Why cancer is plagued with low 5 year progression free survival rate

Abstract?

When we hear the word “ cancer”, we generally get shivers down the spine & we pray no one even develops this devastating umbrella of diseases. Yes, cancer is referred to as the umbrella of multiple diseases-200 distinct diseases. Each cancer type be it brain, oral, colon or breast has different subtypes, each one having different biochemical phenotype at molecular level.?

Our biochemistry is as unique as our fingerprint & no two individuals share more than 5% of biology. Biology is not about genes but epigenetic or gene expression since we all have 98% genetic homogeneity.?

Every individual’s cellular ecosystem is unique & distinctive & given that cancer arises from our own cells, each cancer is different as our biochemistry is. Unfortunately, the solutions to manage cancer or kill tumors are the same for every type of cancer. No wonder the survival rate is dismal.

The basic premise of cancer being the outcome of genetic mutations & eliminating tumors with chemotherapies, radiation or targeted therapy only is flawed. As such the healthcare system has not been able to find any solutions to manage cancer effectively, leave prevention or diagnosis. The following paragraphs throws light on the right scientific approach of resolving cancer by integrating different aspects of human biology & adopting a nutritional therapeutics + modern medicine approach.

The multicellular mitochondria- key to understanding biochemistry behind cancer

2.5 billion years ago, the pre-mitochondria era, cells in the oxygen less environment on this planet used fermentation pathways to grow & proliferate. This was a spectacularly uncontrolled (dysregulated) growth until the fermentable fuels dissipated & cells died. This is evolutionary biology.

Over time, symbiotic interactions between some specific types of bacteria & other organisms which could harvest energy of oxygen in the cells led to evolution of life & hence multicellularity. This arose with the origin of mitochondria in cytoplasm, triggering regulated growth with mitochondria becoming the control switch that modulated growth of cells while generating ATP, the energy currency for the cells.

With the evolution of life, this multicellular structure- mitochondria in the cytoplasm became the epicenter of energy metabolism. Mitochondria oxidised nutrition to produce ATP( the energy) & releases water vapour as byproduct. This is the most efficient way of producing energy with 89% of energy being produced via oxidative phosphorylation while substrate level phosphorylation contribution to balance energy production

The mitochondria to produce ATP needs constant flow of electrons via electron transport chain(ETC) which is modulated by a signalling molecule- nitric oxide. Nitric oxide controls the flow of electrons via electron transport chain & prevents electron leakage. Production of nitric oxide required a complex biochemical reaction involving 5 electron oxidation of L-arginine to produce Nitric oxide & release L-citruline as a bioproduct. Therefore, the production of ATP via oxidative phosphorylation requires complex biochemical functions that necessitates our body to be? in a homeostasis state.

The origin of cancer driven by metabolic theory of cancer not somatic mutations?

When there is acute damage to mitochondria, it could lead to cell death, however it is low grade chronic damage to mitochondria that leads to mitochondria dysfunction(damaged respiration/respiration insufficiency). When this kill switch goes out of whack, mitochondria goes absurd, there are its abnormalities in structure & function, thereby producing Reactive Oxygen Species(ROS) instead of ATP. ROS is carcinogenic & mutagenic, damaging DNA, RNA? lipids & proteins & leading to genetic mutations. While some germ line mutations may cause mitochondria dysfunction, it accounts for hardly 5% of total genetic mutations, are not 100% penetrant & considered secondary risk factors.

Mitochondria dysfunction in case of cancer( DNA, lipids, proteins damaged)

Source: https://www.researchgate.net/figure/Typical-ultrastructure-of-a-normal-mitochondrion-and-a-mitochondrion-from-a-human_fig2_259349908

There are multiple factors that could lead to mitochondria dysfunction which includes low grade chronic inflammation( caused by microbiome), oxidative stress, genotoxins, environmental toxins & viruses. These all factors taken together are referred to as oncogenic paradoxes.

Since the control switch has gone bust( mitochondria dysfunction), mitochondria can no longer regulate cell growth & cycle. This leads to dysregulated cell growth, triggering onset of cancer.?

Unfortunately, the healthcare system believes & propagates cancer as genetic disease caused by random genetic mutations while research & evidence has found that genetic mutations are downstream epiphenomenon of mitochondria dysfunction. Simply put, genetic mutation is not the cause but the effect of damaged respiration.The underlying cause of all the cancer is mitochondrial dysfunction. Targeting cancer energy metabolism is the right way for successful management of cancer which is unfortunately shunned by the reactive oncology industry.

Over last few years, research has found(1):

-Absence of genetic mutations in some cancers

-Driver mutations, which are claimed to be the primary cause of cancer as per somatic mutation theory, has been found in normal healthy cells.

