Difference between revisions of "Team:HZAU-China/Description"

 
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                 <div class="h1">Background</div>
 
                 <div class="h1">Background</div>
 
                 <p>The importance of cancer treatments has already come to light. This year, we turned to this common
 
                 <p>The importance of cancer treatments has already come to light. This year, we turned to this common
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                     concern and found out a new approach to help its development.</p>
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                     concern and found out a new approach to help its solution.</p>
 
                 <div class="h2">Cancer</div>
 
                 <div class="h2">Cancer</div>
 
                 <p>Cancers, the feral diseases that link to abnormal cell growth and surrounding tissues invasion, were
 
                 <p>Cancers, the feral diseases that link to abnormal cell growth and surrounding tissues invasion, were
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                     the extreme suffering, efficient therapies firmly come into the public consciousness. During these
 
                     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
 
                     years, cancers have impelled the development of medical technology which serves as the powerful
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                     tool to defend against and advances in technology also have led to a rise in life expectancy.
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                     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
 
                     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
 
                     about 18.1 million new cancer cases (17.0 million excluding nonmelanoma skin cancer) and 9.6
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                     It's
 
                     It's
 
                     obvious that we still have a long way to go. </p>
 
                     obvious that we still have a long way to go. </p>
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            </div>
 
  
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            <div id="float02">
 
 
                 <div class="h2">Pyroptosis</div>
 
                 <div class="h2">Pyroptosis</div>
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                 <p>We utilize a newly reported mechanism, the pyroptosis, to treat cancers. Pyroptosis is a lytic form
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                 <p>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
 
                     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
 
                     morphology of pyroptosis is characterized by cell swelling and rupturing which causes releasing of
 
                     cytoplasmic contents of the cell, including proinflammatory cytokines, endogenous ligands,
 
                     cytoplasmic contents of the cell, including proinflammatory cytokines, endogenous ligands,
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                     alarmins, ATP and other danger-associated molecular patterns<sup>3</sup>. What's important is that
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                     alarmins, ATP and other danger-associated molecules<sup>3</sup>. What's important is that
 
                     protein
 
                     protein
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                     Gasdermin D (GSDMD) has been found as an essential effector of pyroptosis in recent studies. When
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                     Gasdermin D (GSDMD) has been found as an essential effector of pyroptosis in recent studies<sup>4</sup>.
 +
                    When
 
                     host cells are defending the infection, full-length Gasdermin D will be cleaved by Caspases and the
 
                     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
 
                     process will expose the N-terminal of Gasdemin D (PFD, pore form domain) from RD (repressor
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                     domain). PFD can oligomerize and form pores on the plasma membrane, sodium and water rush into the
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                     domain). PFD can oligomerize and form pores on the plasma membrane from the intracellular side,and
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                    cell subsequently, causing the cell rupture. But only applicable in the intracellular side.
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                    then sodium and water rush into the cell, causing cell rupture.
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                     Simultaneously, cytokines such as IL-1β, IL-18 are released into the extracellular environment
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                     Simultaneously, cytokines such as IL-1βand IL-18 are released into the extracellular environment
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                     through the Gasdermin pores<sup>4</sup> (Figure 1).</p>
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                     through the Gasdermin pores (<b>Figure 1</b>).</p>
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                 <p>Some points about the relationship of pyroptosis and cancers that are demonstrated in recent
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                 <p>Some features about the relationship between pyroptosis and cancers are demonstrated in recent
 
                     studies:</p>
 
                     studies:</p>
 
                 <p>1. Berberine inhibits the viability of HepG2 cell through induction of pyroptosis<sup>5</sup>.</p>
 
                 <p>1. Berberine inhibits the viability of HepG2 cell through induction of pyroptosis<sup>5</sup>.</p>
 
                 <p>2. Caspase 1 rescues the sensitivity of radiant lethality in prostate cancer, increasing the
 
                 <p>2. Caspase 1 rescues the sensitivity of radiant lethality in prostate cancer, increasing the
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                     proportion of death cancer cells after radiation therapy<sup>6</sup>.</p>
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                     proportion of died cancer cells after radiation therapy<sup>6</sup>.</p>
 
