Cancer with Viruses? McMaster’s Medical Research and Health Ethics Student Journal
IN THIS ISSUE Also in this issue:
Cancer Stem Doctor’s Cells right to refuse patient treatment
Kanzius Machine
Chaperones and Oncolytic Viruses
protein folding
Palliative Surgery Nanotechnology
Loneliness and cardiovascular disease
Psychosocial Implications of Cancer Debate on Canada’s health care IN COLLABORATION WITH
THINK CANCER Issue 14 | Feb 2009
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Table of Contents
Issue 14 | February 2009
Research Articles Presidential Address
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MedWire
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Crystal Chung & Kevin Wang
Oncolytic Viruses Hannah Wigle & Sandeep Koshy
About The McMaster Meducator The McMaster Meducator is an undergraduate medical journal that publishes articles on current topics in health research and medical ethics. We aim to provide an opportunity for undergraduate students to publish their work and share information with their peers. Our protocol strives to maintain the highest standard of academic integrity by having each article edited by a postgraduate in the relevant field. We invite you to offer us your feedback by visiting our website:
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Kanzius Machine Michael Herman
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Palliative Surgery Rohan Kehar
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Cancer Stem Cells Kevin Wang
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www.meducator.org. The McMaster Meducator may be contacted via our e-mail address: meduemail @learnlink.mcmaster.ca
Crystal Chung
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Nanotechnology
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or our mailing address: B.H.Sc. (Honours) Program Attention: The McMaster Meducator Michael G. DeGroote Centre for Learning and Discovery Room 3308 Faculty of Health Sciences 1200 Main Street West Hamilton, Ontario L8N 3Z5
Stresses of Cancer
Michael Chan & Stephanie Dreckmann
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hat does cancer mean to you? It can affect the ones that we are closest to, the ones that we love, and for many of us it already has. We always hear about this disease – another risk factor, another therapy, another statistic. It is easy to get lost in this sea of information without fully appreciating the evolving knowledge on cancer. Today, the incidence of cancer is growing, but the rate of cancer mortality is decreasing with better treatment options*. This issue, in collaboration with the McMaster Cancer Society (MCS), strives to uncover the current advancements and concerns in the field of oncology. Specifically, the origin of cancer is discussed, with an investigation into the cancer stem cell hypothesis. Those interested in targeting cancer cells can explore the therapeutic potential of oncolytic viruses, nanovectors, and the Kanzius machine. Additionally, important issues surrounding the ethics of palliative surgery and other psychosocial implications of cancer are described. This issue provides an overview of cancer therapies and other implications during recovery. This special issue materialized through the joint effort of the McMaster Meducator and the McMaster Cancer Society. The goals of MCS are to support those impacted by cancer and bring awareness to the various issues surrounding this disease. While the society organizes several annual events, such as the Pink Ribbon Campaign and Cranes for Cancer, they continuously provide cancer information to others through a monthly newsletter and website (www.maccancersociety.com). Now, the Meducator provides an additional medium for which students and the community can learn more about the clinical issues and current research within the rapidly expanding field of oncology. Since this issue is completed funded by community donations, we would like to thank those who donated towards the printing and production of this special issue. Without your support and generosity, we could not educate our readers on the ethical concerns and promising research in cancer. Finally, please visit our website, www.meducator.org, to see past issues, find information about submitting articles, and read our MedBulletins. The website also provides a form for inquiries and comments; we want to hear from our readers! On behalf of the writers and staff, we truly hope you enjoy this issue.
Meducator Staff President Crystal Chung Vice-President Jacqueline Ho Editorial Board Veronica Chan Randall Lau Simone Liang Siddhi Mathur Navpreet Rana Manan Shah Fanyu Yang Creative Director Stephanie Low Web Master Avinash Ramsaroop Public Relations Harjot Atwal Graphics & Design Ran Ran Andrew Yuen Junior Executives Ahmad Al-Khatib Alyssa Cantarutti Randal Desouza Keon Maleki Hiten Naik Sangeeta Sutradhar
Post Graduate Editors Dr. Peter Ellis, MBBS, MMED, Ph.D. Dr. Humphrey Fonge, Ph.D.
Sincerely,
Dr. Kevin F. Kelly, Ph.D. Dr. Alexander Louie, MD
Crystal Chung BHSc IV
Kevin Wang (MCS President) BHSc III
*Canadian Cancer Society/National Cancer Institute of Canada: Canadian Cancer Statistics 2008, Toronto, Canada, 2008.
