tag:theconversation.com,2011:/us/topics/tumour-growth-7117/articlesTumour growth – The Conversation2023-01-16T16:05:12Ztag:theconversation.com,2011:article/1977682023-01-16T16:05:12Z2023-01-16T16:05:12ZStopping the cancer cells that thrive on chemotherapy – research into how pancreatic tumors adapt to stress could lead to a new treatment approach<figure><img src="https://images.theconversation.com/files/504479/original/file-20230113-18-eznoq2.jpg?ixlib=rb-1.1.0&rect=0%2C0%2C2414%2C2117&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">Hypoxia, or a state of low oxygen, can encourage tumors to spread. This microscopy image visualizes the microenvironment of a breast tumor.</span> <span class="attribution"><a class="source" href="https://flic.kr/p/HJpd72">Steve Seung-Young Lee, Univ. of Chicago Comprehensive Cancer Center, National Cancer Institute, National Institutes of Health via Flickr</a>, <a class="license" href="http://creativecommons.org/licenses/by-nc/4.0/">CC BY-NC</a></span></figcaption></figure><p>As with weeds in a garden, it is a <a href="https://www.cancerresearchuk.org/about-cancer/what-is-cancer/why-some-cancers-come-back">challenge to fully get rid of cancer cells</a> in the body once they arise. They have a relentless need to continuously expand, even when they are significantly cut back by therapy or surgery. Even a few cancer cells can give rise to new colonies that will eventually outgrow their borders and deplete their local resources. They also tend to wander into places where they are not welcome, creating metastatic colonies at distant sites that can be even more difficult to detect and eliminate.</p>
<p>One explanation for why cancer cells can withstand such inhospitable environments and growing conditions is an old adage: What doesn’t kill them makes them stronger.</p>
<p>At the very earliest stage of tumor formation, even before cancer can be diagnosed, individual cancer cells typically find themselves in an environment lacking nutrients, oxygen or adhesive proteins that help them attach to an area of the body to grow. While most cancer cells will quickly die when faced with such inhospitable conditions, a small percentage can adapt and gain the ability to initiate a tumor colony that will eventually become malignant disease. </p>
<p><a href="https://scholar.google.com/citations?user=e_INeP8AAAAJ&hl=en">We</a> <a href="https://scholar.google.com/citations?user=4Y2R_IgAAAAJ&hl=en">are</a> <a href="https://scholar.google.com/citations?user=e22ajL0AAAAJ&hl=en">researchers</a> studying how these microenvironmental stresses affect tumor initiation and progression. In our <a href="https://www.nature.com/articles/s41556-022-01055-y">new study</a>, we found that the harsh microenvironments of the body can push certain cancer cells to overcome the stress of being isolated and make them more adept at initiating and forming new tumor colonies. Moreover, these cancer cells may adapt even better in the inhospitable and stressful conditions they encounter while trying to establish metastases in other areas of the body or after they are challenged by treatment with chemotherapy or surgery. </p>
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<figcaption><span class="caption">The microenvironment of a cell can significantly influence its function.</span></figcaption>
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<h2>Cancer cells overcoming isolation stress</h2>
<p>We focused on <a href="https://doi.org/10.1001%2Fjama.2021.13027">pancreatic cancer</a>,
one of the most lethal cancers and one that is notoriously resistant to chemotherapy and often not curable with surgery. <a href="https://www.cancer.org/cancer/pancreatic-cancer/detection-diagnosis-staging/survival-rates.html">Almost 90%</a> of pancreatic patients will succumb to cancer recurrence or metastasis within five years after diagnosis. </p>
<p>We wanted to study how tumor formation is affected by what we call “<a href="https://www.nature.com/articles/s41556-022-01055-y">isolation stress</a>,” when cells are deprived of nutrients or oxygen supply because of poor blood vessel formation or because they cannot benefit from making contact with nearby cancer cells. To study how cancer cells respond to these situations, we recreated different forms of isolation stress in cell cultures, in mice and in patient samples by depriving them of oxygen and nutrients or by exposing them to chemotherapeutic drugs. We then measured which genes were turned on or off in pancreatic cancer cells.</p>
<p>We found that pancreatic cancer cells challenged with conditions that mimic isolation stress gain a new receptor on their surface that unstressed cancer cells don’t typically have: <a href="https://doi.org/10.1016/j.bbrc.2015.03.169">lysophosphatidic acid receptor 4, or LPAR4</a>, a protein involved in tumor progression. </p>
<p>When we forced the cancer cells to produce LPAR4 on their surfaces, we found that they were able to form new tumor colonies two to eight times faster than average cancer cells under isolation stress conditions. Also, preventing cancer cells from gaining LPAR4 when they were stressed reduced their ability to form tumor colonies by 80% to 95%. These findings suggest that the ability of cancer cells to gain LPAR4 when they are exposed to stress is both necessary and sufficient to promote tumor initiation.</p>
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<a href="https://images.theconversation.com/files/504478/original/file-20230113-14-t3mmqi.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="Microscopy image of pancreatic cancer metastases arising from multiple different cell clusters" src="https://images.theconversation.com/files/504478/original/file-20230113-14-t3mmqi.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/504478/original/file-20230113-14-t3mmqi.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=458&fit=crop&dpr=1 600w, https://images.theconversation.com/files/504478/original/file-20230113-14-t3mmqi.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=458&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/504478/original/file-20230113-14-t3mmqi.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=458&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/504478/original/file-20230113-14-t3mmqi.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=575&fit=crop&dpr=1 754w, https://images.theconversation.com/files/504478/original/file-20230113-14-t3mmqi.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=575&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/504478/original/file-20230113-14-t3mmqi.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=575&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
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<span class="caption">Tumors contain multiple different types of cancer cells with unique genetic mutations. This image shows a variety of pancreatic cancer cell clusters, each of a different color, within a tumor.</span>
<span class="attribution"><a class="source" href="https://flic.kr/p/GXJM1U">Ravikanth Maddipati, Abramson Cancer Center at the Univ. of Pennsylvania, National Cancer Institute, National Institutes of Health via Flickr</a>, <a class="license" href="http://creativecommons.org/licenses/by-nc/4.0/">CC BY-NC</a></span>
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<h2>How does LPAR4 help build tumors?</h2>
<p>We also found that LPAR4 helps cancer cells achieve tumor initiation by giving them the ability to produce a web of macromolecules, or an <a href="https://doi.org/10.1038/s41467-020-18794-x">extracellular matrix network</a>, that provides them an adhesive foothold within an otherwise inhospitable environment. By producing a halo of their own matrix, cancer cells with LPAR4 can start building their own tumor-supporting niche that provides a refuge from isolation stresses.</p>
<p>We determined that a key component of this extracellular matrix is <a href="https://doi.org/10.3389/fonc.2020.00641">fibronectin</a>. When this protein binds to receptors called integrins on the surface of cells, it triggers a cascade of events that results in the expression of new genes promoting tumor initiation, stress tolerance and cancer progression. Eventually, other cancer cells are recruited into the fibronectin-rich matrix network, and a new satellite tumor colony starts to form. </p>
<p>Considering that tumor cells with LPAR4 can create their own tumor-supporting matrix on the fly, this suggests that LPAR4 may allow individual tumor cells to <a href="https://www.nature.com/articles/s41556-022-01055-y">overcome isolation stress conditions</a> and survive in the bloodstream, the lymphatic system involved in immune responses or distant organs as metastases.</p>
<p>Importantly, we found that isolation stress is not the only way to trigger LPAR4. Exposing pancreatic cancer cells to chemotherapy drugs, which are designed to impose stress upon cancer cells, also triggers an increase of LPAR4 on cancer cells. This finding might explain how such tumor cells could develop drug resistance.</p>