-Some carcinogens does not cause genetic mutations(asbestos)

-Nuclear mitochondria transfer experiments establishing cancer as a mitochondrial metabolic disease.

Specifically nuclear mitochondria transfer experiments demonstrated(2):

-1. Transfer of normal cell cytoplasm(mitochondria) to normal cell nucleus showed regulated growth

-2. Transfer of tumour cell cytoplasm in normal cell nucleus showed dysregulated growth

-3.Transfer of tumour cell cytoplasm in tumour cell nucleus showed dysregulated growth

-4.Transfer of normal cell cytoplasm(mitochondria) to tumour cell nucleus showed regulated growth

Results of these experiments established that nuclear genomic defects(genetic mutations) cannot account for the origin of cancer while normal healthy functioning mitochondria suppresses tumourgenesis.

These data points, research & nuclear transfer experiments clearly bust the myth of cancer being a genetic disease(somatic mutation theory) & establishes the fact that cancer is a mitochondrial metabolic disease

The energy substrates for cancer cells

The question may arise if mitochondria goes bust, how does the cell survive??

The cancer cells (which were normal cells earlier) do not respire, they ferment. These bust cells, who have lost the ability to use oxygen to generate energy, use ancient fermentation pathways to ferment two fermentable fuels-Glucose & glutamine via glycolysis & glutaminolysis pathways. This fuels the growth of cancer cells.

When cancer cells ferment glucose & glutamine in cytoplasm & mitochondria, they secrete by products lactic acid & succinic acid respectively, leading to acidification of Tumor microenvironment(TME).?

To redefine” Cancer is uncontrolled cell division & growth caused by respiration insufficiency( mitochondria dysfunction) followed by compensatory fermentation. In other words, Cancer is a disease of dysregulated energy metabolism thriving on fermentation pathways, fermenting glucose & glutamine.

Gaps in standard of care practices for treating cancer

The current practice of treating cancer with toxic drugs- named as “chemotherapy”,“immunotherapy”, “radiation therapy” or “targeted therapy” have shown limited success with a low 5 year survival rate(<30%). In some cancers such as glioblastoma multiforme(GBM), it is even less than 10%. There are multiple reasons for this dismal performance.

-We have been given to understand that cancer is an outcome of random genetic mutations. However research has found that cancer is mitochondrial metabolic disease & genetic mutations are downstream epiphenomenon. Unfortunately, healthcare system is treating the effects not the underlying cause

-Each cancer cell within a tumour has a different constellation of genetic mutations & these therapies are targeting not all but certain specific mutations. Therefore certain cancer cells bypass this targeting & survive & grow

-Even in case of metastatic cancer, primary & secondary tumors have different genetic mutations as well as two people suffering from the same cancer have different mutations.In other words, there is huge intertumoral & intratumoural heterogeneity.

-The driven mutations, which are claimed to be the cause of cancer, have also been found in healthy cells & therefore these target therapies may kill certain cancer cells but also damage other tissues- Kidney or liver, causing kidney or liver disease or neurological issues later in life.

-The cancer cell ferment glucose & glutamine for their survival & growth & as a byproduct release lactic acid & succinic acid respectively( as mentioned in the previous section).This acidifies tumour microenvironment(TME) which acts as antioxidants shield for cancer cells, making chemotherapy, immunotherapy & other therapies ineffective

-This standard of care neglects the role of these fermentable fuels in growth & proliferation of cancer cells & effectiveness of therapies. A major side effect of cancer is cancer cachexia which directly affects a patient’s appetite & cancer cells extracts all the energy, making the patient lose weight, skeletal muscle & fat. The muscles begin to lose their composition & amino acids will go back into the bloodstream & reach the liver where by a process known as Gluconeogenesis , amino acids will be converted into sugar, raising the blood sugar levels. Besides, as the patient starts losing weight, the healthcare practitioner may make the patient consume a lot of sugar & glucose rich foods to gain weight. This high sugar levels would be fermented by cancer cells, leading to production of lactic acid as a product which further will reduce the effectiveness of standard of care therapies.

Origin of metastasis?

While the cancer cells ferment glucose & glutamine to fuel their growth & secrete lactic acid & succinic acid that makes therapies ineffective & further damages oxidative phosphorylation, they have limited capacity to spread their wings to other body organs. Here comes the role of natural metastatic cells- the macrophages which take the matter in their hands & spread this growth to other body organs.

It has been found that the gene expression profile of metastatic cancer cells is similar to those of macrophages or fusogenic cells of the immune system. Many malignant tumours contain substantial amounts of macrophages. These are referred to tumour associated macrophages(TAM)?

This TAM facilitates metastatic cascade through various processes(3)

-Local Invasion: TAM secretes various chemical byproducts-Protease that breakdown the membrane of area surrounding the tumours?

