The mysterious journey of cancer cells through the body may be guided by an unexpected source: chemical signals from nerve cells.
Imagine your body's nervous system, the same network that allows you to feel and interact with the world, is secretly being used by cancer as a roadmap for its spread. This isn't science fiction—it's a groundbreaking discovery in cancer biology. For years, scientists have known that cancer cells metastasize, but the precise guidance systems they use to navigate the body have remained elusive.
Recent research has uncovered a startling conspiracy: cancer cells can actually migrate toward signals released by nerve cells and their support systems. This article explores the fascinating role of a nerve growth factor called BDNF and its receptor, TrkB, in guiding lung cancer cells to their destinations, potentially explaining one of cancer's most dangerous behaviors.
To understand this covert trafficking system, we first need to meet the main characters in our story.
BDNF is a protein that belongs to the neurotrophin family, substances crucial for the development, survival, and plasticity of neurons in our nervous system. Think of it as a nourishing fertilizer for nerve cells 3 .
Under normal circumstances, BDNF helps our brains learn, form memories, and adapt. However, in various cancers, including lung cancer, this beneficial factor has been hijacked.
If BDNF is the key, then TrkB is the lock. TrkB is a receptor protein found on the surface of many cells. When BDNF binds to TrkB, it activates multiple downstream signaling pathways inside the cell 3 .
Cancer cells, particularly in lung adenocarcinoma and small cell lung cancer, often overexpress TrkB 7 9 .
Tumors are not just masses of cancer cells. They're complex ecosystems teeming with different cell types, collectively known as the tumor microenvironment.
One of the most important residents are cancer-associated fibroblasts (CAFs) which actively communicate with cancer cells and can secrete BDNF 2 8 .
CAF Secretes BDNF
BDNF Binds to TrkB
Cancer Cell Migration
Schematic representation of how CAF-secreted BDNF guides cancer cell migration through TrkB receptor activation
To confirm that BDNF truly guides cancer cell movement, researchers designed experiments to test whether lung cancer cells would actively migrate toward this signal.
Scientists obtained human lung cancer cell lines representing different types of lung cancer. They also sourced lymph node fibroblasts—normal connective tissue cells from lymph nodes, which are common sites of cancer metastasis 2 .
The lymph node fibroblasts were cultured in laboratory dishes, allowing them to secrete their natural factors into the surrounding liquid (culture medium). This "conditioned" medium became enriched with whatever molecules the fibroblasts naturally produce, potentially including BDNF 2 .
Researchers placed the lung cancer cells in a special chamber separated by a porous membrane from another chamber containing either the fibroblast-conditioned media or a control solution. This setup allowed them to measure whether and how quickly the cancer cells moved through the pores toward the test solution 2 .
To specifically prove that BDNF was the key attractant, researchers repeated the experiments while blocking BDNF signaling—either by using antibodies that neutralize BDNF or drugs that inhibit its receptor, TrkB 2 .
The results were striking. Lung cancer cells demonstrated significantly increased migration toward the medium conditioned by lymph node fibroblasts compared to control medium.
When BDNF signaling was blocked, this migration was dramatically reduced, confirming that BDNF was a primary guidance cue. This provided direct evidence that cancer cells can detect and follow BDNF trails secreted by other cells in the body, potentially explaining how they find their way to specific locations like lymph nodes 2 .
| Experimental Condition | Cancer Cell Migration | Implication |
|---|---|---|
| Control medium | Baseline level | Cancer cells show some random movement |
| Fibroblast-conditioned medium | Significantly increased | Fibroblasts secrete factors that attract cancer cells |
| Conditioned medium + BDNF/TrkB blockade | Greatly reduced migration | BDNF is a major chemotactic factor guiding migration |
85% migration rate
25% migration rate
The migration of cancer cells toward BDNF is just one piece of the puzzle. Once the BDNF-TrkB connection is activated, it sets off a cascade of events inside cancer cells that makes them more aggressive and dangerous.
The binding of BDNF to TrkB sets in motion at least three critical signaling pathways inside cancer cells 3 :
Primarily drives cancer cell proliferation and differentiation
Promotes cell survival, inhibits apoptosis (programmed cell death), and enhances migratory ability
Increases cellular plasticity and contributes to angiogenesis (new blood vessel formation)
| Signaling Pathway | Primary Cancer-Promoting Effects |
|---|---|
| RAS-MAPK-ERK | Cell proliferation, differentiation, and survival |
| PI3K/Akt | Anti-apoptosis (cell survival), pro-migratory effects |
| PLCγ | Increased cell plasticity, angiogenesis, VEGF expression |
Perhaps most troublingly, the BDNF-TrkB axis has been implicated in chemotherapy resistance. Cancer cells with activated TrkB signaling become more resilient and better able to survive chemical attacks from cancer drugs, making treatment less effective 2 9 .
Clinical studies have confirmed the troubling relationship between BDNF/TrkB and cancer aggressiveness. In both non-small cell and small cell lung cancer, high levels of BDNF and TrkB are consistently associated with poor prognosis, more advanced disease, and shorter survival times 9 .
| Cancer Type | BDNF/TrkB Expression | Clinical Correlation |
|---|---|---|
| Small Cell Lung Cancer | Significantly higher than in NSCLC | Associated with more aggressive disease and poorer prognosis |
| Non-Small Cell Lung Cancer | TrkB overexpression in 33% of tumors, BDNF positive in 65.5% | Linked to poor prognosis and malignant phenotype |
| Lung Adenocarcinoma | Frequently overexpressed | Promotes growth, metastasis, and chemoresistance |
Understanding these complex biological processes requires specialized tools and techniques. Here are some key reagents and methods that enable this critical research:
By collecting media exposed to specific cell types (like lymph node fibroblasts), scientists can identify factors those cells secrete and how they affect other cells 2 .
These specialized chambers with porous membranes quantitatively measure cell movement toward chemical attractants, providing concrete data on migration patterns 2 .
These molecular tools allow researchers to specifically "turn off" genes of interest, such as the BDNF or TrkB genes, to confirm their role in observed phenomena 2 .
Pharmacological agents that block TrkB receptor activity help validate the importance of this signaling pathway and represent potential therapeutic candidates 3 .
A sensitive method that precisely measures the concentration of secreted factors like BDNF in cell culture media or patient samples 2 .
The discovery that BDNF guides cancer cell migration opens exciting new avenues for cancer treatment. Researchers are actively exploring several promising strategies:
Several TrkB-targeted inhibitors are already in clinical trials for various cancers, including Entrectinib, Larotrectinib, and Repotrectinib. These drugs aim to directly block the connection between BDNF and cancer cells 3 .
Other approaches focus on disrupting the tumor microenvironment that produces BDNF, potentially by targeting cancer-associated fibroblasts or their communication with cancer cells 8 .
The future of cancer treatment may involve combination therapies that simultaneously attack cancer cells directly and disrupt their guidance systems, potentially making metastasis more difficult and existing treatments more effective.
The revelation that lung cancer cells migrate toward BDNF secreted by lymph node fibroblasts represents a paradigm shift in our understanding of cancer metastasis. It suggests that the nervous system and its signaling molecules, once thought to be separate from cancer progression, are actually active participants in the disease process.
This discovery transforms our picture of metastasis from one of random wandering to a more sinister process of guided navigation, with cancer cells actively following chemical trails to their next destination. While much remains to be learned about this complex signaling system, each new finding brings us closer to innovative therapies that could potentially cut the lines of communication that cancers use to spread through the body.
The same nervous system that makes us who we are may unfortunately provide pathways for disease, but understanding these pathways also gives us new opportunities to intervene and save lives.