This article is the first part of Chapter 12 of The Declaration of the Age of Physical Medicine (Yoon Jong-won). It is an academic exposition presenting the author's hypothesis of physical medicine, and the body text, figures, and citations follow the original manuscript.
Cancer occupies the largest proportion in the cause-of-death statistics of Korea and the United States. The report that the age-adjusted cancer mortality rate in the United States decreased by 33% between 1991 and 2021 shows the fact that half a century of humanity's effort has borne clear fruit. But looking at the reverse side of the same statistics, pancreatic cancer, hepatocellular carcinoma, and glioblastoma at the progressive stage remain, for decades, in a domain where the indicators have hardly improved. It is a situation in which the conquered domain and the not-yet-conquered domain are clearly divided.
This asymmetry leaves one question. Why is some cancer easy to conquer, and some cancer so difficult? In the previous chapter we already presented one answer. It is the explanation that the fundamental cause of aging and chronic disease is microcalcification, and that the 200-some diagnostic names are expressions branching from one underlying reality. Then where is cancer located? Does it belong to the domain of microcalcification, or to a completely different domain?
The answer to this question is not simple. It is because cancer is not a single disease. Cancer is divided roughly into five branches according to the cause of occurrence. First, cancer arising as environmental factors pile up (aging-related adult solid cancer); second, cancer due to genetic factors (BRCA1, Lynch syndrome, Li-Fraumeni syndrome); third, cancer whose cause is a virus (cervical cancer, hepatocellular carcinoma, HTLV-1); fourth, cancer arising from a problem in the early stage of development (childhood cancer); and fifth, cancer that begins in the blood (blood cancer). These five branches each have a different "first button" of onset.
The Age of Physical Medicine possesses a language optimized for explaining the first of these branches, "aging-related adult solid cancer." Colorectal, breast, prostate, gastric, liver, pancreatic, lung, kidney, endometrial, bladder, and esophageal cancers, and so on, correspond here. These cancers commonly have a sharply rising incidence after the forties, and grow upon a soil in which the harsh environment of hypoxia, acidosis, inflammation, and microvascular abnormality has accumulated over a long time. Here we can derive one proposition. Aging-related adult solid cancer is a result appearing from the accumulation of an environment with the same root as microcalcification, that is, the bone-calcium outflow "DIAH trigger." Therefore, rather than asserting microcalcification as the sole cause of cancer, it is valid to see cancer and microcalcification as twin-like products born in the same environment.
Of course, cancers whose cause of onset is not the environment lie outside this proposition. But there is one decisive fact that runs through all cancers. Even if the beginnings are each different, from the moment the tumor grows beyond a certain size, the same "microenvironment" is made inside all of them. Oxygen becomes short (hypoxia), the environment turns acidic (acidosis), and chronic inflammation takes root. In the end they fall into the situation of "dual blockade," in which abnormal blood vessels and tissues block the supply of nutrition and the discharge of waste simultaneously. This exactly matches the physicochemical environment that aging-related cancer has slowly made over decades. The proposition that "the beginnings differ but the gate passed through is the same" means precisely this fact.
The body proceeds in the following order. First we set the boundary of the cancer we handle, and examine the asymmetry of the conquered domain and the not-yet-conquered domain. Next we analyze the four axes of the tumor microenvironment and the molecular mechanism of Overflow & Burst, the fifth 7M pattern.
Then we propose the "fifth layer," which intervenes in the environment upon the frame of existing treatment, and unravel the viewpoint that all cancers in the end meet at the same root and converge on the same solution, that is, the proposition that "the beginnings differ but the gate passed through is the same." When we reach the end of this process, the logical spine that runs through the Age of Physical Medicine will become clear.
The Boundary of This Chapter: Which Cancer Do We Handle
The core proposition that sustains the Age of Physical Medicine is established in two stages. The upper proposition is that, at the dimension universal to the cosmos, the cause of the collapse of all things is the dual blockade by gradient, and the lower proposition is that, at the dimension of the human body, the fundamental cause of aging and chronic disease is microcalcification. On the basis of these two propositions the following proposition is derived. Aging-related adult solid cancer and microcalcification are two products born in the same environment (the accumulation of the DIAH trigger).
