An Integrative Approach to Treating Tumor Blood Vessels

• Tumors are known for having excessive blood vessel growth (angiogenesis), but the vessels are abnormal – leaky and disorganized – leading to poor blood flow to the tumor tissue
• Inadequate blood flow creates a low-oxygen (hypoxic) and acidic environment, forcing CFCs (cancer cells) to adapt by activating genes that promote metastasis (spread), treatment resistance, and survival of CFC stem cells
• Conventional treatments often include anti-angiogenic therapies, which block blood vessel growth with an aim to “starve” tumors. This strategy, however, has been shown to fail over time as it further reduces oxygen supply making CFCs more aggressive
• Studies show that by fixing chaotic tumor vessels into a healthy and efficient network instead of destroying them, the tumor tissue shifts towards a less malignant state, the immune system gains better access to eliminate it, and treatments work better
• This article describes how holistic treatment approach using certain natural compounds, oxygen therapies, and physical movement help restore healthy blood vessel function in tumors and lead to better treatment success
• It also highlights the basic difference between conventional therapies and holistic or integrative therapies: conventional therapies utilize a military approach to blindly fight against CFCs, while holistic therapies seek to rebuild and restore health.
  
  

One of the key features of CFCs (cancer) is the continuous and excessive growth of new blood vessels. Tumors cannot grow more than 1 mm without new blood vessels ¹ through a process known as angiogenesis. This is because, whether large or small tumors need a continuous supply of oxygen and nutrients from blood to support their rapid growth.

Understanding the role of angiogenesis has led to the development of anti-angiogenic therapies that block this process of new blood vessel growth in tumors, potentially slowing or stopping entirely tumor growth. Although the strategy sounds promising, the benefit that would arise from the use of drugs that block blood vessel growth – known as anti-angiogenic therapies – the development and hence benefit of such new drugs has been modest, at best. In addition to a multitude of harmful side effects, research has revealed another downside: while these treatments can shrink or slow tumor growth at first, over time, they can actually stimulate CFCs (cancer) to become more aggressive ^{2, 3}.

Here is why: When blood vessel growth and therefore blood flow to a tumor is reduced, even though parts of it may die, the cells that are left behind are now exposed to a low-oxygen (hypoxic) environment due to decreased blood supply. This hypoxic environment requires CFCs adapt, become more aggressive, resist treatment and thereby, more likely to spread.

Furthermore, poor blood flow makes it harder for therapies and immune cells to reach the tumor. Consequently, instead of eliminating the tumor, these therapies actually create a more hostile and harder-to-treat tumor.

Interestingly, most tumors already suffer from poor blood flow. Although they grow more blood vessels, more rapidly these vessels are disorganized, immature and leaky due to their structural deformities ⁴. In healthy tissue, where angiogenesis is at an optimal level, new blood vessels grow in a regulated manner and eventually reach a stage of maturation, where structures such as basement membrane and pericytes are added to the vessel walls. These structures allow the diameter and permeability of the blood vessels to be regulated. However, in tumors, high levels of growth factors, especially VEGF (vascular endothelial growth factor), trigger continuous growth of blood vessels, where they never reach final maturation. Abnormal blood vessels means that blood does not circulate adequately, leading to low oxygen levels (hypoxia) inside the tumor. This hypoxic environment activates the hypoxia-inducible factor-1 alpha (HIF-1α) triggering the activation of over 100 genes ⁵ that increase oxygen supply, and multiple other factors that help CFCs survive, grow and spread.

According to the most recent understanding, instead of trying to destroy tumor blood vessels a better strategy would be to repair them. This could be achieved by balancing the signals that control vessel growth, bringing them to a healthier level that allows vessels acquire a proper structure.

Increased Blood Flow to the Tumor Has Profound Effects:

1. Enhances Other Treatments: Restored blood flow allows therapeutic agents to reach the tumor more efficiently ^6-8. Also, increased oxygen delivery makes the treatments work better since many therapies rely on oxygen to produce the free radicals that kill CFCs ⁹.
2. Reduces Tumor Aggression: Elevated oxygen levels modify gene activity of CFCs, reducing their growth, invasiveness, metastasis and treatment resistance ⁹.
3. Strengthens the Immune Response: Improved blood flow not only helps immune cells to enter the tumor. Elevating oxygen levels is essential for those immune cells to remain active in the tumor and successfully eliminate it ^{10, 11}
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While anti-angiogenic drugs often fail by reducing blood vessel growth too much, increasing evidence is pointing to a smarter approach – using less toxic, well-tolerated therapies that work with the tumor’s biology instead of against it. These treatments do not just block growth signals such as VEGF (mechanism of anti-angiogenic drugs), they help normalize the tumor microenvironment, including its blood vessels, making them healthier and more functional. By addressing root problems such as low oxygen levels (hypoxia), chronic inflammation, and abnormal cellular signaling these therapies help to slow CFC progression in a more natural and sustainable way.

