Recently, the research group led by Prof. Wei Qiang and Associate Professor Yang Lu of the Department of Urinary Surgery of WCH published a research paper titled Biomaterial 3D Collagen I gel Culture Model: A Novel Approach to Investigate Tumorigenesis and Dormancy of Bladder Cancer Cells Induced by the Tumor Microenvironment on Biomaterials（IF=10.317）, disclosing that after inhibiting the integrin α2β1/PI3K/AKT/NF-κB signal pathways, the reversion of non-tumorigenic cell to cancer stem cell with tumorigenic potential induced in the collagen I-based 3D tumor microenvironment can be blocked. Simultaneously, in vivo studies demonstrate that IFN-γ secreted by T cells can trigger those CSCs into dormancy through the IDO/Kyn/AHR/P27 cascade, which elicits chemotherapy resistance and cancer relapse.
As the most common malignant tumor of the urinary system in China, bladder cancer is characterized by low cure rate and high recurrence rate. Most malignant tumors are generally considered as heterogeneous. Just because of the heterogeneity, the tumors cannot be completely removed by means of chemotherapy, which is mainly attributable to the existence and influence of cancer stem cells. The stem cell-like phenotype of tumor induced by the tumor microenvironment may be one of the reasons for the poor effect of chemotherapy on the bladder cancer, with the specific mechanism remaining unknown. This has become an important factor restricting the treatment of bladder cancer and affecting the prognosis of bladder cancer. Therefore, the efforts to explore the cancer stem cell-related therapeutic targets have played an active role in the development of new medicines and new treatment strategies for bladder cancer.
In this study, a three-dimensional cell culture model based on the type I collagen and a subcutaneous tumor bearing model of bladder cancer were established, which confirmed the necessity of the three-dimensional collagen microenvironment in the maintenance of the cancer stem cell-like phenotype. This study found that the inhibition of the integrin α2β1/PI3K/AKT/NF-κB signal pathways could block the reversion of non-tumorigenic cell to cancer stem cell with tumorigenic potential induced by in the collagen I-based 3D tumor microenvironment. Further experiments revealed that inhibiting this integrin α2β1/PI3K/AKT/NF-κB signal pathways can significantly impair the tumorigenic capacity of cancer stem cells. Simultaneously, in vivo studies demonstrate that IFN-γ secreted by T cells can trigger those cancer stem cells into dormancy through the IDO/Kyn/AHR/P27 cascade, which elicit chemotherapy resistance and cancer relapse. To achieve suppressing bladder tumor growth and preventing tumor recurrence, the investigators used IDO and integrin α2β1 signal pathway inhibitors combine with chemotherapeutic agents to awake dormant bladder cancer stem cells and inhibit their tumorigenic ability as well as effectively eliminate cancer stem cells.
This project is designed to conduct an in-depth research on the mechanism in which the tumor microenvironment induces bladder cancer stem cells into tumorigenesis, the results of which can help us better screen and induce bladder cancer cells with the stem cell-like phenotype, and lay a theoretical foundation for the clinical application of tumor stem cell targeted drugs and chemotherapy drugs, thereby providing a new direction for the treatment of bladder cancer.
Qiu Shi, Physician of the Department of Urinary Surgery of WCH and Dr. Qiu Yaqi of the State Key Laboratory of Biotherapy are the first authors; West China Hospital of Sichuan University is the first author institute; Prof. Wei Qiang and Associate Professor Yang Lu of the Department of Urinary Surgery of WCH are the co-corresponding authors of the article. The research has been supported by both programs under the National Natural Science Foundation of China and the National Key R&D Program of China.
