Chapter 24: Cancer progression

StudyBlue printing of Chapter 24: Cancer progression html, body, div, span, applet, object, iframe, h1, h2, h3, h4, h5, h6, p, blockquote, pre, a, abbr, acronym, address, big, cite, code, del, dfn, em, font, img, ins, kbd, q, s, samp, small, strike, strong, sub, sup, tt, var, b, u, i, center, fieldset, form, label, legend, table, caption, tbody, tfoot, thead, tr, th, td { margin: 0; padding: 0; border: 0; outline: 0; font-size: 100%; background: transparent; } body { line-height: 1; } blockquote, q { quotes: none; } blockquote:before, blockquote:after, q:before, q:after { content: ''; content: none; } /* remember to define focus styles! */ :focus { outline: 0; } /* remember to highlight inserts somehow! */ ins { text-decoration: none; } del { text-decoration: line-through; } /* tables still need 'cellspacing="0"' in the markup */ table { border-collapse: collapse; border-spacing: 0; } /* end RESET */ .header { min-width:800px; } .logo { padding:6px 20px 2px 20px; margin:0; font-size:25px; font-weight:bold; color:#808285; position:relative; border-bottom: 1px solid #c5c5c5; } .logo-blue { color:#70adc4; } .logo-desc { font-weight:normal; font-size:19px; color:#cccccc; margin-top:50px; position:absolute; display: none; } .back-button { position:absolute; top:20px; right:20px; font-size:13px; line-height:25px; color:rgb(0,175,225); font-weight:normal; } .back-button a { color:rgb(0,175,225); } .instructions { padding:0; margin:0; width:100%; position:relative; color:rgb(100,100,100); } .step-holder { border-left:1px solid #ededed; margin-left:20px; } .steps { padding:15px 0; float:left; width:24%; border-right:1px solid #ededed; text-align:center; } .steps-01 { } .steps-02 { } .steps-03 { } .steps-04 { } .label { padding:5px 10px; } .print-button { } .print-button a { background-color:rgb(0,175,225); color:white; line-height: 19px; padding:9px 8px 5px 30px; font-size:14px; text-decoration:none; background-image: url(images/printer.png); background-repeat: no-repeat; background-position: 7px 50%; -moz-border-radius: 5px; -webkit-border-radius: 5px; } .print-button a:hover { background-color:black; } .theNote .content { width: 8.0in !important; margin: 5px auto; padding:20px; background-color:white; } .theNote .header { border-bottom: 1px dashed #C8C8C8; font-size: 17px; padding: 0 0 10px; line-height: 19px; color: #00ADE1; min-width:500px; } .theNote .body { font-size: 14px; line-height: 19px; padding: 10px 0; } .theNote{ padding:6px 0; clear:both; background-color: rgb(200,200,200); } .theNote h3{ color: rgb(100,100,100); } .theNote h1, .theNote h3{ background-color:white; padding:2px 20px; width:8.0in !important; margin: 0 auto; font-size: 15px; } .theNote h1{ padding-top: 10px; font-size: 15px; } .theNote h1:first-child{ font-size: 20px; } .theNote h3 { font-size: 14px; font-weight: normal; } #options { border: 3px double #ccc; padding: 5px 12px; margin: 10px 50px 10px 20px; float: left; } #info { border-top: 1px solid #ccc; padding-top: 5px; font-style: italic; } li { margin: 5px 10px 5px 25px; } ul li { list-style: disc; } ol li { list-style: decimal; } img { border: 0; } table { clear: both; width: 100%; border: 1px solid #c5c5c5; border-width: 1px 0; margin: 0; page-break-after: always; } table#page { page-break-after: auto; } td { text-align: center; font-size: 12px; border-bottom: 1px dashed #c5c5c5; height: 1.75in; width: 50%; padding-left: 15px; } .leftside { border-right: 1px solid #cccccc; padding: 0 15px 0 0; } .bottom td { border-bottom: none; } .clearfix { clear:both; line-height:1px; height:1px; } img { max-width:80%; max-height:150px; margin:20px; } @media print {.header { display: none; } .content .header{ display:inherit; } table { border: 1px dashed #bbb; border-width: 1px 0; } .theNote{ background-color:white; } } Cancer is a progressive disease. I t worsens as control of more and more cell biological processes is perturbed, switching them on or off inappropriately and changing the way cells behave in the context of the organism. Benign refers to cancers that proliferate more, but generally look like the tissue of origin and remain in this location. Malignant is when the cells no longer look lie the original cell type and begin to exit their original location (metastasis). One process that is commonly lost is the cells’ ability to undergo programmed cell death (apoptosis). In this process the cells break down the chromatin and organelles, fragment into pieces (blebbing), and are consumed by phagocytosis by surrounding cells. Apoptosis can be induced by a number of