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Oct_02_2014.html
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<h1 id="hallmarksofcancerpart2">Hallmarks of Cancer (Part 2)</h1>
<h2 id="emerginghallmarksandenablingcharacteristics">Emerging Hallmarks and Enabling Characteristics</h2>
<figure>
<img src="http://ars.els-cdn.com/content/image/1-s2.0-S0092867411001279-gr3.jpg" alt="" />
</figure>
<h2 id="emerginghallmarks">Emerging Hallmarks</h2>
<h3 id="evadingimmunedestruction">Evading Immune Destruction</h3>
<blockquote>
<p>“The long-standing theory of immune surveillance proposes that cells and tissues are constantly monitored by an ever-alert immune system, and that such immune surveillance is responsible for recognizing and eliminating the vast majority of incipient cancer cells and thus nascent tumors.” </p>
<p>“Highly immunogenic cancer cell clones are routinely eliminated in immunocompetent hosts—a process that has been referred to as “immunoediting”—leaving behind only weakly immunogenic variants to grow and generate solid tumors; such weakly immunogenic cells can thereafter colonize both immunodeficient and immunocompetent hosts.” </p>
</blockquote>
<h3 id="reprogrammingenergymetabolism">Reprogramming Energy Metabolism</h3>
<blockquote>
<p>"Otto Warburg first observed an anomalous characteristic of cancer cell energy metabolism (Warburg, 1930, Warburg, 1956a and Warburg, 1956b): even in the presence of oxygen, cancer cells can reprogram their glucose metabolism, and thus their energy production, by limiting their energy metabolism largely to glycolysis, leading to a state that has been termed “aerobic glycolysis.” </p>
<p>“… increased glycolysis allows the diversion of glycolytic intermediates into various biosynthetic pathways, including those generating nucleosides and amino acids; this facilitates, in turn, the biosynthesis of the macromolecules and organelles required for assembling new cells” </p>
<p>“… some tumors have been found to contain two subpopulations of cancer cells that differ in their energy-generating pathways. One subpopulation consists of glucose-dependent (“Warburg-effect”) cells that secrete lactate, whereas cells of the second subpopulation preferentially import and utilize the lactate produced by their neighbors as their main energy source, employing part of the citric acid cycle to do so ” </p>
</blockquote>
<h2 id="enablingcharacteristic">Enabling Characteristic</h2>
<h3 id="genomeinstability">Genome Instability</h3>
<blockquote>
<p>“the genomes of tumor cells must acquire increased mutability in order for the process of tumor progression to reach completion in several decades time (Loeb 1991). Malfunction of specific components of these genomic “caretaker” systems has been invoked to explain this increased mutability” </p>
<p>“The most prominent member of these systems is the p53 tumor suppressor protein, which, in response to DNA damage, elicits either cell cycle arrest to allow DNA repair to take place or apoptosis if the damage is excessive” </p>
<p>“a growing number of other genes involved in sensing and repairing DNA damage, or in assuring correct chromosomal segregation during mitosis, is found to be lost in different cancers, labeling these caretakers as tumor suppressors” </p>
<p>“apoptosis may also be a vehicle of genomic instability, in that DNA within apoptotic cell bodies can be incorporated into neighboring cells following phagoctytosis (Holmgren et al. 1999), in principle genetically diversifying any of the constituent cell types of a tumor” </p>
</blockquote>
<h3 id="tumor-promotinginflammation">Tumor-Promoting Inflammation</h3>
<blockquote>
<p>“In the context of neoplasia, however, multiple lines of evidence indicate that immune inflammatory cells can be actively tumor promoting, given that such cells are capable of fostering angiogenesis, cancer cell proliferation, and invasiveness” </p>
<p>“Inflammation can contribute to multiple hallmark capabilities by supplying bioactive molecules to the tumor microenvironment, including growth factors that sustain proliferative signaling, survival factors that limit cell death, proangiogenic factors, extracellular matrix-modifying enzymes that facilitate angiogenesis, invasion, and metastasis, and inductive signals that lead to activation of EMT and other hallmark-facilitating programs” </p>
<p>“Additionally, inflammatory cells can release chemicals, notably reactive oxygen species, that are actively mutagenic for nearby cancer cells, accelerating their genetic evolution toward states of heightened malignancy” </p>
</blockquote>
<h2 id="therapeutictargeting">Therapeutic targeting</h2>
<figure>
<img src="http://ars.els-cdn.com/content/image/1-s2.0-S0092867411001279-gr6.jpg" alt="Targets" />
<figcaption>Targets</figcaption>
</figure>
<h2 id="cancerisaecosystem">Cancer is a ecosystem</h2>
<h3 id="tumormicroenvironment">Tumor microenvironment</h3>
<blockquote>
<p>“Over the past decade, tumors have increasingly been recognized as organs whose complexity approaches and may even exceed that of normal healthy tissues” </p>
</blockquote>
<figure>
<img src="http://ars.els-cdn.com/content/image/1-s2.0-S0092867411001279-gr4.jpg" alt="Tumor microenvironment" />