The domain to which this proposition applies is adult solid cancer that comes together with aging. Colorectal cancer, breast cancer, prostate cancer, gastric cancer, hepatocellular carcinoma, pancreatic cancer, lung cancer, kidney cancer, endometrial cancer, bladder cancer, esophageal cancer, and so on correspond here. These cancers commonly have an incidence that rises steeply after the forties, and grow upon a soil in which the DIAH triggers (deficiency, inflammation, acidosis, hypoxia) have accumulated over a long period. It is a point that exactly matches the environmental conditions of microcalcification handled in the previous chapter.
But there are cancers that the language of this proposition does not reach. First, childhood cancer begins from an abnormality in the process of embryonic development or from a mutation in early life, so it does not pass through a long-term environmental accumulation path. Second, hereditary cancer syndromes in which a genetic factor (germline mutation) is the primary cause, such as BRCA1-related breast and ovarian cancer, Lynch syndrome-related colorectal cancer, and Li-Fraumeni syndrome, are also not unraveled by the language of environment alone. Third, cancers in which infection is the primary cause, such as human papillomavirus-related cervical cancer, hepatitis B and C virus-related liver cancer, and HTLV-1-related adult T-cell leukemia, are also outside this domain. Fourth, most blood cancers including acute leukemia are also in a domain different from the environmental accumulation path.
The reason for clearly pointing out this boundary is simple. It is because the language of microcalcification and environment has the most powerful explanatory force in cancers where the environment is the main stage of onset. If this is forcibly extended to cancers in the outer domain, the explanatory force drops and only misunderstanding increases. We make clear once more the viewpoint that microcalcification is not asserted as the sole cause of all cancers. Cancers whose primary cause is not the environment must first be handled at the onset stage with suitable languages such as genetic testing and preventive surgery, vaccination and infection management, and a developmental approach.
However, we add one fact. Cancers outside this proposition also pass through exactly the same bottleneck section as aging-related cancer in their progression path after onset. Whether hereditary cancer or viral cancer, from the moment the tumor grows beyond a certain size, hypoxic regions arise inside it, acidosis follows, and chronic inflammation becomes fixed. In the end the scenery of dual blockade unfolds, in which an abnormal vascular network and stroma collapse supply and discharge simultaneously.
This is the same as the physicochemical environment that aging-related cancer slowly created over decades. The starting points differ from one another, but the grammar of the environment that accelerates progression is one. The proposition that "the beginnings differ but the gate passed through is the same" points precisely to this fact. This proposition will be unraveled in detail again later.
Figure 1 organizes the place where the language of environment applies and the domains outside it. You can see at a glance the structure in which the 11 kinds of aging-related adult solid cancer are within the domain of environment, and the four branches of cancer outside the boundary, though their causes of onset differ, pass through exactly the same bottleneck section (dual blockade) at the progression stage.
[Figure 1] Cancers the Language of Environment Reaches and Cancers Beyond
| Branch | Primary cause | Language of the onset stage | Bottleneck of the progression stage |
|---|---|---|---|
| Aging-related adult solid cancer | Accumulation of the DIAH trigger environment | The same environment as microcalcification | Dual blockade |
| Hereditary cancer | Germline mutation | Genetic testing, preventive surgery | Dual blockade (the same bottleneck) |
| Cancer with a virus as primary cause | Infection (HPV, HBV, HCV, HTLV-1) | Vaccination, infection management | Dual blockade (the same bottleneck) |
| Childhood cancer, blood cancer | Early development, blood | Developmental approach | Dual blockade (the same bottleneck) |
The Conquered Domain and the Not-Yet-Conquered Domain
Half a century has passed since U.S. President Nixon declared the "War on Cancer" in 1971. During this period humanity has poured enormous resources into cancer research. The annual budget of the U.S. National Cancer Institute (NCI) has exceeded 7 billion dollars, and at one time clinical trials of cancer treatments expanded to occupy half of all pharmaceutical trials worldwide. This investment has clearly borne fruit. Science and technology became precise down to the molecular unit, countless targeted therapies and immunotherapies were introduced, and the accuracy of imaging diagnosis and early detection also developed by leaps.
