Team:HZAU-China/Description
The importance of cancer treatments has already come to light. This year, we turned to this common concern and found out a new approach to help its development.
Cancers, the feral diseases that link to abnormal cell growth and surrounding tissues invasion, were earliest written in the Edwin Smith Papyrus in about 1600 BC1. Because of its high mortality and the extreme suffering, efficient therapies firmly come into the public consciousness. During these years, cancers have impelled the development of medical technology which serves as the powerful tool to defend against and advances in technology, this also have led to a rise in life expectancy. Despite its improvement, the result of Global Cancer Statistics 2018 predicts 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) at the end of 20182. It's obvious that we still have a long way to go.
We utilize a newly reported mechanism, the pyroptosis, to treat cancers. Pyroptosis is a lytic form of inflammatory cell death which is mediated by activation of Caspases 1, 3, 4, 5 and 11. The morphology of pyroptosis is characterized by cell swelling and rupturing which causes releasing of cytoplasmic contents of the cell, including proinflammatory cytokines, endogenous ligands, alarmins, ATP and other danger-associated molecular patterns3. What's important is that protein Gasdermin D (GSDMD) has been found as an essential effector of pyroptosis in recent studies. When host cells are defending the infection, full-length Gasdermin D will be cleaved by Caspases and the process will expose the N-terminal of Gasdemin D (PFD, pore form domain) from RD (repressor domain). PFD can oligomerize and form pores on the plasma membrane, sodium and water rush into the cell subsequently, causing the cell rupture. But only applicable in the intracellular side. Simultaneously, cytokines such as IL-1β, IL-18 are released into the extracellular environment through the Gasdermin pores4 (Figure 1).
Some points about the relationship of pyroptosis and cancers that are demonstrated in recent studies:
1. Berberine inhibits the viability of HepG2 cell through induction of pyroptosis5.
2. Caspase 1 rescues the sensitivity of radiant lethality in prostate cancer, increasing the proportion of death cancer cells after radiation therapy6.
3. Nlrp3-/- mice without pyroptosis pathway are susceptible to catch colitis-associated colon cancer7.
These meaningful studies help us to exploit advantage of pyroptosis in tumor therapy.
Our project aims to cure cancer by triggering pyroptosis through translocate the N-terminal of GSDMD (GSDMD-N275). There are many vectors can be choose such as oncolytic virus, macromolecular carrier and bacteria. In our project, we choose Salmonella enterica serovar Typhimurium str. SL1344 as a carrier. The reason why we chose Salmonella as our carrier are based on following reason. First, in consideration of GSDMD-N275 induced pyroptosis only when delivered cytosolically but not extracellularly, Salmonella is a brilliant candidate as a intracellular parasite. Second, Salmonella is a widely used carrier to cancer therapy because its natural taxis to tumor8.
It's important to highlight our significances.
1. Switch apoptosis to pyroptosis in chemical therapy.
Numerous patients accept chemotherapy during their fight against cancers though there is a terrible
drawback. Chemotherapy drugs can activate caspase-3-mediated pyroptosis in normal tissue while
apoptosis in cancer cells, resulting in severe healthy tissue damage but inefficiency tumor cure9.
But our designed circuit can trigger pyroptosis in cancer cells to solve this problem.
2. Pyroptosis make tumor expose to immune system.
The lysate of cell rupture during pyroptosis can destroy tumor microenvironment which is vital to
tumor growth. Pyroptosis not only releases "find me" signals but also "eat me" signals10.
Pyroptosis induces greater ATP release than apoptosis to attract more immune cells into tumor bed,
which is one of our "find me" signals. Also, ATP can bind to purinergic P2RX7 receptors on DC,
activating the NLRP3/ASC/Caspase-1 inflammasome and secreting interleukin-1β (IL-1β), which is
required for CD8+ T cells to release IFNγ which lysis tumor cells11. The "eat me" signal is the
phosphatidylserine externalization to recruit macrophages to engulf the tumor cells.
