The Tumor Microenvironment
The tissues in the body exist in a complex ecosystem composed of immune cells, stromal cells, blood vessels, nerves, stem cells and the extracellular matrix (ECM). For decades it was believed that tumor cells in this microenvironment existed and grew driven by genetic mutations as a passive presence, a bystander within their terrain, rather than an active participant.
Introduction
In the 1950s-1960s another concept of cancer development proposed that cancer cells developed in the body frequently, but the immune system could recognize and destroy them. This theory implied that cancer developed only if the immune system's surveillance system failed, which seemed to be supported by the increase in cancers in immunodeficiency diseases like HIV, congenital immune deficiencies and organ transplants.
Other competing theories suggested that a few cells will escape the immune system and survive as emerging variants, and those cells evade immune attack, create an immunosuppressive microenvironment and grow and proliferate Currently, the use of sophisticated technology for sequencing mutations in the genome has revealed inconsistencies in the theories that cancer is strictly a genetic disease. Many new cancer therapies have been designed to treat these mutations, yet treatment resistance eventually develops.
Research has also shown that while the immune system is generally considered anti-tumor, it potentially can also be pro-tumor, revealing that the immune surveillance theory is incomplete.
In a recent review article, The End of the Genetic Paradigm, by Drs. Huang, Soto and Sonnenschein, propose an updated advanced explanation for cancer initiation, the tissue organization theory. It presents supportive information that mutations alone do not cause cancer, but does agree that mutations can contribute or are the result of environmental changes.
Rather, complex alterations and adaptations occurring in stromal support cells, intercellular signaling, innate and adaptive immune cells, inflammatory responses and the extracellular matrix are the drivers of cancer development.
They detail the paradox that many cancers have no consistent driver mutations, and that some tissues are found with oncogenic mutations but no cancer. Contemporary research shows
Genes themselves appear to be relatively stable, but an inherited genetic mutation in the DNA accounts for 5-10% of all cancers
Sporadic cancers account for 90-95% of cancers and involve multiple causes such as:
Epigenetic transformation Chronic inflammation Transformation of the tumor microenvironment, TME This would suggest that there are epigenetic and some genetic mutations that create the potential for tumor development but evidence suggests that cancer is not just a disease of the cell but a disease of the tissue.
This conceptual idea while contemporary is really a full circle moment! In the 1880s, Dr Steve Paget hypothesized the seed/soil concept of cancer. The soil is the microenvironment in which cancer grows, and the seeds are the tumor cells, with both required for tumor development and progression.
When a cancer is able to gain a foothold in the body and expands and progresses, its goal is to directly control and exploit its environment for its own advantage
By manipulating its microenvironment creating chronic persistent inflammation
Creating continued epigenetic expressions supportive of cancer
By dysregulating the immune system, recognizing that the immune while normally anti tumor can be manipulated to become pro-tumor.
Producing disruption and change to structural scaffolding and repair mechanisms that allow progression.
This current recognition finds that the normal microenvironment becomes hijacked by the tumor, and its ecosystem is reprogrammed to accommodate the tumor's requirements for protection and survival. Normal pathways are redirected, and normal repair responses are bypassed suggesting that the tumor microenvironment acquires mechanisms that allow it to escape normal limits on cell replication, achieving replicative immortality.
Tumor cells directly manipulate the host's microenvironment to create its own ecosystem engineered to:
Stimulate the release of inflammatory cytokines and chemokines causing continuous triggering of damage associated molecular patterns, DAMPs signaling molecular damage which activates the inflammasome sensors and reprograms the immune system.
Producing growth factors; Epidermal Growth Factor, EGFR which stimulates uncontrolled cell division and cancer progression.
VEGF for blood vessel growth PDGF or platelet derived growth factor which stimulates stromal cells to support cancer growth CSF-1, colony stimulating factor -1 which promotes the increase of tumor-associated macrophages, TAM's which assist tumor growth and therapy resistance.