Dr. Brian D. Lichty, Ph.D. Dr. Joaquin Ortega Ph.D. Dr. Lisa Schwartz, Ph.D.
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Presidential Address
Dear Reader,
MedWire
4 The cost of cancer treatments are increasing at an alarming rate, proving difficult for the average family without private insurance to pay for treatment. The cost of cancer treatment drugs currently range from $25,000 to $81,000.
Despite the sharply increasing cancer rates in Fort Chipewyan, Alberta, a community downstream from oil sands, there has been no correlation found between the oil sands pollution and the increasing cancer rates. Scientists have recently developed an effective way of tailoring breast cancer treatment for individual women. By analyzing the network of protein interactions in breast tissue, a doctor can evaluate how aggressive treatment should be, and how effective this treatment will be. A recent study at the University of Nottingham found a correlation between frequent sexual intercourse and risk of prostate cancer: increased activity in a man’s 20s is associated with greater risk of prostate cancer, whereas increased activity in a man’s 50s seems to be protective against prostrate cancer. A recent study has confirmed that having Hepatitis C significantly increases the risk of various types of liver cancer.
Issue 14 Currently, liver cancer is the third leading cause of cancer deaths around the world. Lung cancer is the first. A study conducted by researchers at the Fred Hutchinson Cancer Research Center reveals that marijuana use may be linked with nonseminoma, a particularly agressive and difficult to treat form of testicular cancer. It was found that those having taken the drug at a younger age were at an increased risk.
Researchers at Washington University have developed a genomic test that can help personalize treatment for breast cancer. By analyzing a set of 50 genes, doctors can determine which of the four main tumor types a patient possesses. Treatment can be designed for that particular type.
The World Cancer Research Fund calculates that a daily intake of 150g of processed meats increases the risk of bowel cancer by 63%.
A baby in Britain was screened for BRCA1 mutations before birth. Although this does not completely protect the child from breast cancer in the future, it does lower the risk for the child and possibly for future offspring.
Researchers from the University of Washington have developed a drug that selectively kills cancer cells. A “chemical homing device” was added to the drug artemisinin, which comes from the sweet wormwood plant used in Chinese medicine. This novel drug binds to the protein signal found on the cell surface, attracts iron, and subsequently reacts with this iron to destroy the cell.
Glioblastoma brain tumour cells release microvesicles called exocytes. Researchers at Massachusetts General Hospital have discovered RNA and proteins within these vesicles that are associated with the tumour cells. This means that the exocytes could be used as biomarkers to assist therapy and monitor how the cells respond to treatment.
Researchers have identified the DNGR-1 receptor on the dendritic immune cell as being responsible for signaling an immune response against areas of excessive necrotic cell death, which is common in the blood deficient tumor environment. This discovery will help researchers develop anti-cancer drugs that harness the immune system.
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Researchers have found that stem cells responsible for the proliferation of leukemic cells exploit the mechanism of division used by embryonic stem cells; normal blood stem cells use a different mechanism for multiplication. Identifying this difference allows scientists to develop drugs that specifically target leukemic stem cells and spare normal blood stem cells.
A recent international study has concluded that vitamin E and selenium do not reduce the risk of prostate cancer. The study was shut down in October after its results suggested an association between vitamin E and increased risk of developing prostate cancer, as well as an association between selenium intake and diabetes.
Researchers from the Keck School of Medicine urge patients undergoing bortezomib therapy from drinking green tea. Bortezomid is an anti-cancer drug, specifically against blood and brain cancers, that can induce tumour cell death. The polyphenols within green tea products seem to counteract the therapeutic effects of the drug.
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Researchers in Cuba have developed a vaccine that extends the life of terminal lung cancer patients by an average of four months or even several years. It has already been approved for use in the general public.
er In the
In the Women’s Antioxidant Cardiovascular Study, no association was found between antioxidant supplements and decreasing cancer incidence or mortality. The study followed 7,627 women for almost ten years as they took beta-carotene, vitamin C, vitamin E, or a combination of them every other day. A study in Sweden found that breast cancer patients participating in art therapy have improved quality of life and health. It is believed that these women, who received radiation therapy, were given artistic freedom to express themselves, thereby reducing stress and countering the psychological side effects of radiation.