<h2>Keeping cancer cells stressed</h2>
<p>Understanding how to cut off the cascade of events that allows cancer cells to become stress-tolerant is important, because it provides a new area to explore for future treatments.</p>
<p>Our team is currently considering potential strategies to prevent cancer cells from utilizing the fibronectin matrix to gain stress tolerance, including drugs that can target the receptors that bind to fibronectin on the surface of tumor cells. One of these drugs, being developed by a company one of us co-founded, is poised to enter clinical trials soon. Other strategies include preventing cancer cells from gaining LPAR4 when they sense stress, or interfering with the signals that promote the generation of the fibronectin matrix.</p>
<p>For patients diagnosed with pancreatic cancer, there is a pressing need to discover how to improve the effectiveness of surgery or chemotherapy. Like combating weeds in your garden, this may require attacking the problem from multiple directions at once.</p><img src="https://counter.theconversation.com/content/197768/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>David Cheresh receives funding from the NIH. He is a co-founder of Alpha Beta Therapeutics, Inc., a company creating new therapeutics to treat cancer, for which he also has equity and serves on the scientific advisory board.</span></em></p><p class="fine-print"><em><span>Chengsheng Wu and Sara Weis do not work for, consult, own shares in or receive funding from any company or organization that would benefit from this article, and have disclosed no relevant affiliations beyond their academic appointment.</span></em></p>Some cancers are notoriously resistant to chemotherapy and not curable with surgery. Stopping tumors from adapting to the harsh microenvironments of the body could be a potential treatment avenue.Chengsheng Wu, Postdoctoral Scholar in Pathology, University of California, San DiegoDavid Cheresh, Professor of Pathology, University of California, San DiegoSara Weis, Senior Scientist in Pathology, University of California, San DiegoLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/1710222021-11-03T13:03:12Z2021-11-03T13:03:12ZA dangerous parasite could be used to treat cancer – new research in mice<figure><img src="https://images.theconversation.com/files/429764/original/file-20211102-20320-1k5ppm9.jpg?ixlib=rb-1.1.0&rect=7%2C0%2C4985%2C3500&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">Not all tumours can be detected by the body's immune system.</span> <span class="attribution"><a class="source" href="https://www.shutterstock.com/image-illustration/tcells-attacking-cancer-cell-illustration-microscopic-313800779">Peddalanka Ramesh Babu/ Shutterstock</a></span></figcaption></figure><p>A parasite commonly found in cats’ faeces might one day help treat cancer. My colleagues and I have discovered that the parasite that causes toxoplasmosis – a condition that can be harmful to pregnant women and those with a suppressed immune system – might be useful at destroying cancer tumours. At least, that’s what <a href="https://jitc.bmj.com/content/9/11/e002970?utm_source=twitter&utm_medium=social&utm_term=hootsuite&utm_content=sme&utm_campaign=usage">our study</a> in mice suggests. </p>
<p>For many years now, researchers have been looking at how they can use the body’s immune system to treat cancer – known as immunotherapy. This is because, alongside protecting us from the harmful effects of bacteria and viruses, our immune system also rids the body of abnormal cells, such as cancer cells. But sometimes these cancerous cells and tumours can develop techniques for evading the body’s immune system, which means that the immune system won’t kill them, and they’ll be allowed to grow and replicate. </p>
<p>One type of immunotherapy is “immune checkpoint blockade therapy”. Our immune system contains a number of so-called “immune checkpoints” that prevent it from destroying healthy cells. But cancer cells can also avoid destruction by taking advantage of this on/off “switch”. The checkpoint can shut down immune cells called T cells and suppress the immune response. This is how some tumours are able to avoid being destroyed by the immune system.</p>
<p>Immune checkpoint blockade therapy works by blocking the checkpoint proteins from binding with their partner proteins and sending the “off” signal. This means that the cancer cells will become “visible” to the T cells, which can then go about destroying the tumour.</p>
<p>While immune checkpoint blockade therapy has shown promise in treating many types of cancer – including <a href="https://pubmed.ncbi.nlm.nih.gov/33316104/">lung cancer</a> and <a href="https://www.nejm.org/doi/10.1056/NEJMoa1910836">melanoma</a> – this type of therapy, and many other immunotherapy treatments, don’t work very well on so-called “cold” tumours. These difficult to treat tumours are surrounded by cells that suppress the body’s immune response, which means immune cells won’t know how to attack it. Types of cancers where cold tumours are common include breast, ovary and prostate cancers. </p>
<p>But our latest research has discovered a method that could improve the treatment of these cold tumours – and it involves using <a href="https://jitc.bmj.com/content/9/11/e002970?utm_source=twitter&utm_medium=social&utm_term=hootsuite&utm_content=sme&utm_campaign=usage">the parasite that causes toxoplasmosis</a>, a relatively common condition that people catch from the faeces of infected cats or infected meat. While it’s typically harmless and often only causes mild flu-like symptoms, it can be serious in pregnant women and those who have a compromised immune system. </p>
<p>Toxoplasmosis is caused by the <em>Toxoplasma gondii</em> parasite. The reason we chose <em>T. gondii</em> is because it is very infectious and has been shown to infect many species of warm-blood animals – including humans. The pathogen is also very tough, secreting proteins that prevent the body’s immune system from acting – ultimately ensuring its own growth, replication and survival. We figured that all these attributes would allow <em>T. gondii</em> to trigger a strong immune response if administered directly into a tumour in the hope that would be enough for the immune system to kill the cancer.</p>
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<img alt="An illustration of __Toxoplasma gondii_ cells inside the body." src="https://images.theconversation.com/files/429765/original/file-20211102-19-onnbh.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/429765/original/file-20211102-19-onnbh.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=406&fit=crop&dpr=1 600w, https://images.theconversation.com/files/429765/original/file-20211102-19-onnbh.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=406&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/429765/original/file-20211102-19-onnbh.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=406&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/429765/original/file-20211102-19-onnbh.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=511&fit=crop&dpr=1 754w, https://images.theconversation.com/files/429765/original/file-20211102-19-onnbh.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=511&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/429765/original/file-20211102-19-onnbh.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=511&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px">
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<span class="caption">We created a genetically modified version of T. gondii in order to elicit an immune response in the body.</span>
<span class="attribution"><a class="source" href="https://www.shutterstock.com/image-illustration/toxoplasma-gondii-disease-3d-illustration-523301842">fotovapl/ Shutterstock</a></span>
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<p>Using the gene-editing technology Crispr, our team engineered a strain of <em>Toxoplasma gondii</em> that lacked the protein that causes disease. We then injected this mutant strain directly into melanoma tumours in mice. We later tested it on colon and lung cancer tumours as well. </p>
<p>We were able to show that injecting the live parasite directly into a cold tumour was able to trigger a strong immune response in mice. We were also able to show that even nearby tumours, which hadn’t been injected, had an increased immune response. </p>
<p>While previous studies have shown that <em>Toxoplasma gondii</em> can be used to <a href="https://theconversation.com/how-a-nasty-brain-eating-parasite-could-help-us-fight-cancer-64267">treat tumours</a> in mice, our study took this finding one step further. We showed that when this engineered parasite was used alongside immune checkpoint blockade therapy, tumour growth was significantly suppressed. The eight mice given dual therapy in the early stages of melanoma saw their tumours shrink significantly, whereas treatment with only immune checkpoint blockade therapy failed to cause any regression in the injected tumours in mice.</p>
