Credit:IL-20RB mediates tumoral response to osteoclastic niches and promotes bone metastasis of lung cancer.

Lung cancer is the leading cause of cancer-related deaths worldwide. Approximately 40% of patients with non-small cell lung cancer (NSCLC) develop bone metastases, with an average survival time of 6 to 10 months after metastasis and a five-year survival rate of less than 5%. Bone metastasis not only increases mortality but also causes severe pain and fractures, significantly impairing patients' quality of life. Therefore, a deeper understanding of the mechanisms underlying lung cancer bone metastasis is crucial for developing new therapeutic approaches. Bone metastasis formation is a complex, multi-step process involving critical interactions between cancer cells and the bone microenvironment. While the bone resorption function of osteoclasts in bone metastasis has been extensively studied, their other roles in the tumor microenvironment are not fully understood. Recent studies have found that osteoclasts not only indirectly support tumor cell growth through bone resorption but may also directly promote tumor cell survival and proliferation through other mechanisms. Interleukin-20 receptor β (IL-20RB) is a cell membrane receptor that forms a heterodimer with IL-20RA or IL-22R, binding to IL-20 subfamily cytokines (including IL-19, IL-20, and IL-24), and activating the JAK1/STAT3 signaling pathway. Studies have shown that IL-20 signaling plays an important role in the development and metastasis of various cancers, such as prostate cancer, oral cancer, and breast cancer. However, the specific role of IL-20RB in bone metastasis has not yet been fully investigated.

Firstly, the researchers conducted RNA sequencing analysis on A549-derived cell lines with varying metastatic potentials and found that IL-20RB was significantly upregulated in cell lines with high bone metastasis potential. This result was further validated in a cohort of lung cancer patients from Shanghai Tenth People’s Hospital and Shanghai Chest Hospital, where IL-20RB expression in tumor tissues was significantly higher than in normal tissues. Moreover, IL-20RB expression was higher in metastatic tumors compared to non-metastatic tumors, and high IL-20RB expression was associated with an increased risk of bone metastasis recurrence and reduced overall survival.

Subsequently, lung cancer cells (A549 and HBM1) with overexpressed or knocked-down IL-20RB were injected intracardially into immunodeficient nude mice to observe bone metastasis and growth. The results showed that IL-20RB overexpression significantly accelerated bone metastasis, leading to increased bone damage, whereas IL-20RB knockdown reduced bone metastatic burden and bone resorption. This indicates that IL-20RB enhances metastatic colonization by promoting tumor cell proliferation in the bone.

The study also found that tumor cells induced osteoclasts to secrete IL-19, which, by activating IL-20RB, initiated the JAK1/STAT3 signaling pathway, thereby enhancing tumor cell proliferation in the bone. Using an IL-19 neutralizing antibody significantly inhibited the proliferation of IL-20RB-expressing tumor cells. In IL-19 knockout mice, tumor cells overexpressing IL-20RB could not form metastases in the bone, indicating that IL-19 is a critical factor for IL-20RB-mediated tumor proliferation and metastasis.

Further in vitro experiments confirmed that IL-19 promotes tumor cell proliferation by activating the JAK1/STAT3 signaling pathway. Additionally, the researchers developed a neutralizing antibody against IL-20RB, LTMA1G11, which significantly inhibited bone metastasis and proliferation of IL-20RB-expressing tumor cells in mouse models. Importantly, long-term use of this antibody in healthy mice did not show significant side effects, indicating good safety.

In summary, the study systematically validated the role of IL-20RB in lung cancer bone metastasis and identified IL-20RB as a novel therapeutic target. The neutralizing antibody against IL-20RB, LTMA1G11, demonstrated significant anti-metastatic effects in both in vivo and in vitro experiments, with good safety profiles. Compared to previous methods, this new therapeutic strategy offers greater targeting specificity, multiple mechanisms of action, and higher clinical application potential. This research provides a deeper understanding of the molecular mechanisms underlying lung cancer bone metastasis, offering essential scientific basis and technical support for developing new anti-cancer therapies.

However, FOXP2 has been found to potentially regulate the expression of IL-20RB, but its specific regulatory mechanisms and other possible regulatory factors still require further validation. Utilizing genomic and proteomic technologies to comprehensively identify and validate the upstream regulatory factors of IL-20RB will aid in a deeper understanding of its expression regulation mechanisms. Future research can expand clinical sample sizes, conduct long-term experimental observations, delve deeper into mechanistic studies, explore its roles in other cancers, and investigate the complex interactions between osteoclasts and tumor cells. These efforts will further refine and validate these findings, advancing cancer treatment progress.

Reference：

He, Yunfei, et al. "IL-20RB mediates tumoral response to osteoclastic niches and promotes bone metastasis of lung cancer." The Journal of Clinical Investigation 132.20 (2022).