Promoting supportive changes in the local metabolic environment, via lactate, ATP and oxidative metabolites that augment immune suppression and enhance its energy production.
Creating an environment of lower oxygen tissue levels called hypoxia, resulting from the expansion of the tumor surpassing its blood supply of oxygen. This stimulates new blood vessel formation, to provide cancer nutrients and allows a shift to non oxygen energy production, a preferred method tumors use to produce energy and tissue remodeling.
Initially when the cellular microenvironment is healthy it is less likely to be supportive of cancer. However, as tumors grow they gain greater influence to beneficially modify and transform the terrain.
The perception that cancer is just independent uncontrolled growing cells requires a shift in viewpoint to recognize that it literally orchestrates the creation of its own complex ecosystem by manipulating the body's normal terrain. The goal being to support its own survival and growth.
Inflammation is a universal response to injuries ranging from minor scrapes to major traumas, infections, allergic reactions, toxicants and other foreign molecules. Initially, there is acute alert, a call to action by our front-line innate immune system resulting in symptoms of heat, redness, swelling, pain, and limited function signaling distress or injury in the local environment. As the alert evolves, if the damage or danger is significant enough and a more specialized long-lasting response is needed, a strategic attack plan is activated that initiates the adaptive immune system. This results in the recruitment of immune cells, stimulates growth and repair factors, enhances blood vessel growth and produces structural components, all designed and coordinated to remove the damage, repair the injury, and reestablish homeostasis.
In early cancer the goal is to evade this adaptive response by avoiding danger signals that would provoke it and would potentially attack the cancer.
However, as the tumor grows it becomes capable of hijacking these normal responses creating its own tumor microenvironment, TME, allowing it to develop chronic dysregulated Inflammation.
Tumor Associated Chronic Inflammation
Stimulation of inflammation in the TME can come from the immune system's attack on the cancer, which is associated with cell death from oncologic therapies.
But the majority is tumor-driven, non-resolving and misdirected to help the tumor.
Tumors are able to:
Generate proinflammatory cytokines including TGF-1 which encourages cell growth, and chemokines.
Recruit and reprogram immune cells to become immune suppressive.
Prolong, amplify, and maintain inflammatory responses resulting in persistent signals of damage or danger. This situation can activate an inflammatory response called the inflammasome pathway, within immune cells, which detects ongoing significant danger or injury in the terrain, which, if severe enough, drives a highly inflammatory form of programmed cell death called pyroptosis. (Please see the website's in-depth article on this topic)
Tumor Associated Immune Suppression in Tumor Microenvironment, TME
In the normal immune system, actions are designed to destroy cancer cells.
The innate immune system's responses are generalized, non-specific, and act rapidly, the first responders to foreign antigens, utilizing macrophages, neutrophils and dendritic cells.
If the innate immune system determines that danger and damage are significant it can trigger The adaptive immune system, designed to react to specific antigens, and create an immunologic memory for that antigen. Normally, cancer cells express abnormal antigens that T cells, B cells and natural killer cells (NK) can recognize but (Referencing the section from, Current Biology. 2020 August 17;30 (16) Drs. Anderson and Simon)
In the TME, immune cells change and play a significant and pivotal role in supporting cancer growth and spread.
T cell interactions in cancer involve specific tasks to counter cancer proliferation.
Normally, CD8 T cells recognize receptors on cancer cells and hone in and destroy them. They also suppress angiogenesis, new blood vessel formation and produce interferon which activates antitumor immunity.
In the TME, CD8 cells are suppressed by the cytokines TGF-B and IL 10 and tumor associated macrophages, (TAMs). They also become overworked and exhausted from chronic stimulation from tumor antigens and eventually become less effective in the transformed metabolic environment.
Normally, CD4 T cells are anti-tumor immune cells that can exist in multiple subsets.
Th1 cells are proinflammatory CD4 cells that support CD8 T cells In the TME, these responses are suppressed.
Regulatory T cells, Tregs strongly suppress the immune response In the TME, tumors recruit them to suppress immune responses.