triggers, including massive activation of p53 by DNA damage. Immune cells can trigger apoptosis of target cells by secreting ligand (fas) that binds and activates a receptor system. Binding results in trimerization and the recruitment of pro-proteases (procaspases). In this complex the pro domain is cleaved off and the pro-proteases are converted to active proteases. Caspases activate more and more caspases, which in turn cleave specific target proteins at specific locations. This can inactivate (red) or activate (green) the target protein, thus driving the cellular events of apopotosis. A critical development later in cancer progression is the acquisition of tumor vasculature, which results from communication of cancer cells with the surrounding cells and the vascular cells. Low oxygen levels that occur when the tumor outgrows its blood supply induce the hypoxia response. The cells under hypoxia acquire more mutations, act more aggressively, and are more resistant to chemo and radiation. HIF transcription factors induce the response of cells to hypoxia. HIF1a is normally made and immediately degraded. Low oxygen prevent ubiquitylation and so it accumulates, dimerizes with HIF1b, and activates transcriptional responses of cells. One product of HIF transcription is VEGF, which is secreted and activates RTK signaling on nearby vascular endothelial cells, inducing proliferation and the formation of blood vessels into the tumor. Interestingly, the presence of a large primary tumor can prevent secondary metastatic tumors from acquiring vasculature. In metastasis, individual cells receive signals or acquire mutations that drive them to detach cell-cell junctions, migrate and invade through surrounding tissues, and colonize often distant sirtes with small tumors. These can lay dormant for decades in some cancers and can develop into large tumors once activated. One reason metastatic tumor growth is blocked by the presence of the primary tumor is the activity of all the matrix metalloproteases (MMPs) on the surface of invasive cancer and immune cells in the primary tumor. These MMPs break down the ECM and the resulting fragments block cellular responses to VEGF. Only the large VEGF signal from the primary tumor can overcome this systemic inhibition. The point of the following slides is to cover the types of genetic and epigenetic changes that occur in cancer cells and drive cancer progression. These include gene duplications, deletion, point mutations, and chromosome rearrangements that can fuse two proteins together to make new proteins with new (and aberrant) functions. cancer is initiated when a single cell acquires a mutation in one of its critical genes. To get full blow cancer it takes multiple this single mutation causes the cell and it progeny to divide over and over again hyperplasic-rapidly dividing additional mutation are aquired with in the population untill orginal cell type is almost impossible to figure out at the carcinoma phase, cell begin to be invasive creating metastatic tumors surrounding cells can optain the mutations, some that are harmful, some don't effect, and some that create stronger cell which drives cancer progression Steps in cancer progression benign - 1. Increased prolifereation ( normally to much proliferation is stopped by G1 regulation, but this control is lost) 2. lose of contact inhibition 3. Deregulation of the cell cycle 4. Increased mutations- gateway Malignant 1. Increased mutation- gateway 2. cell adhesion changes 3. increased migratory and invasive ehavor 4. Increased survival what proteins could you target to prevent this progression ( therapies) proteins invovled in preventing cell cycle from continuing cadherin/catein p53- mutator phenotype,causes cancer actin- invovled in cell adhesion e2farb-increased proliferation inrtgrin- wanting to migrate away actin regulatory regulatory proteins of tumors recruit new blood vessels tumor in order to grown needs oxygen to grown( past a diameter of 2 mm) oxygen sensing by cells under normal condition product transcription factor Hif-1a but without, can't ubil and so it binds with hif-1b to turn on g proteins when they become metastic they break through and get to vascular system to get to new place. but to do that they have to cut through the tisssue. this creates ECm fragements prevent smaller tumors from getting blood vessels (via VEGF) the cancer seems to always to move to the same places colon for example always go to the liver. (seed hypothesis) dormancy is different in different cells proteins, biological treatment tend to have fewer side effects