<p>We also showed that the dual treatment was far more effective at not only shrinking tumours but also improving the survival rate of mice when compared with using immune checkpoint blockade therapy alone. All eight mice who only received immune checkpoint blockade therapy died within 39 days – while seven out of eight mice who received the dual treatment were still alive after 60 days. We also saw an increase in a number of different types of helpful immune cells – which ultimately improved the response of melanoma tumours in particular to treatments. </p>
<p>Our research joins a body of evidence that parasites – including the <a href="https://www.frontiersin.org/articles/10.3389/fphar.2019.01137/full">canine tapeworm</a> <em>Echinococcus granulosus</em> – can work against different types of cancer. <a href="https://theconversation.com/could-friendly-bacteria-be-used-to-treat-cancer-63356">Bacteria</a>, <a href="https://theconversation.com/bladder-cancer-how-we-used-a-common-cold-virus-to-defeat-it-119901">viruses</a> and bacteriophages (viruses that attack bacteria), are also being trialled as potential cancer treatments. </p>
<p>It’s important to note that this study is only in mice, and it will take many years and many more studies before we know if this therapy works in humans. Nevertheless, it’s an exciting step in the right direction and adds to the growing evidence base that pathogens might be helpful tools in our fight against tough-to-treat cancers.</p><img src="https://counter.theconversation.com/content/171022/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Hany Elsheikha does not work for, consult, own shares in or receive funding from any company or organisation that would benefit from this article, and has disclosed no relevant affiliations beyond their academic appointment.</span></em></p>The parasite which causes toxoplasmosis has shown promise in treating difficult tumours in mice.Hany Elsheikha, Associate Professor of Parasitology, University of NottinghamLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/1562792021-06-27T12:35:37Z2021-06-27T12:35:37ZHow tiny gold particles injected into tumours could improve radiation treatment for cancer<figure><img src="https://images.theconversation.com/files/406256/original/file-20210614-107575-sauotc.jpg?ixlib=rb-1.1.0&rect=212%2C139%2C4448%2C3399&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">The limiting factor in cancer radiotherapy is that doses high enough to try to cure tumours also damage surrounding normal tissues.</span> <span class="attribution"><span class="source">(Shutterstock)</span></span></figcaption></figure><p>Cancer is the second leading cause of death globally. In 2018, there were 18.1 million new cases and <a href="https://www.cancer.gov/about-cancer/understanding/statistics">9.5 million cancer-related deaths worldwide</a>. By 2040, the number of new cancer cases per year is expected to rise to 29.5 million and the number of cancer-related deaths to 16.4 million. </p>
<p>Approximately <a href="https://doi.org/10.1016/j.radonc.2014.03.024">50 per cent of all cancer patients can benefit from radiotherapy</a> in the management of their disease. About half of those patients are <a href="http://hdl.handle.net/10986/22552">diagnosed early enough that their cancer may be curable</a>. For many cancers including breast, prostate, cervix, head and neck, lung and brain cancers, curative treatment includes radiation therapy. However, because radiotherapy destroys healthy cells as well as tumour cells, doses are limited.</p>
<p><a href="https://www.cancer.ca/en/cancer-information/diagnosis-and-treatment/radiation-therapy/?region=on">Radiotherapy</a>, also called radiation therapy, is used alone to treat cancer or with other treatment options such as chemotherapy and surgery. It may also be used to shrink the tumour before surgery. In radiotherapy, tumour cells — which divide much faster than other surrounding healthy cells — are destroyed by damaging their DNA. </p>
<h2>Side-effects limit radiation dose</h2>
<p>The limiting factor in radiotherapy is that doses high enough to try to cure high-risk (locally advanced) non-metastatic tumours also damage surrounding normal tissues. Currently, we are at the limit of radiotherapy dose that can be given to patients. To further improve survival, there is a need for new methods that enhance radiation effectiveness while reducing side-effects.</p>
<p>One way to accomplish this is by making tumour cells more sensitive to radiation, so those cells are more easily damaged by radiation therapy. Using <a href="https://doi.org/10.1667/rr1984.1">gold nanoparticles as radiosensitizers</a> has shown promising results. These gold nanoparticles can be introduced intravenously to accumulate in the tumour by exploiting the faulty walls of the tumour’s blood vessels, <a href="https://doi.org/10.3390/cancers10030084">which tend to be leaky because of fast growth</a>. </p>
<p>Gold nanoparticles interact with X-ray photons used in radiation treatment which produces electrons, which then interact with water molecules to produce free radicals. These free-radicals can damage cells, lowering the survival of those cells. </p>
<p>Understanding the complex biological system present in and around the tumour is essential for optimizing the use of the radiosensitizing GNPs, as <a href="https://doi.org/10.1016/j.ijrobp.2015.09.032">outlined by a consortium of labs</a>, including our own nanoscience and technology development laboratory at University of Victoria. </p>
<h2>Targeting interactions inside the tumour</h2>
<p>In this work, we discuss the importance of looking into which cellular components within the tumour microenvironment take up the gold nanoparticles and become radiosensitized. We are particularly interested in cells called activated fibroblasts, which are associated with wound healing and have anti-tumourogenic properties, meaning they help fight tumour growth. </p>
<p>However, activated fibroblasts can be recruited by the tumour cells, and become cancer-associated fibroblasts (CAFs). Instead of anti-tumourigenic properties, CAFs promote the proliferation and metastasis of tumours. </p>
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<a href="https://images.theconversation.com/files/387339/original/file-20210302-15-4fg45x.png?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="Illustration of the types of cells found in the microenvironment of a tumour." src="https://images.theconversation.com/files/387339/original/file-20210302-15-4fg45x.png?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/387339/original/file-20210302-15-4fg45x.png?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=486&fit=crop&dpr=1 600w, https://images.theconversation.com/files/387339/original/file-20210302-15-4fg45x.png?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=486&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/387339/original/file-20210302-15-4fg45x.png?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=486&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/387339/original/file-20210302-15-4fg45x.png?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=610&fit=crop&dpr=1 754w, https://images.theconversation.com/files/387339/original/file-20210302-15-4fg45x.png?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=610&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/387339/original/file-20210302-15-4fg45x.png?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=610&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
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<span class="caption">Incorporating gold nanoparticles into current radiation treatment protocols had three goals: to enhance killing of tumour cells, to target CAFs and to protect fibroblasts.</span>
<span class="attribution"><span class="source">Reproduced with permission (Bromma et al.(2020), Sci Reports, 10, 2181).</span>, <span class="license">Author provided</span></span>
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<p>The function of CAFs supports the idea that tumours are “wounds that do not heal,” and targeting CAFs may prove beneficial towards improved cancer treatment outcomes. </p>
<p>As illustrated in the image above, our research on incorporating gold nanoparticles into current radiation treatment protocols had three goals: to enhance killing of tumour cells, to target CAFs and to protect fibroblasts. </p>
<p>For radiosensitizing to be effective in improving radiation treatment, the cells targeted by the treatment (the ones associated with cancer growth) need to have high uptake of the radiosensitizing particles, while the beneficial cells need to have a low uptake. This makes the targeted cells are more easily destroyed by radiation therapy at doses that patients can tolerate. </p>