B cells under normal conditions are antitumor, interacting with T cells to produce antibodies and cytokines against tumors, and support CD4 and CD8 T cell activation.
In the TME, tumors release factors that alter antibody production, reduce interaction with T cells and shift some actions toward immune suppression.
NK cells normally kill tumor cells, induce apoptosis, non-inflammatory cell death, and activate macrophages and CD8 T cells.
In the TME, NK cells are inhibited by transforming growth factor beta, (TGF-B), produced by the tumor, a cytokine that supports cancer growth.
Stromal Cells support overall tissue structural integrity and are connective tissue cells.
They can differentiate into different cell types, fibroblasts, adipocytes or fat cells, and blood vessel lining cells, endothelial cells. Fibroblasts produce the extracellular matrix (ECM) which is composed of collagen, proteoglycans, signaling molecules and fibronectin. Normally, the ECM provides structural support, and regulates cell movement and behavior.
Normally, in an inflammatory state, the ECM creates matrix support for tissue repair until normal tissue structure is restored.
In the TME, fibroblasts become cancer-associated fibroblasts, CAF, and are re-programmed to create large amounts of ECM. This allows remodeling the ECM and increases cancer cell spread while at the same time it builds a protective fibrous shield around the tumor called desmoplasia. This physically can prevent immune cells and cancer drugs from penetrating the tumor.
During chronic inflammation CAFs, besides building up fibrous tissues also release matrix metalloproteinases, MMPs. These are enzymes that break down tissues to encourage cancer spread and release growth factors stored in the ECM and allowing ongoing blood vessel growth.
Neutrophils are part of the leukocyte family of white blood cells that includes macrophages, lymphocytes and monocytes. They are our front-line defense against pathogens. In early cancer, they promote increased inflammation and the release of cytokines to encourage apoptosis, non-inflammatory cell death, of the tumor cells.
In the TME cancer setting they are converted to promote tumor growth by changing the ECM, increasing blood vessel growth factor (VEGF) and generating matrix metalloprotease 9 (MMP) which breaks down the ECM which allows local cancer cells to extent to other tissue, and invade lymphatics and blood vessels to spread.
Adipocytes normally are known to store fat, helping to maintain energy balance by storing and releasing their energy as needed. They release hormones that regulate appetite, Leptin, and a hormone adiponectin which increases insulin sensitivity.
In the TME, especially in breast tissue which is composed primarily of adipose tissue, breast cancer cells stimulate the breakdown of fat cells to release free fatty acids which the cancer can use for energy production, to make cell membranes and exosomes, small vesicles that increase growth and suppress immune responses.
Dendritic Cells (DC)
The dendritic cells are antigen presenting cells that capture and present antigens to T cells in the lymph nodes. This allows the immune system to decide whether to initiate a T cell response or accept the cell.
In the TME, tumor cells manipulate the DCs to allow tumor cells to be present and not be attacked by the immune system.
Sources Producing Chronic Inflammation
An environment with preexisting chronic inflammation, provides changes already existent that cancer finds favorable to exploit. This terrain pattern is becoming more common from the impact of constant exposures to environmental toxicants, unhealthy lifestyles, and persistent infections.
Within this environment there exist proto-oncogenes which are normal genes that regulate cell growth and replication and are needed for proper cell functioning. However, in conditions of ongoing chronic inflammation they can become transformed and develop into oncogenes, activating uncontrolled growth or inhibiting tumor suppression.
In this process:
There is persistent inflammatory signaling of cytokines and growth factors keeping tissues in continuous repair mode.
These inflammatory cytokines activate signalling pathways needed for repair and recovery, activating many of these proto-oncogenes for repair pathways.
Chronic persistent inflammation causes increased DNA damage and if mutations occur it can convert proto-oncogenes into oncogenes affecting KRAS- cell growth and division BRAF-cell growth EGFR epidermal growth factor receptor, or HER-2 in breast cancer MYC- cell proliferation
Inflammation also creates epigenetic genetic changes that alter gene expression,
Inflammation can inhibit tumor suppressors Our daily lives involve constant exposure to potential health hazards.
