Saturday, June 9, 2018

Theory of Cancer

A fundamental characteristic of cancer cells is their inclination toward anaerobic respiration leading to the conversion of glucose into lactic acid instead of carbon dioxide.

Rising lactic acid and inflammation promote each other in a malicious cycle {ref}. The onset and progression of inflammation can be triggered by a variety of factors: chronic stressors that may have contributed to the development of cancer {ref|ref|ref|ref|ref|ref}, the tumor itself, the body’s response to the tumor, or cancer treatments (surgery, RX, chemotherapy). Additionally, dietary, lifestyle and environmental factors also contribute. 

Incessant inflammation results in increased expression of HIF1α {ref|refwhich further stimulates the glycolytic process, causing the production of more lactate contributing to persistent and increasing sub-toxic ammonia levels.

Before the Great Oxygenation Event, there was very little oxygen in the atmosphere. Instead, the atmosphere contained elevated levels of ammonia {ref}, which was an important source of energy for one-celled organisms. 

In the context of cancer, cancer cells tend to thrive in environments low in oxygen where ammonia serves as a signaling molecule that triggers cellular growth and division {ref}. An increase in the amount of ammonia in tissues and a decrease in the ability of the body to excrete it raises lactic acid and interferes with the uptake of oxygen {ref}. This, in turn, leads to hypoxia and produces a shift towards glycolysis, perpetuating the deadly cycle

Cancer appears to be a metabolic disruption, and ammonia is both its catalyst and energy source {ref}.
 
Hypothesis: ammonia is the catalyst of cancer development


Adjuvant anticancer strategies

From the given hypothesis, I propose the following anticancer strategies:
  • detox ammonia
  • decrease lactic acid/lactate
  • suppress LDHA
  • suppress STAT3
  • suppress PDK
  • suppress HIF1-alpha
  • suppress glycolysis
  • reduce inflammation
  • apply cytotoxicity
  • boost T&NK cells
  • maximize efficacy through the potential of synergistic effects and combined anticancer treatments.
  • anticancer diet 

Theories and Hypotheses


1. Cancer, a genetic disease
DNA

Cancer cells have gene mutations and will unceasingly continue to replicate. Gene mutations can be either inherited or acquired. At present, this is the main theory.

Examples of inherited mutations:
  • Hereditary breast-ovarian cancer syndrome
  • Lynch Syndrome
  • Li-Fraumeni syndrome
  • Cowden syndrome
Acquired: dysregulation of more than 700 genes at multiple steps in cell signaling pathways.

2. Cancer, a metabolic disease


Can cancer metabolism be targeted to stop cancer proliferation?

Toxic accelerated aging
According to San-Millán and Brooks GA "Lactate is probably the only metabolic compound involved and necessary in all main sequela for carcinogenesis, specifically: angiogenesis, immune escape, cell migration, metastasis, and self-sufficient metabolism. We hypothesize that lactogenesis for carcinogenesis is the explanation and purpose of the Warburg Effect. Accordingly, therapies to limit lactate exchange and signaling within and among cancer cells should be priorities for discovery".

This study suggests cancer to be a metabolic disorder rather than a genetic disease. Problems:

"Warburg, Koch, and Szent-Gyorgyi had a comprehensive view of biology, in which the aerobic production of lactate, resulting from a respiratory defect, itself was functionally related to the nature of cancer." - Ray Peat, Ph.D. (1936-2022).

3. Cancer, an evolutionary throwback (atavistic reversion theory)


Cancer tumors are able to survive with very little oxygen, this supports the idea that cancer emerged when the amount of oxygen in the atmosphere was extremely low when life first appeared on our planet.

Suggested treatments:
  • Increase oxygen in the body
  • Focus on the immune system, help trigger the patient's own immune system cells to attack cancer
If cancer is part of the history of the cell and for whatever reason the cell reverted to that ancient function, trying to forever halt cancer via metabolic pathways as mentioned above, seems to be a near-impossible task to accomplish since many cancer cells will survive the most inhospitable and nutrient-deficient conditions.