3. Pyroptosis recombine with antibody-dependent cellular cytotoxicity (ADCC) will become more
efficient.
Some monoclonal antibodies such as trastuzumab (TRAST), alemtuzumab, cetuximab and panitumumab
have been taken on board for both solid tumors and hematologic malignancies treatments through
ADCC12. It's a special way to recruit nature kill cell (NK cell), macrophages, γδ T cells, and
dendritic cells to against cancer. However lower activity of NK cell hinder the development of this
approach13. In our project, we give a new insight to solve this problem. IL-18 released from
pyroptotic cells can stimulate natural killer cell proliferation and activation14. Meanwhile
pyroptosis also up-regulates intercellular cell adhesion molecule-1 (ICAM-1 or CD54) which binds to
alpha integrin on the tumor cell result in enhancing the ability of combination between NK cells
and tumor cells15.
4. Safe utilization of the N-terminal of GSDMD.
Recent studies demonstrated that the N-terminal of GSDMD executes the function through bind to
inositol phosphate (present in inner leaflet of cell membrane) in eukaryotic cell but cardiolipin
(present in the inner and outer leaflets of cell membranes) in bacteria16. Thus, the N-terminal of
GSDMD releasing from bacteria in extracellular is avirulent and attack both tumor cells and
redundant bacteria.
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2. Bray, F. et al. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA A J. Clin. 00, 1–31 (2018).
3. Kovacs, S. B. & Miao, E. A. Gasdermins: Effectors of Pyroptosis. Trends Cell Biol 27, 673-684, doi:10.1016/j.tcb.2017.05.005 (2017).
4. Ding, J. et al. Pore-forming activity and structural autoinhibition of the gasdermin family. Nature 535, 111-116, doi:10.1038/nature18590 (2016).
5. Pyroptosis is involved in the pathogenesis of human hepatocellular carcinoma (2016).
6. Rachel N. Winter, A. K., Andrew Borkowski, and Natasha Kyprianou. Loss of Caspase-3 Protein Expression in Human Prostate Cancer. CANCER RESEARCH 61, 1227-1232 (2001).
7. Allen, I. C. et al. The NLRP3 inflammasome functions as a negative regulator of tumorigenesis during colitis-associated cancer. J Exp Med 207, 1045-1056, doi:10.1084/jem.20100050 (2010).
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9. Wang, Y. et al. Chemotherapy drugs induce pyroptosis through caspase-3 cleavage of a gasdermin. Nature 547, 99-103, doi:10.1038/nature22393 (2017).
10. Wang, Q. et al. Pyroptotic cells externalize eat-me and release find-me signals and are efficiently engulfed by macrophages. Int Immunol 25, 363-372, doi:10.1093/intimm/dxs161 (2013).
11. Ghiringhelli, F. et al. Activation of the NLRP3 inflammasome in dendritic cells induces IL-1beta-dependent adaptive immunity against tumors. Nat Med 15, 1170-1178, doi:10.1038/nm.2028 (2009).
12. Nelson, A. L. & Reichert, J. M. Development trends for therapeutic antibody fragments. Nat. Biotechnol. 27, 331–337 (2009).
13. Kohrt, H. E. et al. Combination strategies to enhance antitumor ADCC. Immunotherapy 4, 511–527 (2012).
14. Cheng, M., Chen, Y., Xiao, W., Sun, R. & Tian, Z. NK cell-based immunotherapy for malignant diseases. Cell. Mol. Immunol. 10, 230–252 (2013).
15. Kohrt, H., Rajasekaran, N., Chester, C., Yonezawa, A. & Zhao, X. Enhancement of antibody-dependent cell mediated cytotoxicity: a new era in cancer treatment. ImmunoTargets Ther. 91 (2015). doi:10.2147/ITT.S61292
16. Liu, X. et al. Inflammasome-activated gasdermin D causes pyroptosis by forming membrane pores. Nature 535, 153-158, doi:10.1038/nature18629 (2016).