There are many recognized carcinogens in organophosphate pesticides from contamination in dairy, meat and fish, herbicides from petroleum distillates and glyphosate, hydrocarbons from petroleum and coal sources, phthalates, perfluorocarbons, solvents, and BPA and parabens, xenoestrogens (chemicals that mimic estrogen in the body) and thousands more.
Many of these have long been recognized as potential initiators of cancer, and known to be associated with mutations that directly change the DNA, but additionally scientific evidence has demonstrated that there can be: alteration in the expression of the DNA, without changing the DNA, called epigenetics. Both processes result in aberrant manifestations of the genetic code.
Epigenetic Expressions Contributing to Cancer include
Silencing of tumor suppression
Activation of growth-promoting genes
Resistance to apoptosis
Alterations of the gene makeup increasing their mutation potential To compare direct DNA changes, versus epigenetic changes, imagine DNA as being the English instruction manual for putting together some apparatus that is written in Chinese. The concept related to a genetic mutation suggests that when the steps in the instructions were written, they were written incorrectly and then translated incorrectly, so the apparatus couldn’t be assembled accurately. Epigenetic change would imply that the original Chinese manual of instructions was correct, but when it was translated into English, some steps in the translation were incorrect, and again the apparatus could not be assembled.
Modifiable lifestyle factors: obesity, excessive stress, physical inactivity, excessive alcohol consumption, processed foods and poor diet and smoking are also recognized to pose long-term health risks producing chronic inflammation and the potential for cancer initiation or the development of autoimmune disease.
Persistent infections are highlighted as a significant source of inflammation and some bacteria, such as H. pylori, and viruses, such as Epstein-Barr, Hepatitis B & C and HPV, are oncogenic.
While others, Lyme disease and its co-infections, other herpes family viruses, mycotoxins, fungus, parasites and chronic intestinal dysbiosis become persistent due to difficulty treating, creating ongoing chronic inflammation.
Recognizing that these known causes are associated with the initiation of cancer as well as its recurrence offers opportunities for primary prevention and inhibiting or reducing recurrence risk following treatment, secondary prevention.
Understanding the dependence that cancer has on the microenvironment for its survival opens and encourages the development of new cancer therapies. By preventing its control of the host's cellular, structural and molecular systems deprives it of the necessary ancillary support it relies on.
Prevention
Examining the possibilities of toxic burden, lifestyle and persistent infection becomes an essential for both primary and secondary preventive actions to affect the tumor microenvironment. Certainly, in secondary situations of having completed treatments the initial approach, while similar to primary, must be slow and with a reduced dosage of any supplements or herbal therapies. Initiating intense action can cause ill effects, until recovery from the depletions of therapy have been corrected.
Many causes of chronic inflammation can be evaluated and preventive measures instituted.
First, clean water and air purification at home and/or work will offer a reduction in exposures plus washing fruit and veggies and buying organic or clean foods, if affordable. Another often overlooked issue are the ingredients not just in foods but skin care, makeup, and cleaning products.
There are also sophisticated laboratory tests available to assess many types of toxins. Stool testing is available to evaluate digestive function and the microbiome, if there are GI issues, alongside lab testing to uncover chronic infections. Knowing factors initiating chronic inflammation allows focusing on their reduction and removal.
On the website in-depth topics available:
cancer prevention through exercise / monographs on preventive supplements / diet recommendations for prevention / chronic infections/ Chinese medicine support during treatments/fasting / ultra processed foods / reducing toxic burden
Western Treatment Targets for the TME
Immune checkpoint drugs, PD-1 inhibitors, are a class of immunotherapy drugs that enhance the immune system's ability to fight cancer. Currently there are four, but the most familiar are Keytruda and Opdivo. Some cancer cells can make PD-L1 on their surface that when bound to PD-1 receptors on T cells stops them from attacking the tumor. The PD-1 drugs block this interaction enhancing the T cells response to the tumors.