As for the reason, could it be that a normal cell becomes cancerous because of adaptation? Is the cell trying to adapt or cope with a changing habitat e.g. less oxygen, more ammonia, etc.? So the cell activates genes that a billion years ago were an efficient mechanism to deal with such an environment.



4. Theory of cancer stem cells (CSC)

The cancer stem cell hypothesis proposes that tumors are comprised of a heterogeneous cell population, with only a subset of cells being responsible for the initiation, maintenance and progression of the disease. This subset of cells, referred to as cancer stem cells (CSCs), are thought to be responsible for the aggressiveness of tumors, and may be resistant to chemotherapy and radiation. CSCs are believed to possess several key characteristics, such as self-renewal, tumor-initiating ability and the ability to differentiate into other cancer cell types.



5. Cancer is a wound that does not heal

Chronic irritation theory. {Ref}

Dr. John Prudden’s 31 Cases: Treating Cancer with Bovine Tracheal Cartilage. "Dr. John F. Prudden (1920-1998), found that bovine tracheal cartilage had a powerful and consistently positive effect on wound healing, arthritis, cancer, and other diseases."



6. Melancholy as a risk factor for cancer


  • Depression and the Immune System: A Close Connection {Ref}

“Don't carry the experience of life as a wound – let it become wisdom.” Sadhguru

7. Cancer is caused by nutritional deficiencies

{ref}

Hypothesis
"One overarching hypothesis can explain all these disparate features. The hypothesis is that there is an
essential agent—or combination of agents—which is protective against the development of breast cancer; under certain conditions this agent is able to leach out, permitting breast cancer to develop.

The agent is a micro-nutrient, trace element, vitamin, or proto-vitamin found in soils in varying amounts in different localities. It is taken up by plants, and grains, and possibly fruits, to enter the food chain in differing quantities in different areas or by different cultures with different dietary habits.

The concentrations in soils, then in plants, determine the amount in the food chain, which therefore varies according to the geographical region or locality. Thus the levels in humans will differ according to the geographical region or locality within a country and the food culture of the local population. The differences in soil and plant concentrations in different countries, and the different dietary habits, account for the wide variation between breast cancer incidence in, for instance, China and Japan as compared to many Western countries.

Differences in concentrations between different localities within a country also account for differences in incidence of breast cancer in different parts of, say, China where on average incidence is low, or western parts of the USA where it is high. The amount of the agent, or lack of it, in the blood or tissues and possibly breast tissue of individuals in the human population is a major determinant of breast cancer incidence.

The agent is probably fat-soluble, such that an increased amount of body fat is able to absorb a greater amount of the agent as compared to lean individuals. This depletes the levels of the agent in body tissues and thus accounts for the association of higher incidence in women who are or become obese.

Increased fat intake as in a Western diet therefore produces systemic depletion of the agent, accounting for the higher incidence in Western countries or those that have adopted a Western diet. For example, because of high concentrations of this protective factor in Japanese foodstuffs, in one study overweight Japanese women had a lower incidence than lighter Dutch women [3].

As foodstuffs are processed or moved from one country (or locality) to another, breast cancer incidence becomes more homogenous. Additionally, the greater incidence of breast cancer in the higher social classes in the 1950s and 1960s (e.g., in the UK) due to the greater consumption of fatty foods by the higher social classes has now been reversed as those in the lower classes now consume more fatty and sugar-filled foods.

Increase of breast cancer incidence with age is related to the agent leaching out as a result of age-induced changes or not being as fully absorbed.

Oestrogens (estrogens) are tumour promoters, stimulating oestrogen-dependent breast tissue when levels of this critical agent fall below a specific individual threshold. In areas or populations where the tissue levels of this agent are low, high oestrogen concentrations will be associated with increased incidence, but where tissue levels of the agent are high, incidence of breast cancer will be low despite high oestrogen levels from natural or artificial sources. This accounts, for instance, for the Japanese/Dutch results referred to above.