Natural Compounds

Natural compounds stand out as powerful, multi-functional alternatives for CFC (cancer) therapy. Unlike anti-angiogenic drugs, that usually target a single cellular pathway, natural compounds affect the tumor on multiple levels ¹². For example, curcumin, a compound found in turmeric, with its strong antioxidant and anti-inflammatory properties, has been shown to silence key pathways for abnormal blood vessel growth in CFCs such as NF-kB and HIF-1 α (hypoxia-inducible factor-1 alpha) ¹³.

Another great advantage of natural compounds is their low toxicity. They do not cause harmful side effects such as increased risk of bleeding or suppressed immune system as anti-angiogenic drugs do. In contrast, many natural compounds enhance the immune system and promote blood vessel growth in times when it is needed, such as during wound healing ¹⁴.

Recent studies using animals have shown how certain natural compounds with anti-angiogenic properties can “normalize” tumor blood vessels, leading to better blood circulation and oxygen delivery, and reduced tumor growth. This process includes removing immature, leaky blood vessels and remodeling the remaining ones into a more stable and functional network.

The combination of Curcumin and Astragalus was found to significantly slow tumor growth in mice with primary liver CFCs ¹⁵. Moreover, it improved the structure and stability of tumor blood vessels, making them more mature and organized.

Epigallocatechin-3-gallate (EGCG) from green tea triggered temporary normalization of tumor vessels which included decreased abnormal blood vessel density, improved vessel function and blood flow and less leakiness, reduced tumor swelling and hypoxia (lack of oxygen) ¹⁶. During this “normalization period” tumors absorbed more of the chemotherapy drug cisplatin resulting in significantly reduced tumor growth compared to cisplatin alone.

Tanshinones from Danshen, a traditional Chinese medicinal herb commonly used for heart health, were shown to restore function of tumor blood vessels by rebalancing signals that control blood vessel growth and stability ¹⁷. They suppressed excess Angiopoietin 2 which is often overproduced in tumors and disrupts vessel stability leading to their leakiness and poor function. As a result, tanshinones stabilized vessel walls (with strengthened endothelial junctions and increased pericyte coverage) which reduced leakage, improved oxygen delivery and slowed tumor growth.

Clinical Trials with Natural Compounds

Several clinical trials have demonstrated that natural compounds not only slow CFC (cancer) progression and extend survival, but they do so without adding significant adverse effects (side effects).

To make a real-life comparison between a natural substance and standard treatment with an anti-angiogenic drug, here are a few clinical trials where such a combination has been used in the treatment of advanced colorectal CFCs (a setting similar to the clinical trial in Part 1).

1. Curcumin

• This trial compared two groups of people: one receiving curcumin (orally 200 mg daily) along with standard treatment of chemotherapy (FOLFIRI) and anti-angiogenic drug (Bevacizumab) while another receiving standard treatment alone ¹⁸.
• Median Overall Survival: 30.7 months with curcumin plus standard treatment versus 4 months with standard treatment alone. Median overall survival (MOS) Point in time where 50% of the patients have died.
• Progression-Free Survival: Significantly improved in the group receiving curcumin without additional adverse effects. Progression-free survival (PFS) is the length of time a patient lives without the condition getting worse
  
  

2. Genistein

• The trial followed three groups: One receiving genistein, a compound found in soy (orally 60 mg/day for 7 days every 2 weeks), with combination treatment of chemotherapy (FOLFOX) and Bevacizumab, second receiving only combination treatment and third chemotherapy (FOLFOX) alone ¹⁹.
• Median Progression-Free Survival: 11.5 months with genistein compared to 4 months with the standard treatment (FOLFOX and Bevacizumab) and 8.0 months with chemotherapy (FOLFOX) alone.
  
  

3. High-Dose Vitamin C

• In this trial one group of people received intravenous vitamin C (1.5 g/kg once a day for 3 days every two weeks) together with standard treatment (FOLFOX and Bevacizumab) while other group was given standard treatment alone ²⁰.
• Progression-free and overall survival improved with Vitamin C
• For RAS mutated tumors, there was a statistically significant benefit: Median Progression-Free Survival 2 months with Vitamin C versus 7.8 months with chemotherapy alone.
  
  

Some other compounds with anti-angiogenic activity ¹²:

Quercetin (from onion, apple etc.),

Apigenin (from celery, parsley, chamomile etc.),

Lycopene (from tomato, watermelon etc.),

Astaxanthin (from microalgae)

Artemisinin (from Artemisia annua L. or sweet wormwood)

Resveratrol (from red grape and berries)

Metronomic Chemotherapy

Metronomic chemotherapy is an alternative to the standard method of using chemotherapy drugs. Instead of giving the maximum tolerated doses with long breaks in between, metronomic chemotherapy involves giving smaller, more frequent doses. This approach has advantages: it reduces side effects of drugs and has unique effects on tumors, especially on their blood vessels and therefore the tumor microenvironment ²¹. It improves blood flow in two ways:

1. Normalizes Blood Vessel Growth: Metronomic chemotherapy has been shown to repair the abnormal tumor blood vessels, improving their function. It increases the levels of a growth factor TSP-1 (thrombospondin-1), a key regulator of blood vessel maturation and stability which is usually downregulated in tumors.
2. Reopens Compressed Blood Vessels: Rapidly growing tumors can squeeze their own blood vessels blocking the blood flow. By killing CFCs metronomic chemotherapy reduces this pressure, reopening the blood vessels and restoring blood flow.
   
