Cancer signaling pathways (pathways)

Content:

Summary (scroll down)
Review of signaling pathways (scroll down)
Overview of agents that block the individual signaling pathways (scroll to)
Links (scroll to)

Summary about cancer signaling pathways

The basic principle – cancer’s broken switches:

Cancer cells survive and grow by abusing the body’s normal internal communication systems, the so-called signaling pathways. You can imagine that the cancer cell’s built-in accelerators for growth are stuck, while its safety brakes are broken.

The strategy – targeting the weak points:

This section provides an overview of substances – both repurposed drugs and dietary supplements – being investigated for their ability to repair or block these failed signals. An effective strategy is usually to combine several substances so that the cancer cell is attacked from multiple angles at once.

Purpose and warning:

The purpose is to provide knowledge and inspiration for a conversation with a qualified practitioner.

The overviews are a tool for dialogue and must never be considered a guide for self-treatment.

What is a signaling pathway

Cancer cells are not just cells that divide uncontrollably; they are also masters at “short-circuiting” or “hijacking” the body’s normal internal communication systems. This communication happens via a complex network of “signaling pathways” that act as on/off switches for virtually all functions in a cell, including growth, survival, and metabolism.

Why signaling pathways are important

In a healthy body, these signaling pathways are tightly regulated. In a cancer cell, they are often locked in a permanently “on” or “off” state, which drives the disease. Understanding these pathways is key to understanding many modern, targeted treatment strategies – both conventional and supplementary (complementary). When the overviews mention that a substance “inhibits mTOR” or “affects NF-kB”, it is these signaling pathways being referred to.

Central signaling pathways

Below are the most central signaling pathways you will encounter in the overviews, with an ultra-short description of their primary role in cancer. (This is elaborated further down in the text).

PI3K/Akt/mTOR: A fundamental “accelerator” for cell growth and survival.
MAPK/ERK: Another fundamental growth and division “engine”, often activated by mutations.
Wnt/β-catenin: A primary “divide” signaling pathway, crucial for cell division and stem cells.
Hedgehog: A “fetal program” that, when incorrectly reactivated, drives uncontrolled growth.
Notch: A “stop maturation” signal that cancer stem cells abuse to remain aggressive.
NF-κB: The central “alarm button” that starts and maintains the inflammation in which cancer can thrive.
STAT3: The “translator” that converts inflammation signals into messages about cell growth.
TGF-β: A “double agent” that can initially inhibit cancer, but later promote spread.
AMPK: The cell’s “emergency brake” and energy sensor that actively counteracts growth.
Hippo-YAP: The body’s “building inspector” that must stop cell division when an organ is the right size.
VEGF: The primary “order form” that tumors use to get new blood vessels built.

Review of the individual signaling pathways

Overall review of the individual signaling pathways:

1. Primary growth and survival pathways (accelerators)

1.1 PI3K/Akt signaling pathway

One can think of the PI3K/Akt signaling pathway as one of the most powerful accelerators for cell growth. In normal cells, an effective brake (a “tumor-suppressor gene” called PTEN) ensures that the accelerator is only activated when necessary.

In many cancers, this brake is broken, so the accelerator is stuck to the floor and gives a constant signal for growth, often via the mTOR signaling pathway.

Inhibiting PI3K/Akt is therefore one of the most important goals in modern cancer treatment.

1.2 MAPK/ERK signaling pathway

This is another of the body’s absolutely central growth “engines”. It is a chain reaction of proteins (RAS -> RAF -> MEK -> ERK) that sends a signal from the cell’s surface into the nucleus that it must grow and divide.

In many cancers (e.g., melanoma and bowel cancer), one of the “cogwheels” in this chain (e.g., BRAF or KRAS) is mutated, so the engine runs in top gear all the time.

Targeted medicine like BRAF inhibitors is designed to block this specific chain reaction.

2. Reactivated developmental pathways (fetal programs)

2.1 Wnt/β-catenin signaling pathway

This is a fundamental signaling pathway that is crucial for cell division, especially in stem cells and in the intestinal mucosa. One can think of it as a “copier” that in healthy cells is turned off most of the time.