Differences in incidence between varying groups may be accounted for by a deficiency gradient in threshold: women with genetic predisposition need only a small fall in levels of the agent; women who develop overt unilateral disease have a moderate deficiency; women with bilateral cancer have a greater deficiency; men with breast cancer have severe depletion."
 

8. Cancer cells that arise from bacteria

BOCC hypothesis {Ref}   It's the Terrain


Evidence supporting this hypothesis


1. There are 10× more bacterial cells than human cells in the human body.
2. Bacteria play a key role in carcinogenesis. 
3. Like bacteria and single-celled eukaryotes (protists, e.g., yeast), cancer cells can grow in agar medium and form colonies, proliferate in the absence of anchorage in vitro, and ferment glucose in the absence of oxygen (anaerobic fermentation) with the production of lactic acid.
4. Cancer cell genomes were assembled from DNA fragments all at once in a single catastrophic event (chromothripsis).
5. Cancer cell genomes contain bacterial DNA.
6. Genes of ancient and unicellular origin are highly and preferentially expressed during tumorigenesis.


9. Cancer is a consequence of an acidic body and lymphatic obstruction.



10. Cancer is a delayed severe hypersensitivity reaction.

Reviewing a large body of evidence on many chronic inflammatory diseases and carcinogenesis the author proposes that cancer is a severe form of hypersensitivity responses (immune disorder) in site-specific tissues resulting from the accumulation of exaggerated expression and co-expression of immune responses and the creation of a molecular immune tsunami, primarily in the immune-responsive tissues. {ref}


11. Cancer is first of all a cachexia accompanied by a tumor
It is proposed here that carcinogens deplete a vital substance and induce a metabolic deficiency that ends in cachexia. In order to survive, the organism grows a protective organ-the tumor-that replenishes the missing substance. {Ref}

            What vital substance is missing?


12. Cancer is caused by a loss of efficient use of oxygen

  • Oxygen-Starved Tumor Cells Have Survival Advantage That Promotes Cancer Spread {ref}
  • Stem-like cancer cells grow more rapidly under hypoxic conditions {study}


13. Dysregulation of the urea cycle is prevalent in many cancer types, and it is accompanied by specific mutations resulting from the increased synthesis of pyrimidine.

{ref}

14. Cancer is the result of a homeostatic imbalance

{ref}

15. Cancer is caused by sulfate deficiency

{ref}



SYNERGIES & STRATEGIES 


This Excel spreadsheet contains an extensive list of natural compounds and repurposed drugs that have been found to have synergistic anticancer effects. Furthermore, it provides strategies for targeting cancer signaling pathways and hallmark cancer processes with natural substances and repurposed drugs.



Minerals in Energy Production


Copper plays an important role in energy production by participating in the electron transport chain. It acts as an electron carrier, transferring electrons from one molecule to another. This helps to generate energy from the breakdown of carbohydrates, proteins, and fats. Copper is also involved in the formation of ATP (adenosine triphosphate), an energy-carrying molecule that is used by cells to power their activities.

The formation of ATP requires several minerals. In terms of importance for ATP production, the minerals can be listed in the following order: magnesium, phosphorus, calcium, sodium, potassium, iron, and copper. Magnesium and phosphorus are the most important minerals, as they are necessary for the synthesis of the ATP molecule. Calcium, sodium, and potassium are also important, as they help to maintain the correct balance between ions in the cell. Iron is necessary for the transfer of electrons, and copper is involved in the transfer of electrons between molecules.

Ceruloplasmin is a copper-containing protein that binds to copper ions and transports them throughout the body. It plays an important role in the metabolism of copper, and is necessary for the proper functioning of the nervous system, immune system and cardiovascular system. Ceruloplasmin also helps to regulate levels of copper in the body, and can affect the activity of certain hormones, such as estrogen, testosterone, and thyroid hormone.

