Tumor Cells Form “Cliques” for Metastasis, Our Hospital Finds a New Therapeutic Target in the Immune Escape Mechanism of Pancreatic Carcinoma
Gastrointestinal tumors dominated by pancreatic carcinoma account for about half of all malignant tumors. Pancreatic carcinoma is a kind of malignant gastrointestinal tumor that comes quietly, develops fast and difficult to give prognosis. It’s known as the king of cancer, because early diagnosis is difficult, but metastasis is easy. As a result, elucidating the specific mechanism of relapse and metastasis and finding new molecular therapeutic targets are significant to the development of more effective clinical prevention and treatment strategies. After years of research, Prof. Qiu Zhengjun’s team in our hospital’s General Surgery Department finally made breakthroughs in the mechanism of tumor metastasis: tumor cells domesticate macrophages through exosomes that carry signaling molecules, to escape immune surveillance and achieve distant metastasis. The research results have been published in the latest issue of the internationally authoritative journal on oncology Cancer Research.
First, using the electron microscope and NTA and other technologies, the research team confirmed that hypoxia can increase the exosomes secreted by tumor cells. Immumohistochemical staining showed that there were obviously more exosome markers in the tumor tissue than in the normal tissue nearby.
Next, after the research team co-incubated macrophages with the exosomes secreted by tumor cells in hypoxia, something interesting happened. After taking the exosomes, the macrophages became renegades. They were domesticated into M2 macrophages. It is known that M2 macrophages can participate in anti-inflammatory responses, angiogenesis, and promote tumor growth and metastasis, etc. After being induced by exosomes, M2 macrophages began to help tumor cells to achieve metastasis. This means that in the process of metastasis, tumor cells can effectively use other stromal cells in the tumor microenvironment to form “cliques” to achieve its purpose.
Using the miRNA chip technology, the research team detected that miRNA-301a obviously increased in hypoxia. After macrophages were co-incubated with exosomes rich in miRNA-301a, the miRNA-301a expression in macrophages also increased obviously. Further research and analysis found that miRNA-301a lowered the cancer suppressor gene PTEN and activated PI3Kγ, a key signaling molecule to the M2 polarization of macrophages, to domesticate macrophages. To verify the value of miRNA-301a in tumor diagnosis and prognosis, the research team tested the expression of miRNA-301a in the blood exosomes of tumor patients and found a positive correlation between it and the TNM staging and a negative correlation between it and the survival rate. Through independent regression analysis, it was found that miRNA-301a may be an independent prognostic factor for pancreatic cancer. Moreover, the research team established a model of lung metastasis in nude mice by tail vein injection and found that macrophages induced by exosomes of tumor cells also facilitated tumor cell metastasis.
Through this research, Prof. Qiu Zhengjun's team for the first time confirmed the regulatory role of Exosomal-miR-301a in tumor immune escape and metastasis. As a cancer promotor, Exosomal-miR-301a may become a new therapeutic target for treating gastrointestinal tumors, particularly pancreatic carcinoma. It has important theoretical value and clinical significance.