Science sub-journal: How does oil smoke induce lung cancer? Scientists have found that long-term inhalation of nanoscale carbon black particles can cause damage to lung macrophage function, thereby promoting lung cancer development and metastasis

The latest statistics show that among all cancers in China, the incidence and mortality of lung cancer rank first
.
In 2020, there were about 820,000 new cases of lung cancer in China, accounting for 17.
9% of new cancer cases, and about 710,000 deaths, accounting for 23.
8% of cancer deaths, and 1 in every 4 patients who died of cancer was lung cancer [1].

At present, immunotherapy and targeted therapy have been widely used in the treatment of
lung cancer.
However, due to the heterogeneity of lung cancer, the occurrence of metabolic reprogramming, and the formation of immunosuppressive microenvironment, most patients still do not benefit from targeted therapy and immunotherapy, and early prevention is still the key means of lung cancer prevention and treatment [2].

As we all know, nicotine, benzopyrene and other substances in cigarette smoke can cause lung cancer, in addition, cigarette smoke also contains a large number of ultrafine particles, the same way, kitchen smoke and some incineration smoke also contain a large number of ultrafine particles, these ultrafine particles can be deposited in any part of the respiratory tract, especially respiratory bronchioles and alveoli, thereby affecting the function of
the lungs.
However, the correlation between the inhalation of ultrafine particles and the occurrence and development of lung cancer has not yet been elucidated, and in-depth research on this will help the research and development of comprehensive prevention and
treatment strategies for lung cancer.

Recently, a research team led by Professor Farrah Kheradmand of the Center for Translational Research in Inflammatory Diseases at Baylor College of Medicine published important research results in the journal SCIENCE ADVANCES [3].

The team found that long-term inhalation of nanoscale carbon black particles of 15-75nm can lead to mitochondrial damage and metabolic reprogramming of lung macrophages, which in turn leads to increased lactic acid secretion and immunosuppressive microenvironment formation, promoting the occurrence and metastasis
of lung cancer.

The study confirmed that under the action of other carcinogenic factors, nanocarbon black particles produced by incomplete combustion of tobacco can promote the occurrence and metastasis of lung cancer, in addition to the development of new strategies for lung cancer treatment, reducing exposure is undoubtedly a key prevention and control method
.

Long-term inhalation of ultrafine particles is strongly associated
with death.
Cigarette smoke and some smoke in the environment contain a large number of nanoscale carbon black particles, and long-term inhalation of these nano-carbon black particles can lead to increased secretion of pro-inflammatory cytokines in the lungs, which can further lead to the occurrence of emphysema [4]; At the same time, nanocarbon black particles can also increase reactive oxygen species (ROS) in the lungs, which can lead to lung damage [5].

Common antioxidant drugs and anti-inflammatory drugs can reduce the damage of nanocarbon black particles to the lungs to a certain extent, but the inhaled nano-carbon black particles will not be removed, and they can be engulfed by macrophages and exist in lung tissue for a long time [6], but their relationship with lung cancer occurrence and metastasis has not yet been elucidated
.

In order to clarify the relationship between nanocarbon black particles and lung cancer occurrence and metastasis, the researchers intervened with nanocarbon black particles on two different genotypes of lung cancer model mice
.
The results showed that the inhalation of nanocarbon black particles could accelerate the occurrence and metastasis of lung cancer in mice compared with the control group, and this acceleration effect was independent
of lung cancer subtypes.

Occurrence and metastasis of lung cancer under the intervention of nanocarbon black particles

As one of the core characteristics of tumors, metabolic reprogramming can provide sufficient energy and necessary macromolecular raw materials
for tumor occurrence and metastasis.
In order to explore the effect of nanocarbon black particle intervention on tumor metabolism, the researchers conducted spatial metabolomic analysis of lung tissue of lung cancer model mice after nanocarbon black particle intervention, and the results showed that under the intervention of nanocarbon black particles, the level of lactic acid in lung tissue increased significantly, and the expression level of Ldha, a key enzyme for lactate metabolism, also showed an increasing trend.
Further studies have shown that the increased secretion of lactic acid in lung tissue is mainly derived from lung macrophages
.

The researchers found that the intervention of nanocarbon black particles activated the hypoxia-inducible factor 1α (HIF1α) pathway, which in turn led to increased lactate synthesis in lung macrophages and the formation of
an immunosuppressive microenvironment.
In addition, mitochondria, as key organelles of oxidative phosphorylation, are sensitive to intracellular reactive oxygen species, and the researchers also found that nanocarbon black particles can enter the mitochondria of lung macrophages and damage mitochondrial function
.

Effect of Hif1α knockout in macrophages on immunosuppressive cells under the intervention of nanocarbon black particles

Finally, through the flow cytometry analysis of nanocarbon black particles to intervene in the tumor tissues of mice with lung cancer, the researchers found that nanocarbon black particles could further increase the expression levels of PD-L1, PD-L2 and CD206 in mouse myeloid tumor-infiltrating cells, leading to the formation of
immunosuppressive tumor microenvironment.

At the same time, the researchers extracted lung macrophages from lung cancer model mice that received nano-carbon black particle intervention, and transplanted them allogeneically into lung cancer model mice that did not receive nano-carbon black particle intervention, and found that the incidence and metastasis rate of lung cancer in mice who received allogeneic transplantation were significantly increased, and the expression of CD4+ and CD8+ T cell PD-1 was also significantly increased, which confirmed that nanocarbon black particles could indeed play a cancer-promoting role through lung macrophages and promote the occurrence and metastasis of lung cancer
。

Incidence of lung cancer, metastasis rate and expression of PD-1 in lung tissues in lung macrophage allogeneic transplantation model mice

In general, the study confirmed that nanocarbon black has a promoting effect on lung cancer development and metastasis through two lung cancer model mice with different gene
mutations.
After the intervention of nanocarbon black particles, it can lead to the damage of mitochondria of lung macrophages, and can lead to increased lactic acid secretion of lung macrophages through the HIF1α pathway, and can also increase the expression of immunosuppressive markers such as PD-1, PD-L1, PD-L2, CD206, etc.
, and promote the occurrence and metastasis
of lung cancer.

Inhalation exposure of nanocarbon black particles can cause metabolic reprogramming of lung macrophages, thereby forming an immunosuppressive tumor microenvironment and accelerating the progression of
lung cancer.
It can be seen that smoking is harmless, and reducing exposure to cigarette smoke is crucial
to lung cancer prevention and treatment.

References:

1.
Sung H, Ferlay J, Siegel RL, et al.
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