A Glimpse into the Essence of Tumors and Cancer

窥见肿瘤与癌症本质的一隅——听徐鹰先生报告有感

A Glimpse into the Essence of Tumors and Cancer: Reflections on Mr. Xu Ying’s Report

Previous Understanding: Gene Mutation

From high school, I was taught that the cause of tumors and cancer is mutations in proto-oncogenes and tumor suppressor genes within cell DNA. Proto-oncogenes control cell proliferation, while tumor suppressor genes prevent uncontrolled cell growth. If a tumor suppressor gene fails due to mutation, it can lead to cancer. The human body contains over 30 trillion (3 * 10^19) cells, and each day, we produce and lose billions (10^10) of cells. The probability of a single gene mutating during each cell division is between $10^{-6}$ and $10^{-8}$, and the human genome has about 20,000 genes. Therefore, approximately $10^{-7}\cdot 10^{10}\cdot 2\cdot 10^5\approx 2\cdot 10^8$, or around two million cells, mutate daily. (Update: There are about 60,000 mutations, most of them point mutations, are mentioned in cancer informatics). This leads to the common assertion that our bodies produce many cancer cells each day.

New Perspective: Chronic Inflammation

However, today’s lecture provided a new understanding of tumor development. Professor Xu Ying posits that the onset of cancer is due to “chronic inflammation,” with gene mutations being the result of selection, not the cause. If certain factors (e.g., radiation, infection, tobacco) cause immune cells to continuously react to a specific area, chronic inflammation can occur. In the inflamed area, immune cells release hydrogen peroxide ($H_2{O}_2$) and superoxide ($O_2^{-}$) in an attempt to kill invaders. This chronic inflammation damages local tissues, triggering repair processes. During tissue repair, macrophages release growth factors and cytokines, leading to excessive cell proliferation and increased selective pressure due to oxidative stress.

First Pressure: Oxidative Stress

Oxidative stress occurs when the balance between oxidation and reduction in cells is disrupted, leading to an accumulation of reactive oxygen species (ROS) and reactive nitrogen species (RNS), which cause cell damage and dysfunction. ROS includes:

• Superoxide anion ($O_2^{-}$)
• Hydrogen peroxide ($H_2{O}_2$)
• Hydroxyl radical ($\cdot OH$)
• Singlet oxygen ($¹O_2$)

Hydroxyl radicals can be produced through the Fenton reaction: ${\text{Fe}}^{2+}+{\text{H}}_2{\text{O}}_2\to {\text{Fe}}^{3+}+\cdot \text{OH}+{\text{OH}}^{-}$ This reaction produces hydroxide ions, making the environment alkaline. This will be discussed later.

The development of tumors may be due to this oxidative stress. Cells need to eliminate free radicals to avoid death, creating selective pressure that leads to cancer.

Second Pressure: Hypoxic Stress

Why do tumor cells face hypoxic stress? The process where T cells release hydrogen peroxide and superoxide consumes a lot of oxygen, leading to the Warburg effect in cancer cells, where they use anaerobic respiration to produce energy. This method promotes cell proliferation:

Anaerobic Respiration and Cell Proliferation: Accumulation of Metabolites

A hypoxic environment causes the accumulation of glucose metabolites, which promote the synthesis of nucleotides and lipids, triggering further cell division. For instance, glucose-6-phosphate (G6P) can enter the pentose phosphate pathway to produce nucleotides; dihydroxyacetone phosphate (DHAP) can produce acetyl-CoA through the TCA cycle, contributing to lipid synthesis. These synthesized materials drive cell proliferation.

Possible Third Pressure: pH Stress

Changes in the tumor’s metabolic levels often require producing more hydrogen ions to neutralize the alkaline substances produced by the Fenton reaction. Tumor cells tend to undergo acidic mutations in their proteins. Tumor cells often use anaerobic respiration, known as the Warburg effect, which produces more acidic substances. Additionally, tumor cells favor purine synthesis, which generates extra hydrogen ions during the process. Tumor cells may utilize various biochemical pathways to produce more hydrogen ions to avoid alkalosis.