-Angiogenesis: Macrophages cooperate & coordinate with tumor cells to upregulate various angiogenesis growth factors & enzymes

-Immunosuppression: Macrophages upregulate growth factors & cytokines that suppress antitumor functions of the immune system within the tumor & fuses with cancer cells, thereby becoming rogue

-Extravasion & secondary tumour formation: Macrophages enters the blood circulation & spreads this to other body organs.

In other words: The body senses there is some damage or sort of injury or wound. Macrophages are released in the bloodstream to go to cancer cells to heal the wound. As a part of this process, macrophages throw out growth factors & cytokines which are stimulatory towards these cells ( who have lost their growth control because of their fermentation activity). These macrophages( immune cells) fuse with these cells which results in diluting of cytoplasm of the immune cells with the cytoplasm of the cancer cells, making immune cells shift from respiration to a fermentation model, causing cancer cells to metastasize & spread its wings to different parts of the body. This essentially means, we have a rogue cell, part of the immune system, that is reprogrammed to spread throughout the body as they can easily survive in a hypoxic environment ( the fermentation mechanism comes into action). These cells ferment glucose & glutamine to grow further & hijack our biochemistry.

The spread of cancer to other body organs & secondary tumour formation happens in non random fashion since the macrophages are biochemically programmed to enter specific tissue to repair the damage or wound healing. Therefore the major sites for metastasis are those that have high macrophages turnover- Liver, bones, lungs & kidneys.?

The interesting part is macrophages are also target sites of inflammation & injury & it is not uncommon that? metastatic cancer cells from lungs could find their way up in the mouth following tooth extraction or to the breast following a needle biopsy. Even a benign tumour due to needle biopsy or tooth extraction could result in malignant tumour? This mechanism is referred to an inflammatory oncotaxis(3)

The way forward- Solutions at the intersection of precision therapeutics & standard of care therapies

Since it is now clear that there are huge genetic differences & constellations of genetic mutations heterogeneity within the cancer cells in a tumor( intratumoral), genetic differences in different tumors in primary & secondary tumor sites( intertumoral)? as well different genetic mutations in two individuals for the same cancer, the current standard of care focussing on targeting certain specific tumors results in low effectiveness with certain number of cancer cells bypassing this targeting & resulting in cancer proliferation & growth. This clearly explains why the 5 year survival rate is falling.

There is an urgent need to marry nutritional therapeutics aligned with an individual’s biochemistry with standard of care therapies to successfully manage/resolve cancer. The following steps in that order is the key to reduce the overall mortality & recurrence

-Understand & measure specific pathways triggering inflammation & oxidative stress

-Avoid foods having potential toxins & carcinogens

-Deprive cancer cells of fermentable fuels- Glucose & Glutamine while feeding right nutrition substrates to healthy cells to boost mitochondrial biogenesis & improve mitochondria efficiency.

-Resorting to interventions that target, suppress or block glutamine receptors to starve cancer cells of glutamine in case you are still consuming foods having glutamine. Some of these substrates may include melatonin, Vitamin D & more.

-This will eliminate most of the cancer cells( genetic mutations).

-The remaining group of genetic mutations have similar phenotype at molecular level & could be eliminated by debulking &/or small doses of chemotherapies.

NEVER EVER START WITH STANDARD OF CARE THERAPIES RATHER FIRST ELIMINATE CANCER CELLS HAVING GENETIC MUTATION HETEROGENEITY WITH NUTRITIONAL THERAPEUTICS & THEN GET RID OF BALANCE GROUP OF CANCER CELLS HAVING SIMILAR BIOCHEMICAL PHENOTYPE USING TARGETED THERAPIES

We at Genefitletics are leading a revolution on preventive oncology from the front with focus on prevention & preventive recurrence. We have built a unique cancer detect platform where in we measure the biochemical functions contributing of inflammation & oxidative stress, result in onset of cancer & deliver a data driven cancer preventing therapeutics that deprive cancer cells of fermentable fuels- Glucose & Glutamine while feeding right nutrition substrates to healthy cells.

We have kickstarted this revolution with oral cancer wherein we could identify molecular signatures underlying oral cancer onset at the earliest stage & eliminate them using precision therapeutics before disease manifests. The test is also available to prevent the recurrence of oral cancer for the patients who are in advanced stage of disease by blending nutritional therapeutics with standard of care therapies

Citations

1. https://pubmed.ncbi.nlm.nih.gov/26217661/
2. https://www.mdpi.com/2218-1989/11/9/572
3. https://pmc.ncbi.nlm.nih.gov/articles/PMC3597235/
4. https://link.springer.com/article/10.1186/s40169-018-0185-6