Looking at the specific achievements, based on the American Cancer Society (ACS) report, the age-adjusted cancer mortality rate decreased by about 33% between 1991 and 2021, and thanks to this about 4.1 million lives are estimated to have been additionally saved. The five-year survival rate of certain cancers has improved dramatically. Childhood acute lymphoblastic leukemia, which was practically incurable in the 1960s, now shows a cure rate close to 90%, and chronic myeloid leukemia entered a domain manageable over the long term after the appearance of "Gleevec." Breast cancer, too, has exceeded a five-year survival rate of 90% with the establishment of early screening and hormone therapy.
But the other side is still dark. There are domains where half a century of investment still runs into a wall. The five-year survival rate of pancreatic cancer has hardly moved for decades from the low 10-percent range (about 13% by U.S. standards), and the progressive-stage survival rates of liver cancer and biliary tract cancer are at a similar level. Lung cancer's overall survival is rising thanks to the latest treatments, but it is still the number-one cause of cancer death, and long-term survival at the progressive stage is limited. Ovarian cancer, esophageal cancer, and glioblastoma are the same. Above all, for any cancer, once "distant metastasis" has occurred, long-term survival is still difficult.
This "asymmetry" is the starting point of this chapter. By what are the conquered domain and the not-yet-conquered domain divided? In cancers where early detection is possible, or where a single molecular target is clear, where hormone dependence is strong or the immune system already recognizes them, there has been dazzling progress. On the other hand, in cancers where the microenvironment is complex, cell-to-cell heterogeneity is high, detection is late, and metastasis has already progressed, progress has been slow.
The mainstream strategy of modern oncology is to attack "the cancer cell itself." Toxic anticancer drugs interfere with the cell's DNA replication, targeted therapies suppress mutant proteins, and immunotherapies help the immune system find cancer cells. This strategy is clearly effective. The tumor shrinks and the figures improve. But in many cancers, especially at the progressive stage, the cancer returns after a few months or a few years. Cancer cells of a different nature grow, and lesions appear in other organs.
Existing medicine explains the reason for this frustration as "resistance" and "heterogeneity." It is the explanation that since cells with various mutations are mixed together from the beginning, the tough cells that survived the treatment grow again. At the molecular level it is an accurate explanation. But the question remains. Why are such resistant cells reborn so repeatedly, in a form common to countless patients?
The answer of the "language of gradient" is precisely "environment." The microenvironment of the tissue where the tumor has settled is a harsh ecosystem in which hypoxia, acidosis, chronic inflammation, and abnormal vascular structure are tangled together. For a cell to survive in such an environment it must turn on a special "adaptation program" it does not normally use. It must change its metabolic method, forcibly draw in blood vessels, evade immune surveillance, and even acquire the ability to move across tissue boundaries. The beings that survived this harsh adaptation training are precisely what we call "cancer cells." Cancer is not a simple rebellion of cells but is also a product made by the environment.
This shift of viewpoint is the core. If the environment stays as it is, even if a particular cancer cell is killed, the environment applies the same pressure and makes new cancer cells. Even if one defeats the cell, the soil makes new cancer cells grow. Now we must note that it is not only the tumor that has resistance, but that the environment itself is the stage that makes resistance. If this perspective is correct, we must look more deeply, at the molecular level, into what the environment is and how it operates. That is the subject of the following article.
[Figure 2] The Conquered Domain and the Not-Yet-Conquered Domain: The Scenery of Asymmetry
| Domain | Example cancer types | Change in five-year survival rate | Deciding factor |
|---|---|---|---|
| Conquered domain | Childhood ALL, CML, breast cancer (early) | Practically incurable → 90%↑ | Single molecular target, hormone, early detection |
| Partial progress | Colorectal cancer, melanoma, lung cancer (targeted group) | 30-50% → 60-80% | Targeted, immunotherapy, screening |
| Domain blocked by a wall | Pancreatic cancer, hepatocellular carcinoma (progressive), glioblastoma | Around 10% (stagnant for decades) | Complex microenvironment, molecular heterogeneity, metastasis |
The Tumor Microenvironment: The Result of Environment
The place where a tumor grows is in itself a unique ecosystem. Since Judah Folkman proposed the tumor's dependence on blood-vessel formation in the 1970s, the research of the past half century has revealed the reality of this ecosystem in detail. The components of the tumor microenvironment are divided roughly into four. First, the vascular network made by abnormally proliferated endothelial cells. Second, the stroma formed by activated fibroblasts and immune cells. Third, the metabolic products and signaling molecules that tumor cells emit. Fourth, the physicochemical conditions of hypoxia, acidosis, inflammation, and gradient collapse that all these elements tangle together to make.
