Holistic cancer causes—the story continues.
Redox
Redox is short for reduction and oxidation. The foundation of redox is electrons. Going back, aways, I know. Reduction is the process of gaining electrons. Oxidation is the process of losing electrons. In a very similar way, even connected, think of this redox balance as a buffering homeostasis mechanism used by the body.
The older, general thought was that increased Reactive Oxygen Species (ROS) were the result of redox imbalance. This imbalance would then lead to oxidative stress or what I like to call cellular rust. The idea is that oxidation requires a counter, a buffer if you will, to prevent unrepairable damage to cell structures, i.e., DNA, proteins, cell membranes… The imagery of cellular rust creates a good teaching picture. Take a car, for example, a car left out in the elements will develop a lot of rust. The car still looks like a car but lacks the luster of its youth. The door doesn’t open right, the car doesn’t turn over well…he car simply doesn’t run as it once did. The knowledge of Reactive Nitrogen Species (RNS) and Reactive Sulphuric Species (RSS) expands the impact of redox.
The thinking used to be that that redox was only a negative process via the oxidation requiring reduction and detoxification. Now, a new discovery is changing the entire thinking around redox. More and more, the discussion is around redox potential as a necessary cellular process for communication. Redox potential is a part of the internal cell signaling system [i]. In essence, redox modifies internal signaling to create these secondary messengers via the addition or removal of electrons. Let me restate that. Redox potential is key to cell communication, to cell healing potential, to cell survival potential, and to cancer potential. Redox is key to cell internal and cell-to-cell communication and redox imbalance equals cell communication imbalance. No longer is redox simply an oxidative, destructive process. Instead, redox signaling is a normal cell messaging system that is hijacked by cancer to promote cancer growth, treatment resistance, and metastatic spread [ii] [iii].
This is what I love about science and medicine: new questions produce new answers, which provide new thoughts, which challenges entrenched paradigms to break down walls of rigid thinking. Unfortunately, this creates new walls and paradigms, which should lead to further questions. Science and medicine are for the curious mind. Unfortunately, curious minds need not apply in the current scientific, medical environment, only adherence and loyalty to the system. That is a different topic for a different day.
Tumor Microenvironment (TME)
The perfect example of new thinking through discovery is the TME. Sounds kind of like the TMZ zone between North and South Korea, but the similarity of sounds is as close as they come. The TME is an environment where tumor meets the body. No longer can a cancerous tumor be said to be a solid ball of cells entirely walled off from the body. The TME is a transition zone between cancer and non-cancer. As much as the TME is key to cancer growth, the same TME is key to cancer suppression.
The authors of a 2019 article, Effect of tumor microenvironment on pathogenesis of the head and neck squamous cell carcinoma: a systematic review [iv], said it well:
“The outlook on cancer has changed dramatically and the tumor is no longer viewed as a bulk of malignant cancer cells, but rather as a complex tumor microenvironment (TME) that other subpopulations of cells corrupted by cancer cells get recruited into to form a self-sufficient biological structure. The stromal component of the tumor microenvironment is composed of multiple different cell types, such as cancer-associated fibroblasts, neutrophils, macrophages, regulatory T cells, myeloid-derived suppressor cells, natural killer cells, platelets and mast cells”.
The TME can be anywhere and everywhere. A TME exists around a primary tumor. A TME exists around bone metastasis, liver metastasis, and lung metastasis. It can even be said that a TME exists around circulating tumor cells (CTC) as they interact with the cells of the body. Where ever there is an interaction between the cancer cells and the cells of the body, a TME exists.
To better understand the TME, it helps to understand what makes up a TME. According to current published evidence 1 [v] [vi] [vii], the TME consists of:
- Cancer cells
- Cancer-associated fibroblasts
- Tumor-associated macrophages
- Natural Killer cells
- Treg regulatory T cells
- Tumor-associated neutrophils
- Myeloid-derived suppressor cells
- Platelets
- Endothelial cells
- Mast cells
- Extracellular matrix
The TME is not a singular process. Wherever circulating tumor cells (CTC) land and prosper, so is created a TME. Just as there are millions of cancer cells in a primary tumor, and just as there are millions of circulating tumor cells released from the primary tumor, so are there likely millions of TME. It is simply an interaction zone between a collection of tumor cells and the body. It is the front line. It is the battleground of acid/base, redox potential, ROS, immune system activity, altered cellular metabolism that can be used by cancer to survive and thrive or by the body or therapies to target and eliminate cancer.