<p>These results using 3D tumours grown in the lab are very encouraging. The CAFs had the largest uptake of the gold nanoparticles per cell, with almost triple that of cancer cells, while fibroblasts had a relatively small number. This also translated to a larger increase in DNA damage in the CAFs compared to the other cell types, reducing the activity of the CAFs and slowing tumour growth. </p>
<p>This difference in DNA damage due to selective targeting of cancer-associated cells over normal cells may allow gold nanoparticles to be an effective tool in future cancer radiation therapy, helping to minimize damage to normal tissue while improving local radiation therapy dose to the tumour.</p>
<figure class="align-center zoomable">
<a href="https://images.theconversation.com/files/387338/original/file-20210302-17-fx2m8l.png?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="Gold nanoparticles in red against a green background of the tumour, with a bar graph showing uptake of the nanoparticles." src="https://images.theconversation.com/files/387338/original/file-20210302-17-fx2m8l.png?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/387338/original/file-20210302-17-fx2m8l.png?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=450&fit=crop&dpr=1 600w, https://images.theconversation.com/files/387338/original/file-20210302-17-fx2m8l.png?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=450&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/387338/original/file-20210302-17-fx2m8l.png?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=450&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/387338/original/file-20210302-17-fx2m8l.png?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=566&fit=crop&dpr=1 754w, https://images.theconversation.com/files/387338/original/file-20210302-17-fx2m8l.png?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=566&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/387338/original/file-20210302-17-fx2m8l.png?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=566&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
<figcaption>
<span class="caption">Accumulation of gold nanoparticles (red) in the tumour environment.</span>
<span class="attribution"><span class="source">Reproduced with permission (Bromma et al.(2020), Sci Reports, 10, 2181).</span>, <span class="license">Author provided</span></span>
</figcaption>
</figure>
<p>This study showcases that using gold nanoparticles as a radiosensitizer allows more damage to be propagated to the CAFs, an element that has shown to be largely <a href="https://doi.org/10.1038/s41598-020-68994-0">influential to the progression of cancer</a>. We believe that this work will be a building block towards a more effective treatment regime in the near future. Building a model that can accurately represent the different interactions taking place inside the tumour’s microenvironment is essential to improving treatment results for patients.</p><img src="https://counter.theconversation.com/content/156279/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Devika Basnagge Chithrani receives funding from Natural Sciences and Engineering Research Council, Canada Foundation for innovation, British Columbia Knowledge Development Fund and University of Victoria.. </span></em></p>Higher doses of radiotherapy for cancer treatment destroy more healthy tissue as well as more tumour cells. Gold nanoparticles sensitize tumours to radiation, making treatment more effective.Devika Basnagge Chithrani, Associate professor, Physics and Astronomy/Medical physics, University of VictoriaLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/600612017-05-10T03:50:19Z2017-05-10T03:50:19ZExplainer: what is cancer radiotherapy and why do we need proton beam therapy?<figure><img src="https://images.theconversation.com/files/140413/original/image-20161005-20235-zqbkxz.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">Radiotherapy treats cancer by directing beams of high energy x-rays at the tumour. </span> <span class="attribution"><span class="source">from shutterstock.com</span></span></figcaption></figure><p>In last night’s federal budget, the <a href="http://budget.gov.au/2017-18/content/bp3/download/bp3_03_part_2b.pdf">government dedicated up to A$68 million</a> to help set up Australia’s first proton beam therapy facility in South Australia. The <a href="http://www.health.gov.au/internet/ministers/publishing.nsf/Content/health-mediarel-yr2017-hunt45.htm">government says</a> this will help Australian researchers develop the next generation of cancer treatments, including for complex children’s cancers. </p>
<p>Proton beam therapy is radiation therapy that uses heavier particles (protons) instead of the X-rays used in conventional radiotherapy. These particles can more accurately target tumours closer to vital organs, which can be especially beneficial to patients suffering from brain cancer and children whose organs are still developing and are more vulnerable to damage.</p>
<p>So, the facility will also be an alternative to conventional radiotherapy for treating certain cancer. But what is traditional radiotherapy, and how will access to proton beam therapy improve how we manage cancer?</p>
<h2>What is radiotherapy?</h2>
<p>Radiotherapy, together with surgery, chemotherapy and palliative care, are the cornerstones of cancer treatment. Radiotherapy is recommended for <a href="https://www.ncbi.nlm.nih.gov/pubmed/24833561">half of cancer patients</a>. </p>
<p>It is mostly used when the cancer is localised to one or more areas. Depending on the cancer site and stage, radiotherapy can be used alone or in combination with surgery and chemotherapy. It can be used before or after other treatments to make them more effective by, for example, shrinking the tumour before chemotherapy or treating cancer that remains after surgery.</p>
<figure class="align-right ">
<img alt="" src="https://images.theconversation.com/files/150859/original/image-20161220-26710-1ayj6h4.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=237&fit=clip" srcset="https://images.theconversation.com/files/150859/original/image-20161220-26710-1ayj6h4.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=556&fit=crop&dpr=1 600w, https://images.theconversation.com/files/150859/original/image-20161220-26710-1ayj6h4.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=556&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/150859/original/image-20161220-26710-1ayj6h4.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=556&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/150859/original/image-20161220-26710-1ayj6h4.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=699&fit=crop&dpr=1 754w, https://images.theconversation.com/files/150859/original/image-20161220-26710-1ayj6h4.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=699&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/150859/original/image-20161220-26710-1ayj6h4.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=699&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px">
<figcaption>
<span class="caption">A drawing of the X-ray machine used by Wilhelm Röntgen to produce images of the hand.</span>
<span class="attribution"><span class="source">Golan Levin/Flickr</span>, <a class="license" href="http://creativecommons.org/licenses/by-sa/4.0/">CC BY-SA</a></span>
</figcaption>
</figure>
<p>Most <a href="http://www.cancervic.org.au/about-cancer/types-treatments-trials/radiotherapy">radiotherapy treats cancer</a> by directing beams of high energy X-rays at the tumour (although other radiation beams, such as gamma rays, electron beams or proton/heavy particle beams can also be used). </p>
<p>The X-rays interact with tumour cells, damaging their DNA and restricting their ability to reproduce. But because X-rays don’t differentiate between cancerous and healthy cells, normal tissues can be damaged. Damaged healthy tissue can lead to minor symptoms such as fatigue, or, in rare cases, more serious outcomes such as hospitalisation and death. </p>
<p>Getting the right amount of radiation is a fine balance between therapy and harm. A common way to improve the benefit-to-cure ratio is to fire multiple beams at the tumour from different directions. If they overlap, they can maximise the damage to the tumour while minimising damage to healthy tissue.</p>
<h2>How it works</h2>
<p>Wilhelm Röntgen <a href="http://www.bl.uk/learning/cult/bodies/xray/roentgen.html">discovered X-rays</a> in 1895 and within a year, the link between exposure to too much radiation and skin burns led scientists and doctors to pursue radiation in cancer treatment.</p>
<p>There are three key stages in the radiotherapy process. The patient is first imaged – using such machines as computer tomography (CT) or magnetic resonance imaging (MRI). This estimates the extent of the tumour and helps to understand where it is with respect to healthy tissues and other critical structures. </p>
