitors
Curcumin
Artemisinin
EGCG
Resveratrol
Ginseng
Thymoquinone
Tocotrienols
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Note not an exhaustive list
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Other natural compounds that may impact angiogenesis caution re: in vitro
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## Angiogenesis and invasion pathway interaction with natural compounds
> Dr Nina Fuller-Shavel 2021
# Invasion and metastasis
Dr Nina Fuller-Shavel 2021 Enabling invasion and metastasis
EMT epithelial-mesenchymal transition - in solid tumours (stromal derived factors play a role)
Invasion of the ECM initiates the metastatic cascade and is an active process that can be resolved into several steps
Changes (loosening up) of tumour cell-cell interactions, e.g. cadherin proteins
Degradation of ECM, e.g. via MMPs
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MMP9 is a gelatinase that cleaves type IV collagen of the epithelial and vascular basement membrane and also stimulates release of VEGF from ECM-sequestered pools.
Attachment to novel ECM components
Migration of tumour cells
> Dr Nina Fuller-Shavel 2021
# Key pathways in EMT
Dr Nina Fuller-Shavel 2021 MMPs in invasion
Dr Nina Fuller-Shavel 2021 Premetastatic niche grooming tissues for metastases
The pre-metastatic niche that is created by the TDSFs (tumour- derived secreted factors), BMDCs (tumour-mobilized bone marrow- derived cells), regulatory/suppressive immune cells, and stromal components in the distant organ can be endowed with six enabling characteristics which promote tumour cell colonization and metastasis.
6 characteristics of the pre-metastatic niche can be summarized as:
Immunosuppression
Inflammation
Angiogenesis/vascular permeability
Lymphangiogenesis
Organotropism (affinity for particular organs) and
Reprogramming (metabolic, stromal and epigenetic)
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# Some key pathways in cancer stem cells
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Cancer stem cells and natural compounds with targeting potential not an exhaustive list
Curcumin
Quercetin
Resveratrol and pterostilbene
EGCG
Sulforaphane, I3C and DIM
Genistein
Lycopene
Ursolic acid (tulsi)
Parthenolide (feverfew)
6-shogaol (ginger)
Isoliquiritigenin (licorice)
Vitamin E - tocotrienols
> Dr Nina Fuller-Shavel 2021
# Curcumin some key effects
Dr Nina Fuller-Shavel 2021 Resveratrol and CSCs
Dr Nina Fuller-Shavel 2021 EGCG and cancer
Dr Nina Fuller-Shavel 2021 Ursolic acid and cancer
Dr Nina Fuller-Shavel 2021 Some important TCM herbs and key constituents in cancer support
Panax ginseng and ginsenosides
HPA axis and fatigue support
Astragalus membranaceus and formononetin
Immune function and HPA axis support
Magnolia spp, honokiol and magnolol
Sleep and anxiety support
Salvia miltiorrhiza (Dan Shen) and tanshinones
Tripterygium wilfordii , or thunder god vine, triptolide and celastrol
> Dr Nina Fuller-Shavel 2021
## Summary
Be aware of increased clotting risk in cancer
A number of natural compounds cover angiogenesis, invasion, metastasis and CSC targeting but we are not yet sure about clinical implications for all of these
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Pick a few that you can get really familiar with and read up
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My top list to start with curcumin, glucosinolates, ginger and components, quercetin, tocotrienols, resveratrol, EGCG, thymoquinone/Nigella sativa
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## References
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Bhaskara VK, Mittal B, Mysorekar VV, Amaresh N, Simal-Gandara J. Resveratrol, cancer and cancer stem cells: A review on past to future. Curr Res Food Sci. 2020 Nov 24;3:284-295.
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Dandawate PR, Subramaniam D, Jensen RA, Anant S. Targeting cancer stem cells and signaling pathways by phytochemicals: Novel approach for breast cancer therapy. Semin Cancer Biol. 2016 Oct;40-41:192-208.
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Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011 Mar 4;144(5):646-74.
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Jiang X, Wang J, Deng X, Xiong F, Zhang S, Gong Z, Li X, Cao K, Deng H, He Y, Liao Q, Xiang B, Zhou M, Guo C, Zeng Z, Li G, Li X, Xiong W. The role of microenvironment in tumor angiogenesis. J Exp Clin Cancer Res. 2020 Sep 30;39(1):204.
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Khalid EB, Ayman EE, Rahman H, Abdelkarim G, Najda A. Natural products against cancer angiogenesis. Tumour Biol. 2016 Nov;37(11):14513-14536.
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## References
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Lu K, Bhat M, Basu S. Plants and their active compounds: natural molecules to target angiogenesis. Angiogenesis. 2016 Jul;19(3):287-95.
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Mendelsohn, J., In Gray, J. W., In Howley, P. M., In Israel, M. A., & In Thompson, C. (2015). The molecular basis of cancer.
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Olson OC, Quail DF, Joyce JA. Obesity and the tumor microenvironment. Science. 2017 Dec 1;358(6367):1130-1131.
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Pistollato F, Giampieri F, Battino M. The use of plant-derived bioactive compounds to target cancer stem cells and modulate tumor microenvironment. Food Chem Toxicol. 2015 Jan;75:58-70.
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Przystupski D, Niemczura MJ, Grska A, Supplitt S, Kotowski K, Wawryka P, Rozborska P,
Woniak K, Michel O, Kiebik A, Bartosik W, Saczko J, Kulbacka J. In Search of Panacea-Review of Recent Studies Concerning Nature-Derived Anticancer Agents. Nutrients. 2019 Jun 25;11(6):1426.
> Dr Nina Fuller-Shavel 2021
## References
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Shaikh S, Shaikh J, Naba YS, Doke K, Ahmed K, Yusufi M. Curcumin: reclaiming the lost ground against cancer resistance. Cancer Drug Resist 2021;4:[Online First].
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Shanmugam MK, Warrier S, Kumar AP, Sethi G, Arfuso F. Potential Role of Natural Compounds as Anti-Angiogenic Agents in Cancer. Curr Vasc Pharmacol. 2017;15(6):503-519.
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Subramaniam D, Kaushik G, Dandawate P, Anant S. Targeting Cancer Stem Cells for Chemoprevention of Pancreatic Cancer. Curr Med Chem. 2018;25(22):2585-2594..
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Wang Y, Lu J, Jiang B, Guo J. The roles of curcumin in regulating the tumor immunosuppressive microenvironment. Oncol Lett. 2020 Apr;19(4):3059-3070.
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Yang Y, Yang Y, Yang J, Zhao X, Wei X. Tumor Microenvironment in Ovarian Cancer: Function and Therapeutic Strategy. Front Cell Dev Biol. 2020 Aug 11;8:758.