Zinc impedes overactive calcium signals in cancer cells, which is absent in normal cells, and thus zinc selectively inhibits cancer cell growth{study}. Zinc has been found to reduce the side effects of chemotherapy, including nausea, hair loss, and fatigue. It may also help to enhance the efficacy of certain drugs by increasing their uptake into cancer cells.

Hypoxia


Hypoxia is a medical term used to describe a deficiency in the amount of oxygen reaching tissues in the body, usually due to low environmental oxygen or decreased oxygen delivery from the lungs, heart, or blood vessels. Hypoxia can be acute or chronic, and can occur in any part of the body, including the brain and other organs. Hypoxia can have serious consequences to the body, leading to organ damage, tissue death, and even death. 

Under normoxia, HIF-1α proline hydroxylation promotes proteasomal degradation, while HIF-1α asparagine hydroxylation blocks CBP/p300 binding, thus impairing HIF-1α function. Both prolyl (PHD) and asparaginyl (FIH) hydroxylases require Fe(II), O2, and α-ketoglutarate (αKG). 

Under hypoxia, HIF-1α is not hydroxylated, and its nuclear translocation allows the dimerization with HIF-1β, the combining with the coactivators CBP/p300, and thereby, the binding to hypoxia response elements (HREs), increasing the transcription of target genes.

Hypoxia-Inducible Factor 1

Hypoxia-inducible factor 1 (HIF-1) is a transcription factor, a protein that helps to regulate gene expression in response to changes in oxygen levels. HIF-1 is composed of two subunits, HIF-1α and HIF-1β. HIF-1α is the protein that binds to DNA and regulates gene expression, while HIF-1β is the protein that binds to HIF-1α and helps it to bind to DNA. 

HIF-1 plays an important role in the body’s response to hypoxia, especially in the regulation of the expression of genes that are involved in the body’s adaptation to decreased oxygen levels. When oxygen levels drop, HIF-1α is stabilized and can then bind to DNA and activate gene expression. This gene expression helps the body to adapt to hypoxia, such as increasing the production of proteins that can help increase oxygen delivery to the tissues, and increasing the production of proteins that can help protect cells from damage due to hypoxia.

HIF1 activity affects neither the consumption of glucose nor the release of ammonium or lactate; however, it significantly inhibited the release of the amino acid alanine. {ref}

Hypoxia-Inducible Factor 1-Alpha


HIF-1α is a transcription factor that is activated in response to hypoxia, or low oxygen levels, in tissue, and can activate the expression of genes that are involved in the body’s adaptation to hypoxia. HIF-1α is a key regulator of the response to hypoxia and plays a critical role in the adaptation of cells to changing environments. In hypoxic conditions, HIF-1α activates a variety of genes involved in the regulation of energy metabolism, cell cycle regulation, angiogenesis, and apoptosis

HIF-1α binds to specific regions of the genome known as hypoxia-responsive elements (HREs). It binds to DNA as a heterodimer with ARNT (aryl hydrocarbon receptor nuclear translocator) and recruits transcriptional co-activators, such as p300, to regulate the expression of target genes. 

HIF-1α has been shown to play a major role in cancer progression. HIF-1α upregulates glycolytic gene expression, thus allowing cancer cells to produce more energy and grow faster.  It also upregulates the expression of genes involved in angiogenesis, such as vascular endothelial growth factor (VEGF), and genes involved in cell survival, such as Bcl-2.

The role of HIF-1α in glycolysis has been extensively studied in recent years. It has been shown to upregulate the expression of several key glycolytic enzymes, including HK2, PDH, and glyceraldehyde-3-phosphate dehydrogenase (GAPDH). HIF-1α also activates the transcription of several glucose transporters, such as GLUT1 and GLUT4, which are involved in glucose uptake and metabolism.

