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Editor-in-charge | Xi
Pain is a very unpleasant experience
that everyone knows.
It is triggered by the activation of specialized sensory nerves called nociceptive nerves.
For a long time, pain has been used as a protective mechanism to warn us of potential dangers and injuries
in time.
Cancer pain is one of the
most common presenting symptoms in patients with a variety of tumors.
Although cancer pain has a warning effect in the early stage of tumor development, with the development of tumor, cancer pain becomes more intense and difficult to control, and refractory cancer pain not only seriously affects the quality of life of tumor patients, but also is closely related
to the poor overall survival rate of tumor patients.
These clinical manifestations suggest that cancer pain may be involved in tumor development, but its biological mechanism is unclear
.
On November 16, 2022, Ji Tong/Wang Xu/Sun Shuyang, Department of Oral and Maxillofacial - Head and Neck Oncology, Ninth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, published a long article online at Cell Metabolism Research paper on Cancer cells co-opt nociceptive nerves to thrive in nutrient-poor environments and upon nutrient-starvation therapies.
This study reveals for the first time that tumor cells can actively "hijack" a type of sensory nerve that senses, conducts, and regulates cancer pain-nociceptive sensory nerves when faced with nutrient deficiency in the tumor microenvironment to maintain their own vigorous growth needs
.
This paper not only provides a new mechanism from a biological perspective to understand the regulation of tumor development by cancer pain, but also proposes a new strategy
for using a class of clinical migraine drugs to enhance tumor starvation treatment.
The authors used oral mucosal malignancies with high incidence of cancer pain (oral mucosal squamous cell carcinoma and oral mucosal malignant melanoma) as a model, and found that there were densely distributed nociceptive nerve endings in the tumor microenvironment of mice and humans
.
By chemically and genetically regulating the nociceptive sensory nerves innervated by the oral mucosa of mice, the authors found that blocking nociceptive sensory nerves not only increased the pain threshold of mice, but also significantly inhibited the growth
of tongue transplantation tumors.
Subsequently, in order to explore the mechanism of nociceptive sensory nerves regulating tumor growth, the authors constructed two in vitro co-culture models
.
But unexpectedly, nociceptive sensory nerves had no significant effect
on the growth of tumor cells under normal in vitro culture conditions.
This difference in in vivo and in vivo outcomes suggests that nociceptive sensory nerves regulate tumor growth
in a microenvironment-dependent manner.
Because the authors conducted the experiments on immunodeficient mice, they first ruled out the role
played by immune cells.
Current research in the field of tumor microenvironment shows that various nutrients in the tumor microenvironment will significantly affect the interaction
between cells in the microenvironment.
The authors therefore propose another hypothesis that this difference in in vivo and in vivo results is due to the inability of in vitro models to mimic the complex nutritional microenvironment in which in vivo tumors are located
.
The authors then found through pan-carcinogenic analysis of TCGA, PET-CT imaging and a variety of in vivo models that oral mucosal malignant tumors are in a glucose-starved or even depleted tumor microenvironment, and this is due to aerobic glycolysis as the main energy supply mode of oral mucosal malignant tumor cells
.
Subsequently, the authors found through various in vivo and in vivo rescue experiments that the growth promotion effect of nociceptive sensory nerves on tumor cells depends on a sugar-poor environment
.
In the next step, through in vitro screening, co-culture models and nociceptive sensory nerve-specific CGRP knockout/overexpression mouse models, the authors found that nociceptive sensory nerves promote the growth of tumor cells in a sugar-deficient environment through calcitonin gene-related peptide (CGRP).
CGRP can activate Rap1 in tumor cells to hinder Raptor-mTOR interaction, thereby promoting cytoprotective autophagy
in tumor cells in a sugar-poor environment and a high-glucose environment.
It is worth mentioning that CGRP has been found to play a key role in migraine in recent years; A series of small molecule antagonists and monoclonal antibodies targeting CGRP came into being, and were called "the most important breakthrough in the field of migraine in the past 20 years"
.
Further, the authors thought in turn, "How do tumor cells affect nociceptive sensory nerves in such a nutrient-poor tumor microenvironment?" ”
。 Through transcriptome sequencing, in vitro co-culture model and mouse unilateral tongue transplantation tumor model verification, the authors found that tumor cells actively upregulated a variety of factors to actively "hijack" nociceptive sensory nerve synthesis and secretion of CGRP
under nutrient-deficient conditions.
These results suggest that the tumor microenvironment initiates the interaction
between tumor cells and nociceptive sensory nerves.
Finally, based on these molecular mechanisms, the authors found antiglycolytic therapy (2-DG, clonidamine) and antiangiogenic therapy (anlotinib, bevacizumab).
Both types of tumor starvation therapy can significantly enhance the interaction between tumor cells and nociceptive sensory nerves, and the use of a class of migraine treatment drugs that have been marketed at home and abroad, CGRP receptor antagonists, to block the CGRP effect of nociceptive sensory nerve sources, can significantly enhance the efficacy
of tumor starvation treatment.
In conclusion, this study shows that tumor cells can actively "hijack" nociceptive sensory nerve synthesis and secretion of CGRP when they are nutrient-deficient, thereby promoting their own cellular protective autophagy
.
The use of a migraine treatment drug to block the "aid" of nociceptive sensory nerves to tumor cells can significantly enhance the efficacy
of tumor starvation treatment.
This means that cancer pain plays an unexpected key role in the development of tumors, suggesting that pain control should be a non-negligible part
of tumor treatment.
The corresponding authors of this study are Professor Ji Tong from the Department of Oral and Maxillofacial - Head and Neck Oncology, Ninth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, and researchers Wang Xu and Sun
Shuyang are jointly corresponding.
The first author is Zhang Yu, a doctoral student of the Ninth People's Hospital affiliated to Shanghai Jiao Tong University School of Medicine, and the co-first authors are Lin Chengzhong, Dr.
Liu Zheqi, attending physician of the Ninth People's Hospital affiliated to Shanghai Jiao Tong University School of Medicine, and Sun Yiting
, a doctoral student of oral and craniomaxillofacial medicine.
Original link:
https://doi.
org/10.
1016/j.
cmet.
2022.
10.
012
Platemaker: Eleven
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.