<p>In the second stage, the doctor and treatment team will use these images and the patient’s case history to plan where the radiation beams should be placed – to maximise the damage to the tumour while minimising it to healthy tissues. Complex computer simulations model the interactions of the radiation beams with the patient to give a best estimate of what will happen during treatment.</p>
<figure class="align-center ">
<img alt="" src="https://images.theconversation.com/files/150862/original/image-20161220-26759-1as1d7n.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/150862/original/image-20161220-26759-1as1d7n.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=399&fit=crop&dpr=1 600w, https://images.theconversation.com/files/150862/original/image-20161220-26759-1as1d7n.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=399&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/150862/original/image-20161220-26759-1as1d7n.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=399&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/150862/original/image-20161220-26759-1as1d7n.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=502&fit=crop&dpr=1 754w, https://images.theconversation.com/files/150862/original/image-20161220-26759-1as1d7n.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=502&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/150862/original/image-20161220-26759-1as1d7n.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=502&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px">
<figcaption>
<span class="caption">A single radiotherapy treatment takes 15 to 30 minutes.</span>
<span class="attribution"><span class="source">IAEA Imagebank/Flickr</span>, <a class="license" href="http://creativecommons.org/licenses/by/4.0/">CC BY</a></span>
</figcaption>
</figure>
<p>During the third, treatment-delivery stage, the patient lies still while the treatment beam rotates, delivering radiation from multiple angles.</p>
<p>Each treatment generally takes 15 to 30 minutes. Depending on the cancer and stage, there are between one and 40 individual treatments, typically one treatment a day. The patient cannot feel the radiation being delivered.</p>
<h2>Benefits and side effects</h2>
<p>Radiotherapy’s targeting technology has made a significant difference to many cancers, in particular early-stage lung and prostate cancers. It is now possible to have effective, low toxicity treatments for these with one to five radiotherapy sessions.</p>
<p>For early-stage lung cancer <a href="https://www.ncbi.nlm.nih.gov/pubmed/25981812">studies estimate</a> with radiotherapy, survival three years after diagnosis is at 95%. For prostate cancer, one study <a href="https://www.ncbi.nlm.nih.gov/pubmed/24060175">estimates survival</a> at the five year mark is about 93%. </p>
<p>Side effects for radiotherapy vary markedly between treatment sites, cancer stages and individual patients. They are typically moderate but can be severe. A general side effect of radiotherapy is fatigue. </p>
<figure class="align-right ">
<img alt="" src="https://images.theconversation.com/files/150843/original/image-20161219-24303-13q1xsj.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=237&fit=clip" srcset="https://images.theconversation.com/files/150843/original/image-20161219-24303-13q1xsj.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=450&fit=crop&dpr=1 600w, https://images.theconversation.com/files/150843/original/image-20161219-24303-13q1xsj.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=450&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/150843/original/image-20161219-24303-13q1xsj.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=450&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/150843/original/image-20161219-24303-13q1xsj.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=566&fit=crop&dpr=1 754w, https://images.theconversation.com/files/150843/original/image-20161219-24303-13q1xsj.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=566&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/150843/original/image-20161219-24303-13q1xsj.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=566&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px">
<figcaption>
<span class="caption">Radiotherapy is often used to treat brain tumours.</span>
<span class="attribution"><span class="source">Eric Lewis/Flickr</span>, <a class="license" href="http://creativecommons.org/licenses/by/4.0/">CC BY</a></span>
</figcaption>
</figure>
<p>Other side effects include diarrhoea, appetite loss, dry mouth and difficulty swallowing for head and neck cancer radiotherapy, as well as incontinence and reduction in sexual function for pelvic radiotherapy. </p>
<p>Long-term effects of radiotherapy are a concern, particularly for children. For instance, radiation to treat childhood brain tumours can have <a href="https://theconversation.com/many-survivors-of-childhood-brain-cancer-have-cognitive-difficulties-but-these-can-be-treated-57566">long-lasting cognitive effects</a> that can affect relationships and academic achievement. </p>
<p>Again doctors will need to weigh up the risks and benefits of treatment for individual patients. Proton beam therapy is arguably most beneficial in these cases.</p>
<h2>Other radiotherapy challenges</h2>
<p>There are several challenges to current radiotherapy. It is often difficult to differentiate the tumour from healthy tissue, and even experts do not always agree on where exactly the tumour is.</p>
<p>Radiotherapy can’t easily adapt to the <a href="http://www.sciencedirect.com/science/article/pii/S0360301611036042">complex changes in patients’ anatomy</a> when a patient moves – for instance, when they breathe, swallow, their heart beats or as they digest food. As a result, radiation beams can be off-target, missing the tumour and striking healthy tissue.</p>
<p>Also, we currently treat all parts of the tumour equally, despite knowing <a href="http://link.springer.com/article/10.1007/s10555-007-9056-0">some of the tumour’s regions</a> are more aggressive, resistant to radiation and likely to spread to other parts of the body.</p>
<p>The tumour itself also changes in response to the treatment, further confounding the problem. An ideal radiotherapy solution would image and adapt the treatment continuously based on these changes.</p>
<p>Improvements in technology, including in imaging systems that can better find the tumour, can help overcome these challenges.</p>
<figure>
<iframe width="440" height="260" src="https://www.youtube.com/embed/MS590Xtq9M4?wmode=transparent&start=0" frameborder="0" allowfullscreen=""></iframe>
<figcaption><span class="caption">Proton therapy requires large accelerators to give protons enough energy to penetrate deep into patients.</span></figcaption>
</figure>
<h2>Proton beam therapy and other innovations</h2>
<p>Proton beam therapy will help maximise benefits for many patients, including those with cancers near the spinal cord and pelvis. It requires large accelerators to give protons enough energy to penetrate deep into patients. The energetic protons are transported into the treatment room using complex steering magnets and directed to the tumour inside the patient.</p>
<p>Protons slow down and lose energy inside the patient, with most of the energy loss planned to occur in the tumour. This reduces energy loss in healthy tissues and reduces side effects. </p>
<p>The problems of changing patient anatomy and physiology in other forms of radiotherapy are also challenges for proton beam therapy. </p>
<p>Australia has a <a href="http://sydney.edu.au/medicine/radiation-physics/research-projects/nano-x.php">number of research teams</a> tackling such challenges, including developing <a href="http://sydney.edu.au/medicine/radiation-physics/research-projects/MRI-linac-program.php">new radiation treatment devices</a>, breathing aids for cancer patients, radiation measurement devices, shorter and more convenient treatment schedules and the optimal combination of radiotherapy with other treatments, such as chemotherapy and immunotherapy.</p><img src="https://counter.theconversation.com/content/60061/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Paul Keall is an NHMRC Professorial Research Fellow at the University of Sydney. He is a director and shareholder of three start-up companies. He receives research funding from government and industry sources. </span></em></p>Getting the right amount of radiation is a fine balance between therapy and harm. A common way to improve the benefit-to-cure ratio is to fire multiple beams at the tumour from different directions.Paul Keall, Professor and NHMRC Australian Fellow, Medicine, University of SydneyLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/634302016-09-12T15:40:08Z2016-09-12T15:40:08ZFossil evidence reveals that cancer in humans goes back 1.7 million years<figure><img src="https://images.theconversation.com/files/137218/original/image-20160909-13375-q954u.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">The earliest hominin cancer.</span> <span class="attribution"><span class="source">Patrick Randolph-Quinney (University of Central Lancashire/University of the Witwatersrand)</span></span></figcaption></figure><p>Cancer is often viewed as a fundamentally modern and monolithic disease. Many people think its rise and spread has been driven almost exclusively by the developed world’s toxins and poisons; by our bad eating habits, lifestyles, and the very air we breathe.</p>