Many cancer types overexpress Hypoxia-Inducible Factor-1 Alpha {ref}.

HIF-1 stimulates the expression of GLS1 (Glutaminase 1).

ELF3 is a transcription factor that induces angiogenesis by transcriptionally increasing IGF1 expression. Hypoxia enhances the effect of ELF3 on angiogenesis.


https://doi.org/10.15252/embr.202152977



Activators of the HIF pathway


Natural and synthetic compounds as HIF-1α inhibitors


Targeting HIF-1α by Natural and Synthetic Compounds: A Promising Approach for Anti-Cancer Therapeutics Development {ref}

Cancer and the Cellular Response to Hypoxia (Maria Adamaki, Anastasia Georgountzou and Maria Moschovi)


Lactate metabolism in human health and disease {ref}

Proper cell functioning: adequate nutrition, adequate oxygen supply, proper pH balance, healthy cell structure, appropriate cell membrane, appropriate cell signaling, appropriate gene expression, appropriate enzyme activity, proper cell division, and appropriate metabolic activity.



Cancer thus seems to be a metabolic disruption, and ammonia its catalyst.
Por lo tanto, el cáncer parece ser una alteración metabólica y el amoníaco su catalizador.
Kanker lijkt dus een verstoring van de stofwisseling te zijn en ammoniak de katalysator.
Le cancer apparaît ainsi comme un dérèglement métabolique et l'ammoniac comme son catalyseur.
O câncer, portanto, parece ser uma perturbação metabólica, e a amônia, seu catalisador.
Таким образом, рак, по-видимому, является нарушением обмена веществ, а аммиак — его катализатором.
因此,癌症似乎是一種代謝紊亂,而氨則是其催化劑。
Kræft synes således at være en metabolisk forstyrrelse, og ammoniak dens katalysator.
Cancer verkar alltså vara en metabolisk störning och ammoniak dess katalysator.
Krebs scheint also eine Stoffwechselstörung zu sein und Ammoniak sein Auslöser.
Il cancro sembra quindi essere una perturbazione metabolica e l'ammoniaca il suo catalizzatore.
وهكذا يبدو أن السرطان هو اضطراب استقلابي ، والأمونيا حافز لها.
したがって、癌は代謝の混乱を引き起こし、アンモニアはその触媒であると考えられます。

 


References & Sources



  • https://www.researchgate.net/figure/Comparison-of-metabolic-pathways-and-their-energetic-efficiencies-Compared-to-the_fig5_361606739

  • Prokaryotes were the earliest life forms. Mitochondria likely evolved from engulfed prokaryotes that once lived as independent organisms. Ammonia-assimilating enzymes are all localized to the mitochondria. 
  • Viruses may have existed before bacteria, archaea, or eukaryotes.{ref}
  • STAT3
  • Life, death, and autophagy in cancer: NF-κB turns up everywhere {ref}
  • All-Trans Retinoic Acid Enhances both the Signaling for Priming and the Glycolysis for Activation of NLRP3 Inflammasome in Human Macrophage {ref}
  • RAS and MYC: Co-conspirators in Cancer {ref}
  • Fatty acid oxidation protects cancer cells from apoptosis by increasing mitochondrial membrane lipids {ref}


β-catenin Activation Reprograms Ammonia Metabolism to Promote Senescence Resistance in Hepatocellular Carcinoma {study}


Last update: March 3, 2024

2 comments:

  1. Interesting theory of cancer.

    https://www.researchgate.net/publication/307089086_Hepatocellular_Carcinoma_as_a_Paradigm_for_a_Systemic_Evolutionary_Approach_to_Cancer

    https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6801598/

    ReplyDelete

100 Natural Anti-Cancer Substances

AHCC   🛈 Allicin   🛈 Aloe Vera   🛈 Andrographis extract   🛈 Anthocyanin  🛈 Apigenin   🛈 Artemisinin   🛈 Ashitaba   🛈 Ashwagandha   ...