<figcaption>Tumor microenvironment</figcaption>
</figure>
<figure>
<img src="http://ars.els-cdn.com/content/image/1-s2.0-S0092867411001279-gr5.jpg" alt="Tumor microenvironment 2" />
<figcaption>Tumor microenvironment 2</figcaption>
</figure>
<h3 id="cancerstemcellscsc">Cancer stem cells (CSC)</h3>
<blockquote>
<p>“cells with properties of CSCs are more resistant to various commonly used chemotherapeutic treatments (Singh and Settleman, 2010, Creighton et al., 2009 and Buck et al., 2007). Their persistence may help to explain the almost-inevitable disease recurrence following apparently successful debulking of human solid tumors by radiation and various forms of chemotherapy. Indeed, CSCs may well prove to underlie certain forms of tumor dormancy, whereby latent cancer cells persist for years or even decades after surgical resection or radio/chemotherapy, only to suddenly erupt and generate life-threatening disease” </p>
<p>“certain tumors may acquire stromal support by inducing some of their own cancer cells to undergo various types of metamorphosis to produce stromal cell types rather than relying on recruited host cells to provide their functions” </p>
</blockquote>
<h2 id="tyrosinekinasesastargetsforcancertherapy">Tyrosine Kinases as Targets for Cancer Therapy</h2>
<p>Some of the most well-known examples of targeted cancer therapy are focused on inhibition of tyrosine kinase activity (e.g. tradenames Gleevec, Herceptin and Avastin): </p>
<blockquote>
<p>The prime example of a dysregulated TK in the hematologic cancers is BCR-ABL, which has been implicated as the direct cause of CML.41 Imatinib mesylate (Gleevec), a 2-phenylaminopyrimidine compound that is a specific inhibitor of several TKs — namely, ABL, ABL-related gene product (ARG), c-KIT, and PDGF receptor (PDGFR) — induces complete hematologic and cytogenetic remissions in most patients with chronic-phase CML </p>
<p>The ERBB2 or HER–2 receptor TK is overexpressed through gene amplification in 20 to 25 percent of invasive primary and metastatic breast cancers and is associated with a poor prognosis.61 Trastuzumab (Herceptin), a recombinant humanized monoclonal antibody against HER–2, increases response rates and improves survival when added to chemotherapy for metastatic HER–2–overexpressing breast cancer,63 and in combination with adjuvant chemotherapy, it decreases recurrence in women who have early-stage breast cancer with HER–2 overexpression </p>
<p>Vascular endothelial growth factor (VEGF) is essential for angiogenesis, and either it or its two receptor TKs (VEGFR–1 and VEGFR–2) are overexpressed in many non–small-cell lung cancers and breast, prostate, renal-cell, and colorectal cancers.104 A pivotal phase 3 study in metastatic colorectal cancer demonstrated that the addition of bevacizumab (Avastin), a humanized anti-VEGF monoclonal antibody, to irinotecan, fluorouracil, and leucovorin led to significant prolongation of survival. </p>
</blockquote>
<figure>
<img src="http://upload.wikimedia.org/wikipedia/commons/thumb/b/b0/Signal_transduction_pathways.svg/825px-Signal_transduction_pathways.svg.png" alt="Signaling pathways" />
<figcaption>Signaling pathways</figcaption>
</figure>
<figure>
<img src="figs/normal_tk.png" alt="Regulation of tyrosine kinases" />
<figcaption>Regulation of tyrosine kinases</figcaption>
</figure>
<figure>
<img src="figs/dysregulated_tk.png" alt="Dysgregulated tyrosine kinases in cancer" />
<figcaption>Dysgregulated tyrosine kinases in cancer</figcaption>
</figure>
<h3 id="mechanaismsoftkdysregulatonincancer">Mechanaisms of TK dysregulaton in cancer</h3>
<ul>
<li>Increase ligand (autocrine or via heterotypic signaling)</li>
<li>Increase receptor</li>
<li>Consittutively active receptor</li>
<li>Fusion protein (constitutive signaling)</li>
<li>Decrease inhibiotrs (e.g. phosphatase)</li>
</ul>
<p><img src="http://upload.wikimedia.org/wikipedia/commons/thumb/4/4d/Philadelphia_Chromosom.svg/450px-Philadelphia_Chromosom.svg.png" alt="Philadelphia chromosome" /><br/>
From <a href="http://en.wikipedia.org/wiki/Philadelphia_chromosome">http://en.wikipedia.org/wiki/Philadelphia_chromosome</a> </p>
<h3 id="challengesfortyrosinekinaseblockersincancer">Challenges for tyrosine kinase blockers in cancer</h3>
<ul>
<li>Toxicity - TKs function in normal cells too</li>
<li>Resistance - evolutionary pressure leads to resistant mutants</li>
<li>Redundancy - alternative signalign pathways means that montherarpy often only has modest effects on survivial (Imatinib in CML is notable exception)</li>
<li><p>Cost </p>
<blockquote>
<p>The addition of bevacizumab to standard treatment can prolong the lives of breast and lung cancer patients by several months, at a cost of $100,000 a year in the United States.[54] For colorectal cancer, Robert J. Mayer wrote in the New England Journal of Medicine that bevacizumab extended life by 4.7 months (20.3 months vs. 15.6 months) in the initial study, at a cost of $42,800 to $55,000. </p>
</blockquote></li>
</ul>
<p>From <a href="http://en.wikipedia.org/wiki/Bevacizumab#Costs">http://en.wikipedia.org/wiki/Bevacizumab#Costs</a></p>
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