                 <p>3. <i>Nlrp3</i><sup>-/-</sup> mice without pyroptosis pathway are susceptible to catch
 
                 <p>3. <i>Nlrp3</i><sup>-/-</sup> mice without pyroptosis pathway are susceptible to catch
 
                     colitis-associated colon cancer<sup>7</sup>.</p>
 
                     colitis-associated colon cancer<sup>7</sup>.</p>
 
                 <p>These meaningful studies help us to exploit advantage of pyroptosis in tumor therapy.</p>
 
                 <p>These meaningful studies help us to exploit advantage of pyroptosis in tumor therapy.</p>
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                <div style="width: 80%; margin: 0px auto">
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                    <img src="https://static.igem.org/mediawiki/2018/1/13/T--HZAU-China--description1.jpg" width="100%">
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                </div>
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                <p style="width: 100%; text-align: center !important;"><b>Figure 1.</b> Schematic diagram of
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                    pyroptosis.</p>
 
                 <div class="h2">Carrier</div>
 
                 <div class="h2">Carrier</div>
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                 <p>Our project aims to cure cancer by triggering pyroptosis through translocate the N-terminal of GSDMD
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                 <p>Our project aims to cure cancer by triggering pyroptosis through translocating the N-terminal of
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                     (GSDMD-N275). There are many vectors can be choose such as oncolytic virus, macromolecular carrier and
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                    GSDMD
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                     bacteria. In our project, we choose <i>Salmonella enterica</i> serovar Typhimurium str. SL1344
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                     (GSDMD-N275). There are many vectors can be used such as oncolytic virus, macromolecular carrier
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                     as a carrier. The reason why we chose <i>Salmonella</i> as our carrier are based on following reason.
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                    and
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                     First, in consideration of GSDMD-N275 induced pyroptosis only when delivered cytosolically but not
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                     bacteria. In our project, we chose <i>Salmonella enterica</i> serovar Typhimurium str. SL1344
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                    extracellularly, <i>Salmonella</i> is a brilliant candidate as a intracellular parasite. Second,
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                     as a carrier. Why we chose <i>Salmonella</i> as our carrier is based on the following reasons.
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                    <i>Salmonella</i> is a widely used carrier to cancer therapy because its natural taxis to tumor<sup>8</sup>.
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                     First, GSDMD-N275 can only induce pyroptosis from the inside of a cell, therefore <i>Salmonella</i>
 +
                    is a
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                    brilliant candidate as an intracellular parasite. Second, <i>Salmonella</i> is a widely used
 +
                    carrier to cancer therapy because its natural taxis to tumor<sup>8</sup>.
 
                 </p>
 
                 </p>
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            </div>
  
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            <div id="float02">
 
                 <div class="h1">Significance</div>
 
                 <div class="h1">Significance</div>
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                 <p>It's important to highlight our significances.</p>
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                 <p>It's important to highlight the significance our project.</p><br>
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                 <p> <b>1. Switch apoptosis to pyroptosis in chemical therapy.</b><br>
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                 <p> <b>1. Switch apoptosis to pyroptosis in chemical therapy</b><br>
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                     Numerous patients accept chemotherapy during their fight against cancers though there is a terrible
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                     Numerous patients accept chemotherapy during their fight against cancers though there are terrible
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                     drawback. Chemotherapy drugs can activate caspase-3-mediated pyroptosis in normal tissue while
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                     drawbacks. Chemotherapy drugs can activate caspase-3-mediated pyroptosis in normal cells while
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                     apoptosis in cancer cells, resulting in severe healthy tissue damage but inefficiency tumor cure<sup>9</sup>.
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                     apoptosis in cancer cells, resulting in severe healthy tissue damage and inefficient tumor cure<sup>9</sup>.
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                     But our designed circuit can trigger pyroptosis in cancer cells to solve this problem.</p>
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                     However, our designed circuit can trigger pyroptosis in cancer cells to solve this problem (<b>Figure
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                 <p> <b>2. Pyroptosis make tumor expose to immune system.</b><br>
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                        2</b>).</p>
 +
                <div style="width: 80%; margin: 0px auto">
 +
                    <img src="https://static.igem.org/mediawiki/2018/0/0a/T--HZAU-China--description2.jpg" width="100%">
 +
                </div>
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                <p><b>Figure 2.</b> Difference between traditional approach and our approach for cancer therapy. G refers to GSDMD-N275 and E refers to GSDME.</p><br>
 +
                 <p> <b>2. Pyroptosis make tumor expose to immune system</b><br>
 