Immune dysfunction
There are two answers to cancer: the prevention of cancer and the immune system. The first and best answer is always never to get cancer. However, if cancer occurs, the best answer to cancer is not found in a drug, in surgery, or radiation. The answer is the immune system—the already present, though dysfunctional immune system. The immune system is the integrated, created defense system designed to protect the body from all invaders, foreign and domestic. Foreign invaders would be viruses, bacteria, and parasites. Cancer falls into the domestic category. Dysfunction and suppression of the immune system is key to cancer survival, growth, spread, and metastasis [viii] [ix]. Equally important, the support and targeting of the immune system is a significant answer to the many questions that is cancer.
Though cancer is an adaptation to its environment for the purpose of survival, cancer manipulates the local environment to further its survival [x]. For cancer to survive and thrive:
- cancer must change the tumor microenvironment (TME)
- undergo epithelial to mesenchymal change
- invade locally
- avoid apoptosis (programmed cell death)
- change genetic expression (epigenetics)
- get mobile
- recruit lymphatics (lymphagenesis)
- recruit vascular supply (angiogenesis)
- intravasate
- disseminate
- extravasate
- physically escape the primary tumor
- escape the immune system
- Circulate systemically
- metastasize
As important as these steps are, immune suppression and immune escape are critical to tumor survival locally and its spread systemically. What is very interesting is that maximum tolerated chemotherapy has been shown to play a role in the acceleration of TME manipulation to promote the metastatic spread of cancer [xi] [xii] [xiii].
Hormones
I have written so much about hormones over the years. So much can be said about hormones: hormones are signals, hormones are a language, hormones are a means of communication, hormones are metabolites, hormones can be toxins. Hormones are so much more than a number. The old cliche still works best—hormones are best when working together in symphony. Men are not just testosterone; no more than women are only estrogen. It is amazing how long that marketing bit has stuck in the general consciousness. There was a marketing slogan for a while, “know your number”…as if health was simply a number of a hormone. So factually and intellectually dishonest. A balanced hormone symphony requires:
- proper hormone evaluation
- knowledge of hormone levels
- hormone balance
- knowledge of hormone metabolites
- hormone receptors
- understanding of outside influences
- physiologic hormone therapy if required
Hormone metabolites are often overlooked and are the most under-appreciated perspective of hormones. Yet, from a cancer perspective, they can be the most impactful. Hormones are much more than just “know your number,” whether high or low. In many cases, with cancer, what the body is doing with the hormones through metabolism is the actual problem. Actual estrogen levels can be low in ER+ breast cancer, but the metabolism of estrogens produces metabolites that are even more estrogenic and more carcinogenic than the parent compound itself.
Not to leave progesterone out of the mix, the general call is that all progesterone is safe in women with breast cancer. From a hormone metabolite perspective, irrespective of the PR status, that could not be further from the truth. If a woman has dominant 5-alpha reductase enzyme activity, then the resulting progesterone metabolites can increase breast cancer risk through the production of 5alpha-pregnane metabolites [xiv] [xv] [xvi]. But, if the 4-pregnenes are the dominant progesterone metabolite pathway, then progesterone does appear to reduce breast cancer risk [xvii] [xviii]. What the body does with the hormones is just as important, if not more important, then the number of the parent hormone.
The hormone metabolite story doesn’t apply just to women. Take testosterone and colorectal cancer, for example. Colorectal cancer can be estrogen-sensitive. Yes, I realize that estrogen is not testosterone; that is where hormone metabolism comes into play. Testosterone therapy in men with colorectal cancer with low testosterone, but high estradiol from high aromatase enzyme activity, will result in adding fuel to the fire of colorectal cancer. Let me explain. Aromatase is the enzyme that is responsible for testosterone to estradiol conversion. In men, it is abdominal fat that drives this show. With current numbers, published by the National Institutes of Health, at 73.7% of adult men either overweight or obese, this show is on full display for all to see. It is elevated estradiol and other estrogens, from abdominal fat, which are the primary cause of low testosterone in middle-aged to older men. In this example, which is far too common in men these days, testosterone therapy would drive estradiol production due to elevated aromatase activity to increase drive cancer growth [xix]. Only focusing on a hormone number without a big picture hormone metabolism perspective can provide fuel for the fire of cancer and make matters worse.
[i] Kim, E.-K.; Jang, M.; Song, M.-J.; Kim, D.; Kim, Y.; Jang, H.H. Redox-Mediated Mechanism of Chemoresistance in Cancer Cells. Antioxidants. 2019, 8, 471.
[ii] Kim EK, Jang M, Song MJ, Kim D, Kim Y, Jang HH. Redox-Mediated Mechanism of Chemoresistance in Cancer Cells. Antioxidants (Basel). Oct 2019;8(10):471. doi:10.3390/antiox8100471
[iii] Kim EK, Jang M, Song MJ, Kim D, Kim Y, Jang HH. Redox-Mediated Mechanism of Chemoresistance in Cancer Cells. Antioxidants.2019; 8.471.
