The sense of smell is the oldest primitive sense of life, but the human understanding of smell did not make a breakthrough until 1991.
That year, American scientist Richard Axel and his postdoc Linda B. Buck discovered the olfactory receptor molecular family,[1] for which they won the 2004 Nobel Prize in Physiology or Medicine.
Today, the sense of smell is a big deal again.
Liu Chong's team from Zhejiang University School of Medicine published a blockbuster study in the journal Nature[2], in which they found in mouse models of glioma carrying specific gene mutations that the sense of smell can activate the corresponding functional neural circuits and directly regulate the occurrence of gliomas through the neurotrophic factor IGF1 signaling pathway.
It is understood that this is also the first time that the sense of smell can directly regulate the occurrence of glioma. In addition, this study reveals a unique direct link between smell and glioma occurrence, providing new ideas and targets for the clinical diagnosis and treatment of glioma.
In connection with previous studies that have shown that visual stimulation can promote the occurrence of optic gliomas in mice with NF1 mutations [3], one can't help but wonder if the stimulation that causes neuronal activity in the case of certain genetic mutations may be the trigger for gliomas?
Take a screenshot of the first page of the study
Glioma is one of the most common brain tumors in neurosurgery, but it is also the most malignant and intractable disease, and patients with glioblastoma have only a survival period of more than ten months after all treatments (surgery, radiotherapy and chemotherapy, etc.). Therefore, it is urgent to develop new ideas and targets to break the current dilemma of clinical diagnosis and treatment.
Professor Liu Chong's team has long been committed to the mechanism of glioma occurrence and development, and they found in the mouse model of primary glioma (CKO model, conditional knockout tumor suppressor genes Trp53 and Nf1) that mimic the origin of adult oligodendrocyte precursors (OPCs) constructed in the previous period that the probability of glioma occurring in olfactory bulbs (the first station of olfactory sensory neuron conduction) is also high, and the probability of glioma in other centers related to smell (presodoptory nucleus, olfactory nodules, piriform cortex, amygdala, etc.) is also high. But compared to the olfactory bulb, the period of occurrence is later.
Through further dissection of olfactory bulb substructures, they found that tumors were almost always present and confined to the synaptic glomerular layer. The synaptic glomerular layer is the information exchange region of the first-order neurons (olfactory receptor neurons, ORNs) and the second-order neurons (M/T cells) in the olfactory loop.
This finding suggests that the activity of neurons caused by the sense of smell may play an important role in the development of gliomas.
In the CKO model, tumors are almost always present and confined to the synaptic pellet layer of the olfactory bulb
To further investigate the causal relationship between olfactory and glioma occurrence, Liu's team used chemical genetics techniques to construct Omp-hM4Di and Omp-hM3Dq transgenic mice that can specifically manipulate olfactory neuronal activity and integrate them into the CKO model.
By using the transgenic receptor agonist clozapine in mice, olfactory receptor agonists can be superpolarized in Omp-hM4Di mice, inhibiting olfactory-feeling neuronal activity, thereby weakening neuronal activation caused by external olfactory stimulation; in Omp-hM3Dq mice, olfactory-sensing neuron cell membranes can be depolarized, resulting in olfactory-receptive neurons over-activated without external olfactory stimulation.
This technique allows researchers to intervene in the olfactory input of mice to explore whether olfactory activity directly contributes to the development of gliomas.
Unsurprisingly, long-term use of clozapine significantly reduced the olfactory bulb tumor volume in CKO_OMP-hM4Di mice, that is, tumor growth was inhibited after olfactory sensory neuronal activity was inhibited, while in CKO_OMP-hM3Dq mice, long-term use of clozapine significantly increased the tumor volume, that is, when olfactory sensing neuron activity was continuously activated, tumor growth was promoted.
To more physiologically intervene in the mouse's olfactory-feeling neuronal activity, the researchers reduced olfactory stimulation to that side nostril by blocking one side of the nostril (unilateral olfactory deprivation) in CKO mice.
By blocking one side of the nostril of the CKO mouse (unilateral olfactory deprivation)
to reduce olfactory irritation to the nostrils on this side
This simple physical olfactory intervention can significantly reduce the volume of olfactory-deprived lateral olfactory bulb tumors and significantly reduce the proliferation of mutated OPC cells in the synaptic glomeruli.
The above studies confirm that olfactory sensory neuronal activity caused by olfactory stimulation can regulate the growth of gliomas, so what is the internal mechanism of it?
