Cancer pain is a common symptom of advanced cancer. Cancer pain not only seriously affects the quality of life of patients, but also increases disease progression and mortality. New research from the Faculty of Medicine at The Chinese University of Hong Kong (CUHK) has discovered that a novel phenomenon called “macrophage to neuron-like cell transition (MNT)” generates pain-sensing neurons in the lung cancer microenvironment, leading to cancer pain. In this way, MNT may become a precise therapeutic target for primary cancer pain.
Some cancer pain patients suffer from the phenomenon of being “resistant to all conventional medicines,” and even painkillers cannot help relieve the pain, which may be related to some unknown pathological mechanism. The CUHK team was able to effectively reduce the number of cancer-related neurons and thus reduced pain in experiments on mice by gene deletion or drug inhibition of macrophage Smad3. This result shows that MNT may become a precise therapeutic target for primary cancer pain treatment points. The findings have been published in the international scientific journal “Science Advances.”
Neuron formation (or tumour innervation) is a common but unexplained symptom in cancer whose pathology and function have remained unclear. There is growing evidence that it is closely related to patient mortality, disease progression, and cancer-associated pain.
To further understand tumour-associated neurons, identify the source of pain-sensing neurons, and identify precise therapeutic targets for primary cancer pain, the team employed the latest single-cell RNA sequencing technology and discovered the individual cell information that was previously masked in tumour specimens using conventional detection methods. The discovery of such nociceptive (pain feeling) neurons in lung cancer strongly suggest the existence of macrophage markers and demonstrate a direct relationship between the immune system and cancer pain.
The research team further extracted all macrophage lineage cells precisely from the lung cancer dataset and reconstructed their developmental pathways using the latest bioinformatics strategies. This led to the discovery of a novel mechanism called MNT, which allows macrophages to directly convert into pain neurons in the tumour microenvironment, triggering cancer pain.
MNT is commonly detected in lung, kidney, and liver cancer patient specimens, and the research team demonstrated that MNT causes and promotes pain in tumour-bearing mice, revealing its importance in primary cancer pain.
To develop its precision mediation for primary cancer pain, the research team used chromatin immunoprecipitation to analyze the genomic changes in macrophages when MNT was conducted under cancerous conditions. Finally, it was determined that the transcription factor Smad3 is the key element in the initiation of MNT by macrophages.
The research team has confirmed through experiments that gene deletion or drug inhibition of macrophage Smad3 can effectively reduce the number of cancer-related neurons and thus pain in mice. This means that MNT may become a precise therapeutic target treatment for primary cancer pain, making precise therapeutic target treatment of cancer pain a reality.
In this regard, Prof. To Ka-fai, Chairman Professor in the Department of Anatomical and Cellular Pathology, Faculty of Medicine, CUHK said, “Cancer pain brings physical and psychological suffering to patients with advanced cancer, and there is still no clinical solution. When they cannot bear the pain, it may cause tragedy. We hope that the discovery of MNT can bring a ray of hope to cancer patients and help them, and their families escape the effects of such painful experience.”