This point was not heavily discussed in the professor’s book but was a significant topic during the lecture. If my understanding of this part is incorrect, please correct me.（Update: Ref：Cancer Is A Survival Process under Persistent Microenvironmental and Cellular Stresses）

Tumor Progression: High-Frequency Mutations

Tumor cells may activate high-frequency mutation genes, similar to how B cells (a type of immune cell) produce antibodies. To produce suitable, diverse antibodies, B cells activate a gene that increases their mutation rate. In adenomas, Xu’s team also found that genes enabling high-frequency mutations in cells were activated. This activation might be due to oxidative stress. It is a cellular instinct to seek mutations for survival under high oxidative pressure. In ancient times, high oxidative pressure often indicated invaders, so cells released oxidizing agents to kill them. Cells would then seek mutations to co-evolve with invaders, enhancing their defenses.

Even though there are no invaders here, high oxidative pressure achieves a similar effect by activating the potential for high-frequency mutations.

From Tumor to Cancer: Invasion and Metastasis

“Cancer should be understood as the inevitable choice for cells to survive under increasing survival pressure in an increasingly hostile microenvironment; the microenvironment co-evolves with pathological cells, and the proliferation of pathological cells is the realization of their survival.” (Tumor Informatics, Xu Ying)

During cancer development, the Warburg effect accumulates a lot of lactic acid, killing surrounding normal cells and allowing cancer cells to invade nearby areas.

During metastasis, cancer cells face a completely different environment. From a previously hypoxic environment, metastatic cancer cells encounter a well-oxygenated environment. Due to prolonged hypoxia, the cholesterol content on their membranes is very low (as cholesterol synthesis requires oxygen). Cholesterol reduces oxygen permeability, so metastatic cancer cells face a high-oxygen environment, which is destructive due to oxygen’s oxidative properties. To adapt, metastatic cells must quickly accumulate cholesterol to reduce oxygen permeability and avoid death. They start synthesizing cholesterol, some of which gets oxidized. The oxidized part converts to sex hormones, further promoting the proliferation of these metastatic cells.

If the metastatic cells survive, they will grow in a new environment rich in growth factors and unaffected by immune responses. Targeting the cholesterol-to-sex hormone conversion process (as mentioned in the lecture) could be an effective pathway.

Insights

Avoid Anthropomorphic Descriptions

I noticed that many cancer researchers prefer anthropomorphic descriptions. We can compare cancer cells to survival-driven “villains,” with many interesting analogies. These analogies are engaging and help us understand and remember the properties of tumor cells. However, such analogies can be misleading.

For instance, tumors do not have free will. Tumor metastasis is not due to a transfer need (not the tumor’s subjective will) but results from multiple factors (such as lactic acid accumulation damaging tissues). Anthropomorphic descriptions can lead to errors like reversing cause and effect. Tumor metastasis results from tumor development, not its purpose.

Moreover, we should provide more examples. While understanding tumors, we might confuse concepts like “cause,” “result,”, “phenomenon” and “purpose.” For example, we previously understood “gene mutation” as the cause of tumors, but mutations are the inevitable result of environmental selection.

Importance of Biochemical Pathways

The frequently mentioned Fenton reaction, for instance. Inhibiting iron might also suppress cancer, like reducing iron intake. Iron can only be metabolized through blood loss. Discovering these meaningful conclusions requires a solid biochemical foundation. Understanding the entire cancer process and detailed analysis might reveal more significant conclusions. Combining this with relevant technologies, such as AI, could lead to more meaningful research topics.

Others

It was fortunate to listen to such an enlightening lecture on my birthday and write my first blog post. This blog might contain many errors, as I study computer science and have a weak biochemical background. Apologies for any mistakes or misguidance. Some aspects, like why cancer tends to produce hydrogen atoms and their relationship with the high pH inside and low pH outside cancer cells, were beyond my research capacity to conclude satisfactorily.

Professor Xu Ying mentioned that tumor research is currently in a golden era. With a deep understanding of tumors, even casual classroom assignments can become interesting topics. Continuous learning, accumulation, and reading will eventually yield rewards.

徐鹰 - 师资概况 - 南方科技大学 (sustech.edu.cn) YING XU - Faculty - SUSTech

Ref

[1] 《肿瘤信息学》，徐鹰