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A recent survey by the American Cancer Society suggests that the high cost of cancer treatments play a greater role than lapses in medical science in preventing many patients from overcoming the disease. The caps on insurance benefits and the loss of employment during treatment are central to patients’ inability to raise the necessary funds. A study conducted in Japan found that drinking coffee may have a protective mechanism against cancers developing in the oral cavity or throat. Those drinking one or more cups of coffee a day had a reduced risk of getting these cancers when compared to those who do not drink coffee.
Researchers in Sweden trained dogs to sniff out early-stage ovarian cancer. This was inspired by a previous study, in 2004, where dogs could detect bladder cancer by sniffing the urine of affected patients. However, these dogs will probably not be used in clinical practice due to varying accuracy rates.
Researchers are at the early stages of developing a urine test for prostate cancer patients. It would help identify the specific type of cancer by detecting a metabolite called sarcosine, which is more prevalent in more aggressive forms of the cancer. This would allow doctors to better determine whether or not a patient requires urgent treatment (ie. surgery) or not.
Imatinib, a drug used to fight leukemia, has been found to reverse the effects of type 1 diabetes in mice. Since this type of autoimmune diabetes depends on tyrosine kinases in the immune system, this drug acts as a tyrosine kinase inhibitor, preventing progression of the disease even after treatment is discontinued.
The Journal of the National Cancer Institute released a report suggesting that mammograms may do more harm than good for those who carry a BRCA mutation. Since patients are exposed to radiation during the procedure, researchers are now trying to determine the point at which screening is no longer beneficial. A study in the Australian Dental Journal found that alcohol-containing mouth washes increase the risk of developing oral cancers. This occurs because the ethanol in the mouthwash burns the lining of the mouth, exposing it to carcinogenic substances. While exercise has been heralded as an important cancer-preventing activity, present research suggests that exercise is only effective in conjunction with enough rest. With regular exercise and sleep, a woman’s overall cancer risk decreases. Researchers at the Roswell Park Cancer Institute have found that broccoli provides a protective effect against cancer in smokers. Decreases in risk ranged from 20%-55% reduction depending on the vegetables consumed and the smoking habits of the patient. Greater risk reduction was found in heavy smokers.
Instead of getting surgery to remove a tumour, doctors can now use an electric current to heat and destroy it. By following medical images and inserting a needle into the tumour, the cancerous tissue can be destroyed and the patient would only need to stay in the hospital for one night. Researchers in British Columbia found a correlation between environmental contaminants and nonHodgkin Lymphoma (NHL). Patients with NHL had higher levels of organochlorine pesticides and polychlorinated biphenyls in their blood. Exposure to these contaminants seems to double the risk of getting NHL. A new study published in Cancer claims that obese women may be at greater risk of ovarian cancer in comparison to women with average weights. www.meducator.org
MedWire
After a review of 52 studies, US scientists have concluded that active people are 24% less likely to develop colon cancer than the least active.
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Targetting and Arming Oncolytic Viruses Chemotherapy and radiation therapy have been beneficial cancer treatments; however, they lack tissue specificity and induces toxic effects on healthy cells. The use of armed oncolytic viruses presents an alternative to the side effects of current treatment and is at the forefront of current cancer therapies. Hannah Wigle Sandeep Koshy
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ancer is the abnormal and uncontrolled division of cells that have the ability to invade adjacent tissues and potentially metastasize to other regions in the body (Vogelstein & Kinzler, 2004). In 2008, approximately 166 400 Canadians were diagnosed with cancer, a number that will continue to increase along with our growing and aging population (Canadian Cancer Society/National Cancer Institute of Canada: Canadian Cancer Statistics 2008, Toronto, Canada, 2008). While chemotherapy and radiotherapy have been a beneficial treatment for many patients, they are relatively nonspecific to tumour tissue and present significant disadvantages. Rather than targeting cancerous cells, chemotherapy acts Figure 1 Receptor-based selective infection of cancer cells by an oncolytic virus. The virus interacts with a specific cell-surface receptor to mediate cell entry. This receptor is overexpressed on tumour cells (dark) relative to normal cells (light) which increases the probability of infecting malignant cells. Some normal cells may still be infected but to a much lesser extent.