As tumors grow, they outstrip their blood supply and create low oxygen levels in their environment causing them to stimulate the release of VEGF, vascular endothelial growth factor to promote new blood vessel growth to gain nutrients and be able to spread.
Antiangiogenic drug therapies are available that focus on inhibiting VEGF signaling to prevent the formation of new blood vessels.
An Antigen Presenting Cell Vaccine has been developed. A study from 2011 In patients with symptomatic or minimally symptomatic metastatic prostate cancer patients, resistant to hormone blockade used the sipuleucel-T vaccine called Provenge. It is thought to work by providing APCs, antigen presenting cells, to stimulate a T cell response targeted at prosthetic acid phosphate, an antigen highly expressed in prostate cancer cells. The vaccine uses the patient's own blood to isolate prostate antigen presenting cells including dendritic cells, growing them and then infusing them back into the patient.
The treatment group had improved overall survival, and a 22% overall reduced risk of death compared with controls.
Traditional Chinese Medicine
The metalloproteinases (MMP) are enzymes that degrade the structural components of the extracellular matrix and promote metastasis.
A study from 2013, Drs. Deng, Wang, Lu and others, evaluated the effects of the formula, Yi Qi Fu Sheng (YQFS), a qi tonic used for fatigue, weakness and depressed immune function. It is composed of the base of Astragalus, Ginseng and Licorice with the possible addition of Codonopsis, Red Date and Fresh Ginger according to symptom pattern.
In lab studies and mouse models of transplanted human colon cancer cells YQFS inhibited colon cancer cell proliferation and induced apoptosis. From the perspective of the TME, YQFS reduced tumor invasion and migration by inhibiting a mitogen activated kinase, a signaling molecule that inhibited metalloproteinase enzymes from breaking down the extracellular matrix (ECM).
In Chinese medicine, a diagnosis and the therapy provided is based on syndrome pattern differentiation. It uses the diagnostic techniques of history taking, palpation and examination to determine the core or "root" cause of the disease. And while therapy for symptoms are addressed, an important goal is treatment of the underlying fundamental driving factors.
A study used mice with transplanted pancreatic cancer as a model and established patterns of dysfunction that included dampness and heat, or poor digestion with inflammation, spleen deficiency or digestive weakness and blood stasis, a consequence of diminished vital qi energy from digestion being unable to circulate nutrients.
The findings revealed that each of these patterns created a different microenvironment, and based on the pattern presentation, affected the types of cytokines secreted and their effects on tumor growth. The researchers suggested that if a specific pattern could be differentiated for treatment the appropriate herbal treatment might influence the responses in the microenvironment.
Natural Therapies to Alter the TME
Targeting Lipid Metabolism in Cancer Therapy
Limiting lipid production in cancer cells impacts cell membrane function and interferes with signaling in the TME Dr Otto Warburg in the 1920s recognized that cancer cells utilize large amounts of glucose for metabolism and growth, called the Warburg Effect. He reported that they preferentially use a process called glycolysis as their primary source of energy, which secondarily also creates many needed building block materials for cancer growth. These include carbohydrates, proteins, nucleic acids and fatty acids.
Lipids are one group of molecules in the fatty acid family that in cancer cells serve as an energy source helping ATP energy production, sustaining cell membrane integrity, and the production of specific lipid signaling molecules. Cancer does this by generating the overexpression of signaling pathways that generate enzymes that use NADPH and acetyl-CoA from glucose and the amino acid glutamine to produce these lipids.
Because of these beneficial effects on cancer growth, they are an obvious target for cancer therapy.
Resveratrol and luteolin are capable of modulating crucial enzymes and signaling pathways that generate lipids by blocking the acetyl-CoA. Resveratrol can inhibit genes involved in lipid synthesis, and downregulates signaling pathways that increase apoptosis.