<p>Actually, cancer is not a single disease. It is also far from modern. New fossil evidence suggests that its origins lie deep in prehistory.</p>
<p>We recently published two papers in the South African Journal of Science that describe the discovery and diagnosis of the <a href="http://sajs.co.za/osteogenic-tumour-australopithecus-sediba-earliest-hominin-evidence-neoplastic-disease/patrick-s-randolph-quinney-scott-williams-maryna-steyn-marc-r-meyer-jacqueline-s-smilg-steven-e">earliest benign tumour</a> and <a href="http://sajs.co.za/earliest-hominin-cancer-1-7-million-year-old-osteosarcoma-swartkrans-cave-south-africa/edward-j-odes-patrick-s-randolph-quinney-maryna-steyn-zach-throckmorton-jacqueline-s-smilg-bernhard">earliest malignant cancer</a> to affect the human family.</p>
<p>Tumours and cancers are collectively known as <a href="http://www.cancerantiquity.org/neoplastic-disease">neoplastic diseases</a>. Until now, the oldest evidence of neoplasia in the hominin fossil record dated back <a href="http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0064539">120,000 years</a>. This was found in a rib fragment of a Neanderthal from Krapina in Croatia. </p>
<p>But our <a href="http://sajs.co.za/earliest-hominin-cancer-1-7-million-year-old-osteosarcoma-swartkrans-cave-south-africa/edward-j-odes-patrick-s-randolph-quinney-maryna-steyn-zach-throckmorton-jacqueline-s-smilg-bernhard">discovery</a>, in two South African cave sites, offers definitive evidence of cancer in hominins – human ancestors – as far back as 1.7 million years ago.</p>
<h2>Finding the earliest cancer</h2>
<p>Our research involved two overlapping teams of multi-disciplinary scientists. Some specialised in human evolutionary anatomy, others in ancient and modern diseases. Others are experts in the latest medical and research-based non-invasive imaging techniques. </p>
<p>The aim was to marry the work of scientists who focus extensively on the morphology of dry or fossil bone – including bone diseases – with medical specialists who are practised in diagnosing disease in living humans.</p>
<figure>
<iframe width="440" height="260" src="https://www.youtube.com/embed/65TjgYFB9uw?wmode=transparent&start=0" frameborder="0" allowfullscreen=""></iframe>
<figcaption><span class="caption">Wits University video of the discovery of the earliest hominin cancer.</span></figcaption>
</figure>
<p>These discoveries were made possible by state-of-the-art 3D imaging techniques. We used <a href="https://www.wits.ac.za/microct/">Micro-Focus X-ray Computed Tomography</a>, or Micro-CT imaging. This is similar to the more familiar medical CAT scans, but allows a much greater degree of resolution.</p>
<p>Another technique, <a href="http://www.esrf.eu/files/live/sites/www/files/events/Seminars/2015,01,19%20ESRF%20palaeontology%20lecture-compressed.pdf">Phase Contrast X-ray Synchrotron Microtomography</a>, was also used. It is widely accepted globally as the global standard for 3D imaging of fossils without causing them any damage.</p>
<h2>Fossil evidence</h2>
<p>Finding any cancer or neoplastic disease in the archaeological record has always been a contentious issue. </p>
<p>In 2010 two scientists published <a href="http://www.manchester.ac.uk/discover/news/scientists-suggest-that-cancer-is-man-made">a study</a> based on their analysis of Egyptian mummies. They found extremely low incidences of benign tumours and an almost complete absence of malignancy. They concluded: </p>
<blockquote>
<p>There is nothing in the natural environment that can cause cancer. So it has to be a man-made disease, down to pollution and changes to our diet and lifestyle. </p>
</blockquote>
<p>Our findings prove that they are wrong. We made two relevant fossil discoveries which falsify their claims. One was an example of a benign tumour and the other a malignant cancer.</p>
<p>The benign tumour comes from the site of Malapa, and is dated to 1.98 million years ago. This is a case of <a href="http://orthoinfo.aaos.org/topic.cfm?topic=A00507">osteoid osteoma</a>, a benign bone tumour. It was found in a vertebra of the <a href="http://www.timeslive.co.za/local/2010/06/01/fossil-named-karabo">well-known</a> <em>Australopithecus sediba</em> child <a href="http://www.timeslive.co.za/local/2010/06/01/fossil-named-karabo">Karabo</a>. </p>
<figure class="align-left ">
<img alt="" src="https://images.theconversation.com/files/136308/original/image-20160901-1015-nund08.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=237&fit=clip" srcset="https://images.theconversation.com/files/136308/original/image-20160901-1015-nund08.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=947&fit=crop&dpr=1 600w, https://images.theconversation.com/files/136308/original/image-20160901-1015-nund08.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=947&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/136308/original/image-20160901-1015-nund08.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=947&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/136308/original/image-20160901-1015-nund08.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=1191&fit=crop&dpr=1 754w, https://images.theconversation.com/files/136308/original/image-20160901-1015-nund08.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=1191&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/136308/original/image-20160901-1015-nund08.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=1191&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px">
<figcaption>
<span class="caption">Vertebra U.W. 88-37. Sixth thoracic vertebra of juvenile <em>Australopithecus sediba</em>. The tumour’s segmented boundaries are rendered solid pink.</span>
<span class="attribution"><span class="source">Paul Tafforeau (ESRF)</span></span>
</figcaption>
</figure>
<p>The tumour would probably have caused pain and discomfort, but would not have been directly responsible for Karabo’s death. However, the disease may have limited his ability to climb and move, and may have been implicated in the manner of his death. Results <a href="http://www.nature.com/articles/srep15120">published in 2015</a> suggest Karabo was the victim of a fall from a height into a natural death trap. </p>
<p>The second fossil find is perhaps the more important. A foot bone from Swartkrans cave provides the <a href="http://sajs.co.za/earliest-hominin-cancer-1-7-million-year-old-osteosarcoma-swartkrans-cave-south-africa/edward-j-odes-patrick-s-randolph-quinney-maryna-steyn-zach-throckmorton-jacqueline-s-smilg-bernhard">earliest evidence</a> for a malignant human cancer, and is dated to roughly 1.7 million years ago. </p>
<figure class="align-right ">
<img alt="" src="https://images.theconversation.com/files/132800/original/image-20160802-17185-1nrw745.jpeg?ixlib=rb-1.1.0&q=45&auto=format&w=237&fit=clip" srcset="https://images.theconversation.com/files/132800/original/image-20160802-17185-1nrw745.jpeg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=379&fit=crop&dpr=1 600w, https://images.theconversation.com/files/132800/original/image-20160802-17185-1nrw745.jpeg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=379&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/132800/original/image-20160802-17185-1nrw745.jpeg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=379&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/132800/original/image-20160802-17185-1nrw745.jpeg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=476&fit=crop&dpr=1 754w, https://images.theconversation.com/files/132800/original/image-20160802-17185-1nrw745.jpeg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=476&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/132800/original/image-20160802-17185-1nrw745.jpeg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=476&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px">
<figcaption>
<span class="caption">The earliest hominin cancer. Volume rendered Micro-CT image of the external morphology, showing the extent of expansion of osteosarcoma beyond the surface of the bone.</span>
<span class="attribution"><span class="source">Patrick Randolph-Quinney (University of Central Lancashire/University of the Witwatersrand)</span></span>
</figcaption>
</figure>