[iv] Peltanova, B., Raudenska, M. & Masarik, M. Effect of tumor microenvironment on pathogenesis of the head and neck squamous cell carcinoma: a systematic review. Mol Cancer. 2019;18(63). https://doi.org/10.1186/s12943-019-0983-5
[v] Ribeiro Franco PI, Rodrigues AP, de Menezes LB, Pacheco Miguel M. Tumor microenvironment components: Allies of cancer progression. Pathol Res Pract. 2020;216(1):152729. doi:10.1016/j.prp.2019.152729
[vi] Hinshaw DC, Shevde LA. The Tumor Microenvironment Innately Modulates Cancer Progression. Cancer Res. 2019;79(18):4557-4566. doi:10.1158/0008-5472.CAN-18-3962
[vii] Wei R, Liu S, Zhang S, Min L, Zhu S. Cellular and Extracellular Components in Tumor Microenvironment and Their Application in Early Diagnosis of Cancers. Analytical Cellular Pathology. Jan 2020; https://doi.org/10.1155/2020/6283796
[viii] Santegoets SJ, Welters MJ, van der Burg SH. Monitoring of the Immune Dysfunction in Cancer Patients. Vaccines (Basel). Sep 2016;4(3):29. doi:10.3390/vaccines4030029
[ix] Swartz MA, Iida N, Roberts EW, Sangaletti S, Wong MH, Yull FE, Coussens LM, DeClerck YA. Tumor microenvironment complexity: Emerging roles in cancer therapy. Cancer Res. 2012;72:2473–2480. doi: 10.1158/0008-5472.CAN-12-0122.
[x] Yu Y, Cui J. Present and future of cancer immunotherapy: A tumor microenvironmental perspective. Oncol Lett. 2018;16(4):4105-4113. doi:10.3892/ol.2018.9219
[xi] Karagiannis GS, Condeelis JS, Oktay MH. Chemotherapy-induced metastasis: mechanisms and translational opportunities. Clin Exp Metastasis. 2018;35(4):269-284. doi:10.1007/s10585-017-9870-x
[xii] Karagiannis GS, Condeelis JS, Oktay MH. Chemotherapy-Induced Metastasis: Molecular Mechanisms, Clinical Manifestations, Therapeutic Interventions. Cancer Res. 2019;79(18):4567-4576. doi:10.1158/0008-5472.CAN-19-1147
[xiii] Perelmuter VM, Tashireva LA, Savelieva OE, et al. Mechanisms behind prometastatic changes induced by neoadjuvant chemotherapy in the breast cancer microenvironment. Breast Cancer (Dove Med Press). 2019;11:209-219. doi:10.2147/BCTT.S175161
[xiv] Wiebe JP, Lewis MJ. Activity and expression of progesterone metabolizing 5alpha-reductase, 20alpha-hydroxysteroid oxidoreductase and 3alpha(beta)-hydroxysteroid oxidoreductases in tumorigenic (MCF-7, MDA-MB-231, T-47D) and nontumorigenic (MCF-10A) human breast cancer cells. BMC Cancer. 2003;3:9. doi:10.1186/1471-2407-3-9
[xv] Wiebe JP, Zhang G, Welch I, Cadieux-Pitre HA. Progesterone metabolites regulate induction, growth, and suppression of estrogen- and progesterone receptor-negative human breast cell tumors. Breast Cancer Res. 2013;15(3):R38. doi:10.1186/bcr3422
[xvi] Wiebe JP, Rivas MA, Mercogliano MF, Elizalde PV, Schillaci R. Progesterone-induced stimulation of mammary tumorigenesis is due to the progesterone metabolite, 5α-dihydroprogesterone (5αP) and can be suppressed by the 5α-reductase inhibitor, finasteride. The Journal of Steroid Biochemistry and Molecular Biology. May 2015;149:27-34.
[xvii] Wiebe JP, Lewis MJ, Cialacu V, Pawlak KJ, Zhang G. The role of progesterone metabolites in breast cancer: Potential for new diagnostics and therapeutics. The Journal of Steroid Biochemistry and Molecular Biology. Feb 2005;93(2-5)
[xviii] Wiebe JP, Souter L, Zhang G. Dutasteride affects progesterone metabolizing enzyme activity/expression in human breast cell lines resulting in suppression of cell proliferation and detachment. The Journal of Steroid Biochemistry and Molecular Biology. Aug 2006;100(4-5):129-140.
[xix] Tan RS, Cook KR, Reilly WG. High estrogen in men after injectable testosterone therapy: the low T experience. Am J Mens Health. 2015;9(3):229-234. doi:10.1177/1557988314539000