                     The lysate of cell rupture during pyroptosis can destroy tumor microenvironment which is vital to
 
                     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" signals<sup>10</sup>.
 
                     tumor growth. Pyroptosis not only releases "find me" signals but also "eat me" signals<sup>10</sup>.
 
                     Pyroptosis induces greater ATP release than apoptosis to attract more immune cells into tumor bed,
 
                     Pyroptosis induces greater ATP release than apoptosis to attract more immune cells into tumor bed,
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                     which is one of our "find me" signals. Also, ATP can bind to purinergic P2RX7 receptors on DC,
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                     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
 
                     activating the NLRP3/ASC/Caspase-1 inflammasome and secreting interleukin-1β (IL-1β), which is
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                     required for CD8<sup>+</sup> T cells to release IFNγ which lysis tumor cells<sup>11</sup>. The "eat me" signal is the
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                     required for CD8<sup>+</sup> T cells to release IFN-γ which lyse tumor cells<sup>11</sup>. The "eat
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                     phosphatidylserine externalization to recruit macrophages to engulf the tumor cells.</p>
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                    me" signal is the
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                 <p> <b>3. Pyroptosis recombine with antibody-dependent cellular cytotoxicity (ADCC) will become more
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                     phosphatidylserine externalization which recruits macrophages to engulf the tumor cells (<b>Figure
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                         efficient.</b><br>
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                        3</b>).</p>
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                     Some monoclonal antibodies such as trastuzumab (TRAST), alemtuzumab, cetuximab and panitumumab  
+
                <div style="width: 80%; margin: 0px auto">
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                     have been taken on board for both solid tumors and hematologic malignancies treatments through
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                    <img src="https://static.igem.org/mediawiki/2018/d/d2/T--HZAU-China--description3.jpg" width="100%">
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                     ADCC<sup>12</sup>. It's a special way to recruit nature kill cell (NK cell), macrophages, γδ T cells, and
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                </div>
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                     dendritic cells to against cancer. However lower activity of NK cell hinder the development of this
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                <p style="width: 100%; text-align: center !important;"><b>Figure 3.</b> Schematic diagram of immune
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                     approach<sup>13</sup>. In our project, we give a new insight to solve this problem. IL-18 released from
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                    response during pyroptosis.</p><br>
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                     pyroptotic cells can stimulate natural killer cell proliferation and activation<sup>14</sup>. Meanwhile
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 +
                 <p> <b>3. Pyroptosis combined with antibody-dependent cellular cytotoxicity (ADCC) will become more
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                         efficient</b><br>
 +
                     Some monoclonal antibodies such as trastuzumab (TRAST), alemtuzumab, cetuximab and panitumumab
 +
                     have been utilized for both solid tumors and hematologic malignancies treatments through
 +
                     ADCC<sup>12</sup> (<b>Figure 4</b>). 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
 +
                     approach<sup>13</sup>. In our project, we give a new approach to solve this problem. IL-18 released
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                    from
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                     pyroptotic cells can stimulate NK cells proliferation and activation<sup>14</sup>. Meanwhile,
 
                     pyroptosis also up-regulates intercellular cell adhesion molecule-1 (ICAM-1 or CD54) which binds to
 