<p>This was seen as a large mass of bone growing on the surface of a fifth metatarsal, which is found in the body of the foot, behind the little toe. The external bone mass might have suggested a benign tumour. But when we looked inside the bone, using advanced Micro-CT imaging, we saw that the medullary cavity – the hollow part of a normal tubular bone – was completely obliterated by new bone growth. </p>
<p>This indicated an aggressive bone-forming condition: a cancer. </p>
<p>We used advanced imaging techniques that helped us to visualize the pathological lesion better. We were able to identify new bone growth inside the medullary cavity, which expanded through to the surface. We then compared the mass and the cross-section with modern clinical cases and concluded it was an osteosarcoma, a primary bone malignancy. </p>
<p>This means that the cancer actually started deep in the bone tissue itself, before spreading to the surface. Such cancers are invariably life-threatening if untreated and would lead to death if allowed to divide and spread. The cancer’s presence might also have affected the hominin’s ability to walk and would have been painful when in contact with the ground.</p>
<h2>Understanding palaeo-oncology</h2>
<p>So, is our discovery the earliest evidence for neoplastic disease? In the human lineage, yes. However, much older tumours and cancers have been observed in the fossil record of non-hominins. Cancer is not simply a disease affecting humans. And it is ancient.</p>
<p>The earliest unequivocal case of benign neoplasia is an <a href="http://www.pathologyoutlines.com/topic/boneosteoma.html">osteoma</a> from 300 million years ago. It was found in a <a href="http://onlinelibrary.wiley.com/doi/10.1002/ijc.20610/pdf">fossil fish</a> from North America. Later cases include benign tumours in Jurassic dinosaurs, Cretaceous hadrosaurs, and later European mammoths. The earliest true cancer comes from a <a href="https://books.google.co.za/books?id=y9o_SgXM2U4C&pg=PA20&lpg=PA20&dq=theropod+dinosaur+from+the+late+Jurassic+of+Utah+cancer&source=bl&ots=DXGKRcy-s6&sig=2ZQi25XOxa1bPQitec-Bpee2-r8&hl=en&sa=X&ved=0ahUKEwjKiPGHoILPAhVoD8AKHWgoDMYQ6AEIGjAA#v=onepage&q=theropod%20dinosaur%20from%20the%20late%20Jurassic%20of%20Utah%20cancer&f=false">theropod dinosaur</a> from the late Jurassic of Utah in the US. </p>
<p>Today various cancers and tumours are prevalent in animals. A parasitic cancer called Devil Facial Tumour Disease has been implicated in the collapse of wild Tasmanian Devil populations. Tasmanian Devils are carnivorous marsupials.</p>
<p>In the human world, it is true that rates of tumours and cancers are <a href="http://www.healthdata.org/news-release/new-cancer-cases-rise-globally-death-rates-are-declining-many-countries">accelerating</a> because environmental toxins and other tumour forming factors in the modern (particularly Western) lifestyle. But such diseases were present in the past, even without the influence of modern lifestyles. </p>
<p>However, by any modern standard these primary bone tumours are very rare. Finding them in two of our fossil ancestors is highly unusual. The next step is to ask what mechanisms may be behind the presence of tumours and cancers deep in prehistory and how that may have an impact on the evolution of cancer in the modern world.</p><img src="https://counter.theconversation.com/content/63430/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Edward John Odes receives funding from the NRF of South Africa, The DST/NRF South African Centre of Excellence in Palaeosciences, and the University of the Witwatersrand </span></em></p><p class="fine-print"><em><span>Patrick Randolph-Quinney does not work for, consult, own shares in or receive funding from any company or organisation that would benefit from this article, and has disclosed no relevant affiliations beyond their academic appointment.</span></em></p>Cancer is not the modern disease many believe it to be. New fossil evidence from two South African caves suggests that its origins lie deep in prehistory.Patrick Randolph-Quinney, Senior Lecturer in Biological and Forensic Anthropology, University of Central LancashireEdward John Odes, PhD Candidate in Anatomical Sciences, University of the WitwatersrandLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/479062015-09-23T16:36:52Z2015-09-23T16:36:52ZStarving cancer cells of sugar could be the key to future treatment<figure><img src="https://images.theconversation.com/files/95882/original/image-20150923-2617-1frwddr.jpg?ixlib=rb-1.1.0&rect=0%2C1%2C736%2C547&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">Is sugar the answer for tackling cancer cells?</span> <span class="attribution"><a class="source" href="https://www.flickr.com/photos/wellcomeimages/5814247339/">Flickr/Wellcome Images</a>, <a class="license" href="http://creativecommons.org/licenses/by-nd/4.0/">CC BY-ND</a></span></figcaption></figure><p>All the cells in our bodies are programmed to die. As they get older, our cells accumulate toxic molecules that make them sick. In response, they eventually break down, clearing the way for new, healthy cells to grow. This “<a href="http://www.ncbi.nlm.nih.gov/books/NBK26873/">programmed cell death</a>” is a natural and essential part of our wellbeing. Every day, billions of cells die like this in order for the whole organism to continue functioning as it is supposed to.</p>
<p>But as with any programme, errors can occur and injured cells that are supposed to die continue to grow and divide. These damaged cells can eventually become malignant and generate tumours. In order to <a href="http://www.ncbi.nlm.nih.gov/pubmed/19351640">avoid their programmed cell death</a> in this way, cancer cells reorganise their metabolism so they can cheat death and proliferate indefinitely.</p>
<p>Cancer researchers have <a href="http://www.ncbi.nlm.nih.gov/pubmed/19460998">known for decades</a> that tumours use a faster metabolism than normal cells in our body. <a href="http://www.ncbi.nlm.nih.gov/pubmed/19029908">One classic example</a> of this is that cancer cells increase their consumption of glucose to fuel their rapid growth and strike against programmed cell death. This means that limiting glucose consumption in cancer cells is becoming an <a href="http://www.ncbi.nlm.nih.gov/pubmed/16892078">attractive tool</a> for cancer treatments.</p>
<h2>A new hope?</h2>
<p>You may have seen <a href="http://www.dailymail.co.uk/home/you/article-1025497/The-anti-cancer-diet--introducing-healthy-new-way-life.html">articles</a> or <a href="http://www.canceractive.com/cancer-active-page-link.aspx?n=3087">websites advocating</a> that starving patients of sugar is crucial for getting rid of tumours or that eating less sugar reduces the risk of cancer. The story is not that simple. Cancer cells always <a href="http://www.ncbi.nlm.nih.gov/pubmed/23177934">find alternatives</a> to fuel their tank of glucose, no matter how little sugar we ingest. There is not a direct connection between eating sugar and getting cancer and it is always advisable to talk to your doctor if you have doubt about your diet. </p>
<figure class="align-center ">
<img alt="" src="https://images.theconversation.com/files/95887/original/image-20150923-2648-1vrhcpm.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/95887/original/image-20150923-2648-1vrhcpm.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=400&fit=crop&dpr=1 600w, https://images.theconversation.com/files/95887/original/image-20150923-2648-1vrhcpm.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=400&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/95887/original/image-20150923-2648-1vrhcpm.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=400&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/95887/original/image-20150923-2648-1vrhcpm.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=503&fit=crop&dpr=1 754w, https://images.theconversation.com/files/95887/original/image-20150923-2648-1vrhcpm.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=503&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/95887/original/image-20150923-2648-1vrhcpm.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=503&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px">
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<span class="caption">Chemotherapy – the most common cancer treatment.</span>
<span class="attribution"><a class="source" href="http://www.shutterstock.com/cat.mhtml?lang=en&language=en&ref_site=photo&search_source=search_form&version=llv1&anyorall=all&safesearch=1&use_local_boost=1&autocomplete_id=iewo8m4xx7g4rclor3&searchterm=chemotherapy&show_color_wheel=1&orient=&commercial_ok=&media_type=images&search_cat=&searchtermx=&photographer_name=&people_gender=&people_age=&people_ethnicity=&people_number=&color=&page=1&inline=218458957">www.shutterstock.com</a></span>
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</figure>
