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 solution.
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, 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 molecules3. What's important is that protein Gasdermin D (GSDMD) has been found as an essential effector of pyroptosis in recent studies4. 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 from the intracellular side,and then sodium and water rush into the cell, causing cell rupture. Simultaneously, cytokines such as IL-1βand IL-18 are released into the extracellular environment through the Gasdermin pores (Figure 1).
Some features about the relationship between pyroptosis and cancers 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 died 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.
Figure 1. Schematic diagram of pyroptosis.
Our project aims to cure cancer by triggering pyroptosis through translocating the N-terminal of GSDMD (GSDMD-N275). There are many vectors can be used such as oncolytic virus, macromolecular carrier and bacteria. In our project, we chose Salmonella enterica serovar Typhimurium str. SL1344 as a carrier. Why we chose Salmonella as our carrier is based on the following reasons. First, GSDMD-N275 can only induce pyroptosis from the inside of a cell, therefore Salmonella is a brilliant candidate as an intracellular parasite. Second, Salmonella is a widely used carrier to cancer therapy because its natural taxis to tumor8.
It's important to highlight the significance our project.
1. Switch apoptosis to pyroptosis in chemical therapy
Numerous patients accept chemotherapy during their fight against cancers though there are terrible
drawbacks. Chemotherapy drugs can activate caspase-3-mediated pyroptosis in normal cells while
apoptosis in cancer cells, resulting in severe healthy tissue damage and inefficient tumor cure9.
However, our designed circuit can trigger pyroptosis in cancer cells to solve this problem (Figure
2).
Figure 2. Difference between traditional approach and our approach for cancer therapy. G refers to GSDMD-N275 and E refers to GSDME.
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 the "find me" signals. Also, ATP can bind to purinergic P2RX7 receptors on
dentritic cell (DC),
activating the NLRP3/ASC/Caspase-1 inflammasome and secreting interleukin-1β (IL-1β), which is
required for CD8+ T cells to release IFN-γ which lyse tumor cells11. The "eat
me" signal is the
phosphatidylserine externalization which recruits macrophages to engulf the tumor cells (Figure
3).
Figure 3. Schematic diagram of immune response during pyroptosis.
3. Pyroptosis combined with antibody-dependent cellular cytotoxicity (ADCC) will become more
efficient
Some monoclonal antibodies such as trastuzumab (TRAST), alemtuzumab, cetuximab and panitumumab
have been utilized for both solid tumors and hematologic malignancies treatments through
ADCC12 (Figure 4). It's a special way to recruit natural killer cells (NK cells), macrophages, γδ T
cells, and
dendritic cells to against cancer. However, lower activity of NK cells hinders the development of
this
approach13. In our project, we give a new approach to solve this problem. IL-18 released
from
pyroptotic cells can stimulate NK cells 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, resulting in enhancing the affinity between NK cells and tumor
cells15 (Figure 5).
Figure 4. Schematic diagram of antibody-dependent cellular cytotoxicity.
Figure 5. Activation and proliferation of NK cells.
4. Safe utilization of the N-terminal of GSDMD
Recent studies demonstrated that the N-terminal of GSDMD performs function through binding 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 is avirulent to normal cells (because of its extracellular location
to normal cells), but can attack tumor cells and redundant bacteria from inside.
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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).
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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).
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