                     pyroptosis also up-regulates intercellular cell adhesion molecule-1 (ICAM-1 or CD54) which binds to
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                     alpha integrin on the tumor cell result in enhancing the ability of combination between NK cells
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                     alpha integrin on the tumor cell, resulting in enhancing the affinity between NK cells and tumor
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                    and tumor cells<sup>15</sup>.</p>
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                    cells<sup>15</sup> (<b>Figure 5</b>).</p>
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                 <p> <b>4. Safe utilization of the N-terminal of GSDMD.</b><br>
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                <div style="width: 80%; margin: 0px auto">
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                     Recent studies demonstrated that the N-terminal of GSDMD executes the function through bind to
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                    <img src="https://static.igem.org/mediawiki/2018/e/e4/T--HZAU-China--description4.jpg" width="100%">
 +
                </div>
 +
                <p style="width: 100%; text-align: center !important;"><b>Figure 4. </b>Schematic diagram of antibody-dependent cellular cytotoxicity. </p>
 +
 
 +
                <div style="width: 80%; margin: 0px auto">
 +
                    <img src="https://static.igem.org/mediawiki/2018/f/fa/T--HZAU-China--description5.jpg" width="100%">
 +
                </div>
 +
                <p style="width: 100%; text-align: center !important;"><b>Figure 5. </b> Activation and proliferation of NK cells.</p><br>
 +
                 <p> <b>4. Safe utilization of the N-terminal of GSDMD</b><br>
 +
                     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
 
                     inositol phosphate (present in inner leaflet of cell membrane) in eukaryotic cell but cardiolipin
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                     (present in the inner and outer leaflets of cell membranes) in bacteria<sup>16</sup>. Thus, the N-terminal of
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                     (present in the inner and outer leaflets of cell membranes) in bacteria<sup>16</sup>. Thus, the
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                     GSDMD releasing from bacteria in extracellular is avirulent and attack both tumor cells and
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                    N-terminal of
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                    redundant bacteria.</p>
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                     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.</p>
 
             </div>
 
             </div>
  
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                 <p>4. Ding, J. et al. Pore-forming activity and structural autoinhibition of the gasdermin family.
 
                 <p>4. Ding, J. et al. Pore-forming activity and structural autoinhibition of the gasdermin family.
 
                     Nature 535, 111-116, doi:10.1038/nature18590 (2016).</p>
 
                     Nature 535, 111-116, doi:10.1038/nature18590 (2016).</p>
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                 <p>5. Pyroptosis is involved in the pathogenesis of human hepatocellular carcinoma (2016).</p>
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                 <p>5. Chu Q. et al. Pyroptosis is involved in the pathogenesis of human hepatocellular carcinoma.
 +
                    Oncotarget 7, 84658-84665, doi:10.18632/oncotarget.12384 (2016). </p>
 
                 <p>6. Rachel N. Winter, A. K., Andrew Borkowski, and Natasha Kyprianou. Loss of Caspase-3 Protein
 
                 <p>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).</p>
 
                     Expression in Human Prostate Cancer. CANCER RESEARCH 61, 1227-1232 (2001).</p>
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<h2>Backgroud about pyroptosis</h2>
 
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<p>
 
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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.<sup>1</sup> A recent study reported that Gasdermin D is a essential effector of pyroptosis.<sup>2</sup> Full length Gasdermin D 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)<sup>3</sup>. 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 pore<sup>4</sup> (Fig 1).(找美工画)
 
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</p>
 
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<p>
 
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Some recent studies demonstrated following points：
 
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</p>
 
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<p>
 
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1.Berberin inhibits the viability of HepG2 cell though induction of pyroptosis<sup>5</sup>.
 
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</p>
 
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<p>
 
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2.Caspase 1 rescure the sensitivity of radiant lethality in prostate cancer <sup>6</sup>.
 
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</p>
 
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<p>
 
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3.<em>Nlrp3</em>−/− mice are susceptible to colitis associated colon cancer<sup>7</sup>.
 
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</p>
 
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<p>
 
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According to these studies, we think pyroptosis can be exploited for tumor suppression.
 
