How do abnormal neutrophils help lung cancer spread?
Last reviewed: 14.06.2024
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Lung cancer remains a leading global health problem, causing the largest number of cancer-related deaths worldwide. Central to its development is the tumor microenvironment, which includes complex interactions with immune cells such as neutrophils. Neutrophils were initially thought to be beneficial due to their antitumor activity in early stages of cancer, but it is now understood that they play a dual role, potentially promoting cancer metastasis under the influence of the tumor environment.
A groundbreaking study from Xuzhou Medical University, detailed in the journal of Cancer Biology & Medicine, reveals a new mechanism by which neutrophils accelerate the progression of lung cancer. This study highlights the key function of neutrophils—usually the first responders to inflammation—as they assume protumoral roles in the cancer microenvironment, significantly influencing the dynamics of cancer metastasis.
The study examines the roles of the PARP-1/Alox5/MMP9 axis in regulating lung cancer-associated neutrophil activation and thereby promoting lung cancer progression. Activated by lung cancer cells, neutrophils interact with PARP-1, which then cooperates with another protein, ALOX5. This interaction is important because it enhances the production of MMP-9, an enzyme vital for the destruction of tissue structures and promoting cancer invasion and metastasis.
Using techniques such as immunohistochemistry, the study examines neutrophil infiltration in lung cancer tissue and uses in vitro assays to analyze their effects on the behavior of lung cancer cells. Reduced gene expression and pharmacological inhibition of PARP-1 further explain its role in this process.
Confirmed in mouse models, the results show that blocking PARP-1 can significantly reduce tumor growth, illuminating the complex relationship between the immune system and cancer, while highlighting that synergistic inhibition of PARP-1 may be beneficial for the treatment of lung cancer.
Diagram of the neutrophil PARP-1-ALOX5 mechanism mediated by MMP-9 in lung cancer. Infiltrated neutrophils are increased in lung cancer tissue and negatively correlate with patient prognosis. Following exposure of neutrophils to lung cancer cells, PARP-1 interacts with ALOX5 and enhances protein stabilization through PARillation of ALOX5. Increased ALOX5 metabolites promote MMP-9 production through activation of the ERK and p38 MAPK pathways. Blocking PARP-1 with AG14361 or ALOX5 with Zileuton reduces MMP-9 production and attenuates neutrophil-driven lung cancer progression. Source: Cancer Biology & Medicine (2024). DOI: 10.20892/j.issn.2095-3941.2023.0248
Dr. Junnian Zheng, lead author of the study, commented: “This study not only improves our understanding of the biological interactions between lung cancer cells and neutrophils, but also paves the way for new targeted therapies that can interrupt these interactions and potentially improve outcomes for patients. ".
These results have significant implications, suggesting that targeting the PARP-1-ALOX5-MMP-9 pathway may be a promising approach to suppress neutrophil protumoral activity in lung cancer. This strategy could lead to innovative therapies that slow the progression of lung cancer and enhance the effectiveness of current treatments.