By performing RNA-seq on both sides of olfactory bulb tissue in unilateral olfactory deprivation mice, the researchers screened out 17 gene expressions in the olfactory bulb on the olfactory deprivation side that were significantly downregulated and validated using RT–qPCR. After further screening of multiple genes, it was found that only IGF1 could significantly stimulate the proliferation of OPCs in vitro. In fact, Liu Chong's team has found that IGF1R (the receptor of IGF1) plays an important role in the formation of gliomas of OPC origin in previous studies [5].
The researchers further found that IGF1 in the mouse brain is mainly expressed in the olfactory bulb, and the expression of IGF1 in the olfactory bulb on the olfactory deprivation side is significantly reduced compared with the contralateral side, suggesting that IGF1 may be a key part of olfactory stimulation leading to tumorigenesis and development.
IGF1 is mainly expressed in olfactory bulbs in mouse brains, and the expression of IGF1 in olfactory bulbs on the olfactory deprivation side is significantly reduced compared with the contralateral side
By staining multiple cell markers, the researchers further clarified that IGF1 is expressed by second-order neurons in synaptic globules/cluster cells.
In order to clarify whether the second-level neuronal cap/cluster cells play a key role in glioma formation through IGF1, the researchers used double label chimera analysis technology and double recombinase system to achieve high-resolution lineage tracing of tumor origin and evolution, while performing precise genetic manipulation of the tumor microenvironment.
Using this model, the researchers demonstrated that specific knocking out of IGF1 in second-order neuronal cap/cluster cells significantly inhibits the conversion of OPCs into tumor cells in olfactory bulbs.
Specific knockout of IGF1 in M/T cells significantly inhibits the conversion of OPCs into tumor cells in olfactory bulbs
Finally, in CKO_OMP-hM3Dq mice, the researchers knocked out the IGF1R gene, which activates olfactory neurons while blocking the IGF1-IGF1R signaling pathway, and found that the previously observed pro-tumor effect caused by olfactory neuron activation was completely counteracted.
These results demonstrate that olfactory stimulation regulates glioma occurrence primarily through the IGF1 signaling pathway of second-order neuronal cap/cluster cell sources.
Overall, the study demonstrated that olfactory stimulation can stimulate the secretion of IGF1 by olfactory sensory neuronal neural activity, promoting the occurrence and development of gliomas, once again revealing that external environmental stimulation may be a new glioma precipitating factor. At the same time, the study suggests that IGF1 can be used as a potential new target for glioma therapy.
Schematic diagram of the research mechanism
Since vision and smell have been found to be related to the occurrence of gliomas, will mental activities such as hearing, touch, and even thinking be related to the occurrence of gliomas?
But don't worry, the correlation between visual and olfactory stimulation and glioma found so far is found in mice with genetic mutations (Trp53, NF1), for normal people, there is no evidence that normal sensory stimulation is related to the occurrence of glioma.
It is hoped that more relevant research will provide new ideas and strategies for the diagnosis and treatment of glioma.
bibliography
1.Buck L, Axel R: A novel multigene family may encode odorant receptors: a molecular basis for odor recognition. Cell 1991, 65(1):175-187.
2.Chen P, Wang W, Liu R, Lyu J, Zhang L, Li B, Qiu B, Tian A, Jiang W, Ying H et al: Olfactory sensory experience regulates gliomagenesis via neuronal IGF1. Nature 2022.
3.Pan Y, Hysinger JD, Barron T, Schindler NF, Cobb O, Guo X, Yalcin B, Anastasaki C, Mulinyawe SB, Ponnuswami A et al: NF1 mutation drives neuronal activity-dependent initiation of optic glioma. Nature 2021, 594(7862):277-282.
4.Louis DN, Perry A, Wesseling P, Brat DJ, Cree IA, Figarella-Branger D, Hawkins C, Ng HK, Pfister SM, Reifenberger G et al: The 2021 WHO Classification of Tumors of the Central Nervous System: a summary. Neuro Oncol 2021, 23(8):1231-1251.
5.Tian A, Kang B, Li B, Qiu B, Jiang W, Shao F, Gao Q, Liu R, Cai C, Jing R et al: Oncogenic State and Cell Identity Combinatorially Dictate the Susceptibility of Cells within Glioma Development Hierarchy to IGF1R Targeting. Adv Sci (Weinh) 2020, 7(21):2001724.
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