In many cancers, especially bowel cancer, the “copy button” is locked to the floor, giving the cell a constant signal to make copies of itself.

Inhibiting this pathway is a strategy to stop uncontrolled cell division.

2.2 Hedgehog signaling pathway

This is one of the body’s most fundamental developmental signaling pathways. One can think of it as a kind of “fetal program” that is absolutely crucial when a fetus is developing and organs must be formed correctly. In a healthy adult body, this signaling pathway is turned off in most tissues, as the “construction work” is finished.

The problem arises when cancer cells find a way to reactivate this old fetal program. When the Hedgehog signaling pathway is turned on in an adult cell, it gives it primitive and aggressive characteristics. The cell begins to behave like a fetal cell again with the ability for rapid, uncontrolled growth and to form its own supporting tissue (stroma).

This hijacking of the signaling pathway is especially seen in certain cancers like basal cell carcinoma (a type of skin cancer) and medulloblastoma (a type of brain tumor). Strategies that inhibit the Hedgehog signaling pathway aim to turn off the “wrong” signal and force the cancer cells to stop their primitive growth.

2.3 Notch signaling pathway

This is a fundamental signaling pathway for direct cell-to-cell communication, which is crucial for determining a cell’s fate – especially whether it should remain an immature stem cell or develop (differentiate) into a specialized, normal cell. One can think of it as the cell’s “stop maturation” signal.

In many cancers, especially in the aggressive cancer stem cells, the Notch signaling pathway is “hijacked” and kept constantly active. This prevents the cancer stem cells from maturing and dying as they should. Instead, they are locked in an eternally “young”, self-renewing, and aggressive state, which is one of the primary causes of resistance to treatment and relapse of the disease.

Inhibiting the Notch signaling pathway is therefore a strategy aimed at forcing the cancer stem cells to mature and thus lose their immortal properties. Several dietary supplements (like Curcumin, EGCG, and Resveratrol) are being investigated for their ability to dampen this signaling pathway.

undersøges for deres evne til at dæmpe denne signalvej.

3. Inflammation and immune interaction (smokescreen and betrayal)

3.1 NF-κB signaling pathway

This is the body’s primary “alarm and inflammation system”. In a healthy body, NF-kB is briefly activated to fight an infection or injury. In many cancers, the NF-kB signal has been “hijacked” and is chronically turned on.

This creates a persistent, low-grade (mild) inflammation in and around the tumor, which acts as a growth promoter for the cancer cells, helping them to grow, survive, and form new blood vessels.

Many anti-inflammatory dietary supplements (like Curcumin and Boswellia) work primarily by dampening this signaling pathway.

3.2 STAT3 signaling pathway

STAT3 acts as a “translator” or “middleman” inside the cell. It receives signals from the outside – especially from inflammatory signaling molecules (cytokines) – and translates them into messages inside the cell nucleus to survive, divide, and resist attacks.

In many cancers, STAT3 is overactive and thus helps the cancer cell utilize inflammation to its own advantage.

Inhibiting STAT3 is a way to cut this harmful communication line.

3.3 TGF-β signaling pathway

This signaling pathway is one of the most complex and has a kind of “Dr. Jekyll & Mr. Hyde” dual role in the body. In normal cells and in early stages of cancer, TGF-β (Transforming Growth Factor-beta) acts as a brake. It sends out signals that inhibit cell growth and prevent uncontrolled division, and it helps keep tissue in balance.

In later and more aggressive cancer stages, a “short circuit” often occurs. The cancer cells become resistant to TGF-β’s brake signal. Instead, they begin to abuse the signaling pathway to their own advantage. The same signaling pathway that used to be a brake now becomes a powerful accelerator for metastasis (spread). It helps the cancer cells invade new tissue and create an environment that suppresses the immune system.

Targeting this signaling pathway is therefore an advanced strategy. The goal is not always just to block it, but to try to restore its original brake function or specifically to block its ability to promote spread. This is an active area of research in the fight against metastases.

