Team:HZAU-China/Description
Cancers are diseases that link to abnormal cell growth and they have the potential to invade surrounding tissues. In medicine, the earliest written description of cancer was found in the Edwin Smith Papyrus in about 1600 BC. The history of cancer is accompanied by the history of medical technology development. Advances in medical technology have led to a rise in life expectancy, which has also made cancer come into the public eye more often. Despite advances in cancer therapy, the result of Global Cancer Statistics 2018 shows that there will be about 18.1 million new cancer cases (17.0 million excluding nonmelanoma skin cancer) and 9.6 million cancer deaths (9.5 million excluding nonmelanoma skin cancer) in 20181. In the meantime, cancer is expected to be the leading cause of death and the most important barrier in the way to increase life expectancy in every country of the world in the 21st century.1
Pyroptosis is a lytic form of inflammatory cell death which is induced by caspases 1, 3, 4, 5 and 11. The morpholog of pyroptosis is characterized by cell swelling which causes release of cytoplasmic contents of the cell, including proinflammatory cytokines, endogenous ligands, alarmins, ATP, and other danger-associated molecular patterns.1 A recent study reported that Gasdermin D is a essential effector of pyroptosis.2 Full length GasderminD can be cleave by Caspase when host cell defined the infection. Thus, the N-terminal of Gasdermin D named PTD(pore-forming domain) which can oligomerize to form pore on the plasm membrane is exposured from RD (repressor domain)3. subsequently, sodium and water rush into cell causes the cell swelling result in cell rupture. Simultaneously, IL-1β is released in to extracellular environment though the gasdermin pore4 (Fig 1).(找美工画) Some recent studies demonstrated following points： 1.Berberin inhibits the viability of HepG2 cell though induction of pyroptosis5. 2.Caspase 1 rescure the sensitivity of radiant lethality in prostate cancer 6. 3.Nlrp3−/− mice are susceptible to colitis associated colon cancer7. According to these studies, we think pyroptosis can be exploited for tumor suppression.
Recent study demonstrated that GSDME was expressed in many normal cells but silenced in most cancer cells. So chemotherapy drug activate caspase-3-mediated pyroptosis in normal tissue but caspase-3-mediated apoptosis in cancer cells result in high efficacy of tissue damage but low efficacy of tumor kill8. Our project can trigger pyroptosis in cancer cells through targeted vector in order to switch this process(Fig 2). .(找美工画) What else, the lysate of cell rupture during pyroptosis destroy tumor microenvironment. Pyroptosis not only releases “find me” signal and “eat me” signal9. “Find me” signal such as ATP attracts immune cell into tummor bed. Pyroptosis induce greater ATP release than apoptosis. These signals attract immune cell into tummor bed. On the other hand, ATP bind to purinergic P2RX7 receptors on DC, thus activating the NLRP3/ASC/caspase-1 inflammasome and secreting interleukin-1β (IL-1β) which is required for CD8+ T cells to releasing IFNγ which lysis tumour cells10. During pyroptosis, phosphatidylserine externalization as a “eat me” signal to recruit macrophage to engulf the tumor cells(Fig 3).(找美工画) Therapy combinate Pyroptosis and monoclonal antibody(mAbs) may get batter efficacy. Several monoclonal antibody such as trastuzumab (TRAST), alemtuzumab, cetuximab, panitumumab and ofatumumab, etc, have become one of the classical treatment of both solid tumors and hematologic malignancies11 12.These mAb can taget cancer cell and induce antibody-dependent cellular cytotoxicity(ADCC), a special way to recruit nature kill cell(NK cell), macrophages, γδ T cells, and dendritic cells to against cancer13. Pyroptosis released Tumor Necrosis Factor-α (TNFα) and Interferon-γ(IFN-γ)(Fig.4) will inducing proliferation of NK cell to enhance ADCC14 15. TNFα and IFN-γ can also up-regulated intercellular cell adhesion molecule-1(ICAM-1 or CD54) expression16.ICAM-1 enhance the ability of mAbs target Integrin(such as αvβ3 in our study）and combine with NK cell(Fig.5)17. Strengthen ADCC on the other hand.
