China News Service, May 16. According to Hong Kong Sing Tao.com, the mortality rate of ovarian cancer patients ranks first among many gynecological cancers. The reason is that more than 70% of patients are diagnosed in the late stage of the disease, when most of the cancer cells are already in the abdominal cavity. Diffusion, difficult to treat.
A research team from the School of Biological Sciences at the University of Hong Kong has discovered that cancer cells can exploit a novel interaction with tumor-associated macrophages to promote peritoneal metastasis of ovarian cancer. It has been published in the internationally renowned scientific journal Advanced Science.
It is understood that the morphological and phenotypic characteristics of individual cancer cells are different based on the heterogeneity of tumors, and the multi-layered interaction between cancer cells and the tumor microenvironment makes the treatment of peritoneal metastasis of ovarian cancer very difficult. difficulty.
In the process of peritoneal metastases, the study of cellular and molecular mechanisms is the key to finding therapeutic methods, but the lack of suitable experimental models poses many obstacles.
In addition, traditional cell experiments generally employ batch assays, so the scientific community remains poorly understood about the unique interactions between individual different cancer cell subclones and the tumor microenvironment.
By observing humanized mouse models, the Hong Kong University team found that the Wnt/β-catenin signaling pathway increases the metadherin protein on the surface of metastatic ovarian cells, which in turn transmits signals through CEACAM1 expressed by macrophages. Communication between phagocytes and cancer cells can effectively reduce peritoneal metastasis in immune cells.
Based on the heterogeneity of cancer cells, the research team established an isogenic experimental model that can simulate spontaneous metastasis of ovarian cancer.
Using this model coupled with gene sequencing and bioinformatics analysis, the researchers found that the Wnt/β-catenin signaling pathway was up-regulated in ovarian cancer cells with high metastatic potential.
The Wnt/β-catenin signaling pathway plays an important role in embryonic development and maintenance of tissue homeostasis, as well as in cancer; the upregulation of signaling increases the expression of other oncogenes and contributes to the spread of cancer cells.
Macrophages play a key role in coordinating innate and adaptive immune responses, and are the most abundant immune cells in the ovarian cancer tumor microenvironment.
When the team used "live cell real-time imaging" to analyze the activity behavior of single cells, it was found that when the metastatic cells were co-cultured with macrophages, some of the metastatic cells would be more easily transformed into "polyploid", that is, a kind of cell that can promote Phenotypes of tumor aggressiveness and treatment resistance.
On the other hand, experiments have shown that metastatic cells can polarize macrophages to a tumor-associated phenotype, which in turn contributes to metastatic cell polyploidy.
Subsequent molecular analysis showed that the β-catenin signaling pathway can upregulate metadherin protein on the surface of cancer cells, which in turn transmits signals through CEACAM1 expressed by macrophages.
The team transplanted human ovarian cancer cells into mice with humanized immune systems and demonstrated that blocking macrophage-cancer cell communication by inhibiting metadherin or CEACAM1 effectively reduced peritoneal metastasis.
The study focuses on the discovery that the direct interaction of metastatic cells with macrophages is a potential driving mechanism for polyploidy and genomic instability, one of the reasons for the spread of cancer cells.
The molecular signaling pathways revealed in this study can help to develop therapeutic strategies to inhibit the formation of polyploidy in metastatic cells to control the peritoneal spread of ovarian cancer.
The research team plans to further explore the signaling mechanisms that drive polyploidy formation in metastatic cells, which will greatly advance the understanding of genomic instability in ovarian cancer.