Curcumin and Berberine also interrupt metabolic pathways used for the biosynthesis of lipids,
Regulation of Immune Checkpoint Pathways
As discussed earlier, one approach to enhancing the immune system is to regulate immune checkpoint pathways in the TME. T cells have a protein, a PD-1 receptor, (programmed cell death receptor-1) that normally modulates the immune response to prevent overactive immune reactions. Some cancers can attach and hijack this inhibiting receptor, preventing the immune system from attacking it. Current immunotherapy drugs like Keytruda bind to this cancer inhibiting receptor, preventing its action allowing T cells to attack the cancer.
There are natural substances, baicalin, a glycoside derived from the Chinese herb scute, silibinin a component of silymarin from milk thistle, panaxadiol a biologically active compound from Panax ginseng and the Chinese herbal formula Ginseng and Astragalus that can regulate the signaling pathways that downregulate cancer's PD-L1 binding to the PD-1 receptor that inhibit T cell action. This allows the reprogramming of this immunosuppressive response allowing a greater T cell attack on the cancer.
Reactive oxygen species are essential for the activation of tumor-associated fibroblasts, TAFs. A component of the Chinese herb Pueraria, puerarin, was shown in mice models to downregulate ROS production and reduced TAFs by 6-fold in treated mice compared to controls and improved chemotherapeutic effects in a mouse model with triple-negative breast cancer, synergizing the blockade of the cancer PD-L1 that blocks the immune response.
Amino Acid Regulation
Amino acids are the building blocks of cellular proteins. Limiting their production interferes with nutrient availability for growth and limits the production of signaling molecules needed to recruit beneficial immune cells.
A 2000 year old Chinese herbal formula from the classic Chinese text, The Shang Han Lun, Huang Qin Tang, Scute and Licorice is a classic treatment for colitis and diarrhea. It has been shown to alleviate or delay colitis-associated cancer by maintaining amino acid homeostasis. The implication is that imbalance of the normal regulation of amino acids disrupted by colitis can lead to impaired immune function and gut health. It also modulates the signaling pathway PI3K/AKT/mTOR which is known to stimulate cancer growth. The formula, Wu Mei Wan, Mume, another colitis and diarrhea formula, has also been used, in mice, to block this pathway and prevent colitis-induced colon cancer.
Modifying the TME
Natural products also have the ability to reshape the TME to restore antitumor activity.
Genistein
Genistein is an isoflavone found in high concentrations in soybean and soy products.
There are Phase 1 & 2 randomized studies of men undergoing radical prostatectomy for localized prostate cancer. After treatment, testing was performed on some of the normal cells that were removed from the tissue with the idea that if left they could initiate cancer recurrence.
Metalloproteinase 2 is an enzyme that breaks down the extracellular matrix in the TME and allows cancer cells the ability to migrate and invade. Treating the tissue with genistein decreased MMP-2 gene expression by 24% supporting its link to decreasing prostate metastasis and mortality.
In a phase 2 study, men with progressive prostate cancer were given soymilk three times a day.
for 12 months. The rate of rise of the PSA is an indicator of cancer growth and the soymilk group had a decreased rate of rise indicating a slowing of cancer growth.
Curcumin
As noted above, cancer alters its terrain to provide advantage from immune evasion by generating an immunosuppressive environment, called immunoediting.
NF-kB is the master immune regulator but in cancer it becomes dysregulated. In the TME, it becomes activated and responds with the transcription of hundreds of genes that promote cytokines, cancer growth, new blood vessel formation and impaired immune actions.
Curcumin helps improve this dysregulation of NF-kB by decreasing inflammatory messages and reactivating the effectiveness of CD4 helper cells, natural killer cells and shifting M2 tumor promoting macrophages to M1 tumor suppressor macrophages.
It boosts the activity of immune cells that can recognize and destroy cancer cells while suppressing elements of the immune system that might protect the cancer. This balanced approach helps create an environment where the body can better fight cancer.
A major challenge with curcumin is its poor absorption by the body. However, this can be significantly improved by combining it with black pepper or natural cooking oils, increasing absorption by up to 40 times. This simple combination is more practical and cost-effective than more complex delivery methods.