<p>Researchers <a href="http://www.ncbi.nlm.nih.gov/pubmed/19270154">have demonstrated</a> that cancer cells use glucose to generate the building blocks of the cellular compounds needed for rapid tumour growth. They also use it to <a href="http://www.ncbi.nlm.nih.gov/pubmed/19029908">generate molecules</a> that guard against the toxic accumulation of reactive oxygen species, the cell-damaging molecules that activate programmed cell death. This means that glucose serves as a master protector against cell death.</p>
<p>If the amount of sugar we eat doesn’t affect this process, the question we need to answer is how the cancer cells are instructed to consume more glucose. Who is filling the fuel tank? We have discovered that what allows tumours to evade their natural cause of death in this way is a protein that is overproduced in virtually every human cancer but not in normal cells.</p>
<h2>Turbocharged growth</h2>
<p>In a <a href="http://www.nature.com/ncomms/2015/150810/ncomms8882/full/ncomms8882.html">recent study</a> published in Nature Communications we showed that cancer cells stimulate the over-production of the protein known as PARP14, enabling them to use glucose to turbocharge their growth and override the natural check of cell death. Using a combination of genetic and molecular biology approaches, we have also demonstrated that inhibiting or reducing levels of PARP14 in cancer cells starves them to death.</p>
<p>The best news is that by comparing cancer tissues (biopsies) from patients that has survived cancer and those that have died, we have found that levels of PARP14 were significantly higher in those patients that have died. This means that levels of PARP14 in cancer tissues could also predict how aggressive the cancer would be and what the chances are of a patient’s survival.</p>
<p>This means that a treatment which could block the protein could represent a significant revolution in the future of cancer treatment. What’s more, unlike traditional chemotherapy and radiotherapy, the use of PARP14 inhibitors would only kill cancer cells and not healthy ones. The next step is to design and generate new drugs that can block this protein and work out how to use them safely in patients.</p><img src="https://counter.theconversation.com/content/47906/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Concetta Bubici receives funding from Key Kendall Leukaemia Fund. </span></em></p><p class="fine-print"><em><span>Salvatore Papa receives funding from Foundation for Liver Research and AMMF-Cholangiocarcinoma Charity</span></em></p>Eating less sugar isn’t enough to stop glucose-hungry cancer cells but new research points the way to how we might starve them to death.Concetta Bubici, Lecturer in biomedical science, Brunel University LondonSalvatore Papa, Senior scientist, Institute of Hepatology, Birkbeck, University of LondonLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/203862013-11-18T20:03:00Z2013-11-18T20:03:00ZChilly temperatures help cancers grow<figure><img src="https://images.theconversation.com/files/35502/original/5bgg6mxd-1384773135.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">Hot v cold.</span> <span class="attribution"><span class="source">ssoosay</span></span></figcaption></figure><p>At low temperatures the human body has a hard time. As the cold sets in, blood vessels constrict to maintain heat and some body parts – like fingers and toes – begin to suffer. Metabolism ramps up to fight the cold and shivering sets in. As these conditions continue, everything becomes sluggish as the cells of your body do not work as well. The body enters a state of thermal stress and only the most vital systems, like the brain, are left switched on.</p>
<p>Now, in a paper just published in the <a href="http://www.pnas.org/cgi/doi/10.1073/pnas.1304291110">Proceedings of the National Academy of Sciences</a>, Elizabeth Repasky at Roswell Park Cancer Institute in the US and colleagues suggest that cold has yet another disadvantage – it changes the way cancer cells grow and spread, at least in mice. This raises interesting questions about cancer therapies and many cancer studies, which tend to use mice as animal models.</p>
<p>Repasky found that mice living in a relatively cold environment (around 22°C) had cancers that grew more quickly and aggressively than mice living at a nice thermally comfortable temperature (around 30°C). A cold environment boosted the growth of several different types of cancer, including breast, skin, colon, and pancreas.</p>
<p>It did not matter if mice had lived in the cold for a lifetime before they got cancer—a chilly exposure even after their cancer had become established still made their tumours grow more quickly.</p>
<p>The body’s anti-cancer responses are mostly driven by the immune system’s <a href="http://www.tcells.org/beginners/tcells/">T cells</a>, which recognise and destroy tumor cells based on the altered proteins they produce. Tumours often react to a T-cell attack by producing signals that trick the body into suppressing these immune cells. This battle continues until one side outpaces the other – a lot of anti-cancer treatments given in the clinic help to swing the balance in favour of the immune system.</p>
<p>Both the cold and the comfortable mice had the same numbers of potential cancer-fighting T cells when they were healthy. But the tumour-seeking T cells in the comfortable mice were quicker and better at burrowing into the tumour to attack it. They also secreted more cancer-fighting substances than the cells from cold mice.</p>
<p>In the tumours of cold mice, there were greater numbers of suppressive cells capable of shutting down normal immune responses. Cold temperatures, then, shifted the body’s response from fighting the tumour to accepting it.</p>
<p>Most animal research facilities follow the same housing guidelines, and thus keep mice at colder-than-comfortable temperatures. This could introduce a systemic bias to animal testing where studies are done in conditions that aren’t entirely relevant. For example, what if you were trying a therapy that boosted immune function but did it in mice whose immune function was naturally tamped down? You might see no effect, when it could still be a useful drug. In contrast, something that causes tumour DNA damage might not have the same problem.</p>
<h2>Cancers are cold</h2>
<p>When we feel cold, we engage in warming behaviours – turning the thermostat up a notch, or thriftily putting on an extra layer of clothes. Mice are exactly the same – if they feel cold, they move to a warmer spot. When healthy mice get to choose what temperature they want to hang out at, with options at 22, 28, 30, 34 or 38°C, they typically migrate into the comfortable 30°C room. Mice with tumours tend to choose the hottest 38°C room. Cancer patients also commonly <a href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3012377/">report</a> suffering deep chills, especially following treatment.</p>
<p>It’s possible that growing tumours may induce a cold stress that probably promotes their own survival. We do not know exactly how this works yet, but this research still has important implications for cancer patients and their treatments. Could administering cancer therapies in a sauna – like setting improve their tumour – fighting potential and slow cancer growth?</p>
<p>Such approaches have been tried in small trials for <a href="http://clincancerres.aacrjournals.org/content/10/13/4287.abstract?ijkey=38a112b8a70d12ef6d1146a57d07bf615f96bbf8&amp;keytype2=tf_ipsecsha">breast cancer</a>, <a href="http://www.ncbi.nlm.nih.gov/pubmed/23549781">angiosarcoma</a> and <a href="http://www.thelancet.com/journals/lanonc/article/PIIS1470-2045%2810%2970071-1/fulltext">sarcoma</a>. They show that increasing body temperature to a mild fever over the course of a few hours improves response rates to radiation therapy.</p>
<p>Without large-scale studies no firm conclusions can be drawn, but this evidence suggests that the benefits of heat therapy for cancer may have been overlooked. Perhaps it is time we paid heed to the words of the ancient Greek physician Hippocrates:</p>
<blockquote>
<p>Those who cannot be cured by medicine can be cured by surgery. Those who cannot be cured by surgery can be cured by heat. Those who cannot be cured by heat are to be considered incurable.</p>
</blockquote><img src="https://counter.theconversation.com/content/20386/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Stephanie Swift does not work for, consult, own shares in or receive funding from any company or organisation that would benefit from this article, and has disclosed no relevant affiliations beyond their academic appointment.</span></em></p>At low temperatures the human body has a hard time. As the cold sets in, blood vessels constrict to maintain heat and some body parts – like fingers and toes – begin to suffer. Metabolism ramps up to fight…Stephanie Swift, Researcher, L’Université d’Ottawa/University of OttawaLicensed as Creative Commons – attribution, no derivatives.