From the physical-medicine perspective, the most core one is precisely the fourth condition. For the cells of our body to survive, they must be supplied with oxygen and glucose from the microvasculature. Generally the distance that nutrients can reach by diffusion alone is within 100 to 200 micrometers, and in places such as the brain or myocardium it must be very close, around 20 micrometers, for the balance of supply and discharge to be maintained. As a tumor grows it makes blood vessels itself, but unlike normal blood vessels these vessels are loose in structure and irregular in flow, so the blood flow stagnates or flows backward. As a result, a chronic "hypoxic region" becomes fixed inside the tumor.
Hypoxia is the central trigger that moves this ecosystem. When oxygen becomes short, the cell turns on a switch called "hypoxia-inducible factor (HIF-1α)." This switch simultaneously activates hundreds of genes, and astonishingly, that list almost exactly matches the characteristics of cancer cells. It calls forth new blood vessels, increases glucose uptake, regulates acidity, and produces enzymes that help cell migration. That is, many characteristics of cancer cells are the result of an "adaptation program" to survive in the environment called hypoxia.
To this "acidosis (acidic state)" is added. When a cell in a hypoxic state breaks down only sugar to make energy, lactate and hydrogen ions pour out. Because of this the tumor tissue comes to be far more strongly acidic than normal. This acidic environment is fatal to normal cells but becomes an advantageous fortress for cancer cells that have already finished adapting. Acidosis saps the strength of immune cells and activates enzymes that break down tissue, helping the invasion and metastasis of cancer.
"Chronic inflammation" is the fourth axis. The immune cells and stromal cells gathered around the tumor continuously send inflammation signals. This is like the signal to begin healing when a wound has occurred not turning off and repeating infinitely. The intuition that the 19th-century pathologist Virchow saw through, that "a tumor is a wound that does not heal," has been proven by modern science. This inflammation causes DNA damage and powerfully supports the survival and proliferation of cancer cells.
These four axes interlock and turn like gears. Hypoxia calls forth inflammation, inflammation worsens acidosis, acidosis fixes vascular abnormality, and this again deepens hypoxia. The DIAH triggers handled earlier (deficiency, inflammation, acidosis, hypoxia) are circulating just the same inside the tumor. The four gates that open at the threshold of death, the four gates that are pulled in everyday chronic disease, and the four gates that surge inside the tumor are in the end merely different forms of the same underlying reality.
In fact, the vascular calcification or inflammation that appears in the tissue of chronic-disease patients is physicochemically connected to the background environment in which cancer arises. That chronic-disease patients easily contract cancer is not a coincidence but because they are two fruits growing in the same soil. The proposition that microcalcification and adult solid cancer share the same environmental root gains its validity here.
In the end the tumor microenvironment is a scenery in which the human body's "gradient" has extremely collapsed. As the roads of supply and discharge were blocked, the cell converted into a mode only for survival, and as that process lengthened it rushed toward uncontrollable proliferation and migration. Seen from this viewpoint, cancer is not a betrayal by cells but a tragic terminus created by the collapse of an environment left neglected for too long.