   

With improved blood flow, therapeutic agents and oxygen reach the tumor more efficiently. Increased oxygen levels of the tumor microenvironment improve the immune system’s ability to attack the tumor, releasing its full potential to eliminate CFCs.

Oxygenation Therapies

Oxygenation therapies are used to elevate oxygen levels in the body. This has a profound effect on the low-oxygen (hypoxic) tumor microenvironment ⁹. Bringing more oxygen to the tumor turns off a signaling pathway called HIF-1 (hypoxia inducible factor 1), an oxygen sensor of cells, which is often overactivated in CFCs and a key driver of excessive blood vessel growth, invasiveness, metastasis and therapy resistance.

• Exercise With Oxygen Therapy (EWOT)

This treatment includes physical activity, such as running on a treadmill or cycling on a stationary bicycle while wearing an oxygen mask. In addition to the powerful effect of exercise on the immune system, EWOT significantly improves blood flow and oxygen supply of the entire body, reversing tumor hypoxia.

• EBOO (Extra-Corporeal Blood Ozonation and Oxygenation)

Ozone is a naturally occurring molecule with three oxygen atoms (O3). In ozone therapy or EBOO, part of a person’s blood is drained and mixed with ozone. When introduced into the bloodstream, ozone is converted to oxygen (two O3 produces three O2 molecules), which rapidly increases the oxygen content of the blood. Oxygenated blood is then returned to the body, which has been shown to alleviate hypoxia in tumors. ²². In addition, ozone interacts with various blood components, inducing transient oxidative stress. This dilates blood vessels, increases mitochondrial function (energy production of cells) and stimulates the bone marrow to produce red blood cells with better oxygen carrying capacity ²³. As a result, ozone therapy improves both immediate and long-term oxygen levels and blood flow. Ozone therapy also activates the immune system enhancing the body’s innate defenses against CFCs.

• Hyperthermia

A thermal treatment that raises tumor temperature above 104 °F (40°C) affects the tumor microenvironment and the immune system in various beneficial ways ^{24, 25}. Heat increases blood flow and oxygen delivery to tumors, reducing hypoxia. Elevated body temperature also mimics fever-like conditions which strongly stimulates the immune system to recognize and attack CFCs.

Physical Movement

Despite all the therapies developed, one of the most effective ways to target blood vessels and the tumor microenvironment is free and almost always accessible. Numerous studies have shown the remarkable impact that physical activity has on treating CFCs and improving survival.

Exercise appears to be a unique approach in a way that it can both normalize tumor blood vessels and take advantage of their abnormal structure ²⁶. Since most tumor blood vessels are poorly developed, they cannot constrict like normal vessels. Typically, during physical activity, the body, through neural and hormonal regulation, directs blood to the working muscles by constricting blood vessels in less active organs. As a result, blood flows away from inactive tissues and surges to active muscles – and tumors, as they cannot constrict. Through this mechanism exercise can increase blood flow to the tumor by 200% and reduce oxygen-deficient areas by up to 50%, as has been shown with animal models ²⁶. Even a single session of treadmill running can reduce a tumor’s oxygen deficiency by 15%, showing how quickly exercise can create a positive change in the tumor microenvironment. In addition, this increase in blood circulation has been shown to reduce fluid pressure and remove accumulated lactic acid from the tumor microenvironment making it less favorable for tumor growth and more accessible to therapeutic agents and immune cells.

Unlike anti-angiogenic drugs which can over-shrink the blood vasculature, exercise causes abnormal tumor blood vessels to mature and settle into a stable state. The mechanism behind this is created by increased heart rate and blood flow that exert mechanical forces on blood vessel walls. These forces activate biochemical signaling on the vessel walls, which stimulates them to regenerate and form a healthier structure.

Also contrary to anti-angiogenic drugs like bevacizumab which suppresses the immune system, exercise has been proven to significantly boost the immune function ²⁶. The release of cytokine interleukin-6 (IL-6) from contracting muscles helps guide T-cells to the tumor, increase the number of natural killer (NK) cells and CD8+ T cells by up to 10-fold and 2.5-fold, respectively – all essential for the immune system’s ability to eliminate CFCs.

In conclusion, improving blood flow to the tumor is one of the most important steps in reversing its progression. The goal of a holistic treatment approach, using specific natural compounds, oxygenation therapies, and exercise, is to repair dysfunctional blood vessels by balancing abnormal growth signals in the tumor microenvironment. Restored blood flow makes the tumor more manageable: it becomes less aggressive, while therapeutic agents and immune cells have better access to it.

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