4. The tissue’s control systems (brakes and sensors)

4.1 AMPK signaling pathway

Where most other signaling pathways act as accelerators, the AMPK signaling pathway is the body’s emergency brake and energy sensor. It is activated when the cell is running out of energy (low ATP level).

When AMPK is turned on, it does two things: it turns off energy-demanding processes like cell growth (partly by inhibiting mTOR), and it turns on processes that create energy.

Drugs like Metformin and dietary supplements like Berberine work largely by activating this “emergency brake”, which creates a metabolic crisis in cancer cells.

4.2 Hippo-YAP signaling pathway

This signaling pathway acts as the body’s “building inspector” and is crucial for controlling an organ’s size via a fundamental mechanism called “contact inhibition”. In a healthy tissue where cells are packed tightly, the Hippo signaling pathway is “turned on”. It constantly sends a “STOP!” signal to a protein called YAP, which therefore stays dormant and does not start cell division.

Many cancer cells are masters at turning off this “building inspector”. When the Hippo signaling pathway is turned off, YAP never receives the stop signal. Instead, it becomes overactive, enters the cell nucleus, and turns on a wide range of genes that promote aggressive cell division and survival. The cell has thus lost its ability to sense that there is no more room, and it continues to divide uncontrollably.

This signaling pathway is particularly important in pleural cancer (mesothelioma), but it is also overactive in many other cancers, such as liver and bowel cancer. Finding ways to reactivate the Hippo brake or directly catch the overactive YAP is a very active area of research to restore the cells’ normal stop mechanism.

5. Specific functions (the order form for new blood vessels)

5.1 VEGF signaling pathway

This signaling pathway is the body’s primary system for forming new blood vessels – a process called angiogenesis. One can think of the signaling molecule VEGF (Vascular Endothelial Growth Factor) as an “order form”. In a healthy body, it is used, for example, to order new blood vessels in a wound that needs to heal. When the wound is healed, the orders stop.

Cancer tumors need a constant supply of oxygen and nutrients to be able to grow. Therefore, they “hijack” this mechanism and begin to mass-produce and send out VEGF “order forms”. This tricks the body into building a permanent network of new, often chaotic, blood vessels directly into the tumor, giving it all the fuel it needs to grow aggressively.

An “anti-angiogenesis” strategy is therefore about blocking this process. By inhibiting the VEGF signaling pathway, the tumor is prevented from sending out its “order forms”. Without new blood vessels, the tumor cannot grow large, and it becomes “starved” of oxygen and nutrients.

Comment:

There is a close relationship between the VEGF signaling pathway and Angiogenesis, which is described under Energy pathways. The difference is:

VEGF signaling pathway: is the order itself or the “order form” that the cancer cell sends out. It is an information pathway.
Angiogenesis: is the actual process of building the new blood vessels as a result of the order. It is a physical energy/supply pathway. See also Block the cancer’s energy pathways

Conclusion

Understanding these complex signaling pathways has revolutionized cancer treatment. Instead of only seeing cancer as a disease that must be killed with broad-spectrum chemotherapy, one can increasingly see it as a system with a series of “short-circuited” on/off switches.

The metabolic strategies described here and on the other pages under the topic: Metabolic approaches – block signaling pathways, aim to target and normalize exactly these signaling pathways.

Since cancer cells are often good at finding detours, a combination of substances that target several different signaling pathways simultaneously is often the most promising approach.

This knowledge serves as a foundation for a qualified dialogue with a practitioner about possible supplementary strategies.

Warning

This is in no way a call for self-treatment. Experimenting with treatment on your own, without professional guidance, can be ineffective and potentially dangerous.

Content:

Short summary (scroll to)
Review of signaling pathways (scroll to)
Overview of agents that block the individual signaling pathways (scroll down)
Links (scroll to)

Strategies grouped by signaling pathway

This overview groups the substances according to which signaling pathway they primarily affect. Within each group, the substances are listed in an indicative order, where:

The most well-documented, potent, or centrally acting substances are mentioned first.

This is done to provide a quick overview of the most recognized substances for each signaling pathway, but the ranking is not absolute, as many substances act in several ways. And new research results are constantly emerging.