[Figure 3] The Four Axes of the Tumor Microenvironment: The DIAH Trigger Circulating Inside the Tumor
| Axis | DIAH | Form inside the tumor | Molecular mediator |
|---|---|---|---|
| Hypoxia (H) | Oxygen shortage | 50-150μm hypoxic region | HIF-1α → VEGF, GLUT1 |
| Acidosis (A) | Acidic environment | pH 6.7-7.1 (normal 7.4) | Lactate, hydrogen ions |
| Inflammation (I) | Chronic inflammation | A wound that does not heal | TAM, NF-κB, cytokines |
| Deficiency (D) / gradient collapse | Supply and discharge cutoff | Gradient blockade circuit | Abnormal vascular network, stroma |
The Biology of the Fifth 7M, Overflow & Burst: Calcium Signaling and Metastasis
Earlier we examined the seven damage patterns in which the human body's dual blockade appears organ by organ, that is, the "7M." Among them the fifth, Overflow & Burst, refers to the phenomenon in which cells excessively proliferate or hypertrophy. Cancer is the most extreme expression of this Overflow & Burst, and the core molecular-level mediator that raises this phenomenon is precisely the calcium emphasized in the previous chapter.
In a normal cell the calcium concentration inside and outside the cell maintains a gap (gradient) of about ten thousand-fold. The calcium pump of the cell membrane consumes energy and strictly keeps this gradient. Then when the cell receives an external signal, for a very brief moment this gate opens so that the calcium concentration soars and then returns to its place, and this momentary "calcium wave" plays the role of a switch deciding the cell's division, migration, and death. A healthy cell controls this switch very precisely.
But in cancer cells this control is completely broken. When the calcium pump breaks down in a state of hypoxia and acidosis, the calcium concentration inside the cell stays in a chronically elevated state. According to several studies, in cancer cells the channels that let calcium in increase and the pumps that bail it out again decrease, in a reconfiguration. As a result the cell's proliferation and survival signals stay continuously on, and even damaged cells that should originally die survive and expand their power. Calcium itself is not a toxin, but it becomes the mediator that fixes the cell's growth switch in a broken state.
This structure is revealed most clearly in hepatocellular carcinoma. The hypoxic, inflammatory, and acidotic environment accumulated through hepatitis and cirrhosis in the end leads to the collapse of the calcium regulation system and the activation of the Overflow & Burst program. This is the same in diseases such as myocardial hypertrophy, telling us that the core key of every "Overflow & Burst" pattern in which a cell abnormally enlarges, even if not cancer, is calcium.
The "Warburg effect," in which cancer cells break down sugar and emit lactate instead of using oxygen even in situations where oxygen is sufficient, can also be seen again from an environment-centered viewpoint. In the past this was regarded as a genetic breakdown inside the cell, but the latest studies interpret it as a "rational adaptation" of the cell to survive in a harsh environment. The environment changes the cell's metabolic method, and the changed metabolism again makes the surrounding environment acidic and the environment harsher, so that a bidirectional feedback operates.
The metastasis stage, in which cancer decisively threatens the patient's life, is also clearly explained by the "language of gradient." The "seed and soil" hypothesis proposed in the 19th century has been proven in modern science by the concept of the "pre-metastatic niche." The primary tumor sends signaling substances in advance through the blood, changing the environment of a distant organ beforehand into a soil good for cancer cells to settle in.
From the viewpoint of gradient, metastasis occurs when the primary tumor and the organ to be metastasized to share a common "gradient collapse pattern." For example, if the bone has already weakened from osteoporosis and so on, or the liver has fallen ill with fatty liver or chronic inflammation, the soil in which the seed of cancer will take root is as good as already prepared. Therefore, as much as the effort to kill the cancer cells themselves, managing in advance and healthily the environment of the organ that metastasis will reach (microvascular health, metabolic and inflammatory figures) can become a practical solution that lowers the success rate of metastasis. We will confirm the specific clinical grounds for this in the following article.
[Figure 4] The Molecules of the Fifth 7M, Overflow & Burst: The Unleashing of Calcium Signal Control and Metastasis
| Molecule | Normal state | Cancer state | Basis |
|---|---|---|---|
| Calcium channel | Active only when needed | TRPV6, TRPC6, ORAI1 ↑ | Monteith 2017 |
| Endoplasmic reticulum pump | Reuptake active | SERCA ↓ | Monteith 2017 |
| Transcription factor | Momentary activation | NFAT, CREB, NF-κB chronically active | Cui 2017 |
| Metabolism | Oxidative phosphorylation | Warburg (glycolysis) | Vander Heiden 2009 |