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</p>
 
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<p>
 
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</p>
 
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<h2>Significance</h2>
 
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<p>
 
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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 kill<sup>8</sup>. Our project can trigger pyroptosis in cancer cells through targeted vector in order to switch this process(Fig 2). .(找美工画)
 
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</p>
 
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<p>
 
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What else, the lysate of cell rupture during pyroptosis destroy tumor microenvironment. Pyroptosis not only releases "find me" signal and "eat me" signal<sup>9</sup>. "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 cells<sup>10</sup>. During pyroptosis, phosphatidylserineexternalization as a "eat me" signal to recruit macrophage to engulf the tumor cells(Fig 3).(找美工画)
 
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</p>
 
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<p>
 
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</p>
 
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<p>
 
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</p>
 
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<h2>Reference </h2>
 
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<p>
 
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1        Kovacs, S. B. & Miao, E. A. Gasdermins: Effectors of Pyroptosis. <em>Trends Cell Biol</em> <strong>27</strong>, 673-684, doi:10.1016/j.tcb.2017.05.005 (2017).
 
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</p>
 
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<p>
 
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2        Shi, J.<em> et al.</em> Cleavage of GSDMD by inflammatory caspases determines pyroptotic cell death.<em>Nature</em> <strong>526</strong>, 660-665, doi:10.1038/nature15514 (2015).
 
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</p>
 
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<p>
 
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3        Ding, J.<em> et al.</em> Pore-forming activity and structural autoinhibition of the gasdermin family. <em>Nature<strong>535</strong></em>, 111-116, doi:10.1038/nature18590 (2016).
 
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</p>
 
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<p>
 
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4        Liu, X.<em> et al.</em> Inflammasome-activated gasdermin D causes pyroptosis by forming membrane pores. <em>Nature</em> <strong>535</strong>, 153-158, doi:10.1038/nature18629 (2016).
 
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</p>
 
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<p>
 
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5        Pyroptosis is involved in the pathogenesis of human hepatocellular carcinoma.(2016
 
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</p>
 
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<p>
 
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).
 
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</p>
 
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<p>
 
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6        Rachel N. Winter, A. K., Andrew Borkowski, and Natasha Kyprianou. Loss of Caspase-3 Protein Expression in Human Prostate Cancer. <em>CANCER RESEARCH</em> <strong>61</strong>, 1227-1232 (2001).
 
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</p>
 
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7        Allen, I. C.<em> et al.</em> The NLRP3 inflammasome functions as a negative regulator of tumorigenesis during colitis-associated cancer. <em>J Exp Med</em> <strong>207</strong>, 1045-1056, doi:10.1084/jem.20100050 (2010).
 
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8        Wang, Y.<em> et al.</em> Chemotherapy drugs induce pyroptosis through caspase-3 cleavage of a gasdermin. <em>Nature</em> <strong>547</strong>, 99-103, doi:10.1038/nature22393 (2017).
 
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9        Wang, Q.<em> et al.</em> Pyroptotic cells externalize eat-me and release find-me signals and are efficiently engulfed by macrophages. <em>Int Immunol</em> <strong>25</strong>, 363-372, doi:10.1093/intimm/dxs161 (2013).
 
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10      Ghiringhelli, F.<em> et al.</em> Activation of the NLRP3 inflammasome in dendritic cells induces IL-1beta-dependent adaptive immunity against tumors. <em>Nat Med</em> <strong>15</strong>, 1170-1178, doi:10.1038/nm.2028 (2009).
 
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Latest revision as of 21:16, 17 October 2018

Background

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.

Cancer

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.

Pyroptosis

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.

Carrier

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.

Significance

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.

Reference

1. Steven, Hajdu. A note from history: Landmarks in history of cancer, part 1. Cancer, 117(5), 1097-1102 (2011a).

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. Chu Q. et al. Pyroptosis is involved in the pathogenesis of human hepatocellular carcinoma. Oncotarget 7, 84658-84665, doi:10.18632/oncotarget.12384 (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).

8. Forbes, N. S. Engineering the perfect (bacterial) cancer therapy. Nat Rev Cancer 10, 785-794, doi:10.1038/nrc2934 (2010).

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).

Description

Background

Significance

Reference

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