systemically, indiscriminately inducing toxic effects in healthy tissues (Neri & Schliemann, 2007). Traditional radiotherapy has caused extreme discomfort and produces undesirable side effects, among them infertility and fatigue (Harrison et al., 2000; Meirow & Nugent, 2001; Thachil et al., 2001). Consequently, there has been a push in the field to design treatments that attack defective pathways, while leaving normal tissue relatively unharmed, but are also applicable to a broad range of tumour types (Friedrich et al, 2004). Born amidst these research endeavors is the concept of viral oncolysis – using wild-type or recombinant viruses to selectively infect and kill cancer cells while leaving normal tissues viable (Goldman et al., 2008). This article will
focuses on the current strategies used to isolate such viruses to tumour cells, ways through which to improve their destructive ability, as well as the state of their application in the clinic. Arguably, exquisite tumour targeting is the most valuable asset of oncolytic virotherapy. To create an effective recombinant oncolytic virus, the viral tropism must often be modified with the goal of increased viral affinity for replication in tumour cells. Three main strategies are most frequently used to target viruses to cancer cells: entry through receptors overexpressed on cancer cells, cancerspecific transcription and replication, and exploitation of cancer cell defects (Cattaneo et al., 2008). The first mechanism by which viral tropism can be redefined requires adjusting the virus’ selectivity for cell surface receptors (Figure 1). This can be achieved by genetically inactivating the residues that bind the virus’ natural receptor and introducing alternate residues that enable the virus to bind receptors overexpressed on tumour cells (Vongpunsawad et al., 2004). As such, the probability of the virus attaching, infecting, and replicating within tumour cells is increased. A common approach to introduce this specificity is to use a single-chain fragment variable (scFv) antibody, composed of only the
February 2009
antigen-binding variable regions of the antibody, that is most easily applied to enveloped viruses such as herpes simplex virus (HSV) (Conner et al., 2008). Indeed, some normal cells also express these receptors and become infected to a much lesser extent. Engineering the viral genome to selectively replicate in tumour cells is another effective way of altering viral tropism to achieve selective replication. Normally, after the attachment and injection of the viral genome, replication and propagation begin within the host cell (Kim et al., 2007). Primarily with DNA viruses, it is possible to manipulate the viral genome such that the transcription of essential viral gene products is controlled by a tumour-specific promoter (Figure 2). This strategy has been successfully employed in various models (Berk, 2005). This process results in a virus that is only capable of complete replication within tumour cells. Lastly, the tumour-selective infection of oncolytic viruses can be mediated by the deficient antiviral responses of tumour cells (Figure 3). When normal cells are infected by an RNA virus, they immediately respond to invasion by secreting antiviral cytokines (Janeway et al., 2005). These signals recruit innate immune cells to combat the viral infection, while simultaneously protecting neighboring cells from further viral infection (Randall & Goodbourn, 2008). However, tumour cells display deficiencies in these antiviral responses, facilitating viral infection and lysis. For example, the rhabdovirus, vesicular stomatitis virus (VSV), with its high sensitivity to interferon (Lichty et al., 2004), has been demonstrated to selectively replicate in tumour cells which are often non-responsive to this cytokine (Grander & Einhorn, 1998). In addition to targeting, strategies are often employed to amplify the cytolytic capabilities of oncolytic viruses to increase their efficacy (Cattaneo et al., 2008). Proapoptotic genes can be inserted to induce tumour cell death during the late stages of viral infection, as employed in an oncolytic adenovirus-expressing tumour-necrosis-factorrelated apoptosis-inducing ligand (TRAIL) (Sova et al., 2004). However, this approach can limit viral spread and oncolysis, due to low virus production resulting from premature apoptosis (Cattaneo et al., 2008). Another strategy involves the expression of so-called prodrug convertases by the virus, which converts a harmless systemically delivered prodrug to a cytopathic compound. These genes have been shown to supplement tumour oncolysis in several viral systems, including an HSV-encoding thymidine kinase capable of activating the drug ganciclovir in infected tumour cells
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Figure 2 Transcription-level selective replication. The oncolytic virus binds to both normal (light) and transformed (dark) cells and is taken up by endocytosis or membrane fusion. The genetic material of the virus, in this case double-stranded DNA, is released into the cell. Certain genes in the viral genome have been engineered to depend on a tumour-specific promoter for transcription. Cancer cells that express this promoter allow the synthesis of all viral proteins and facilitate viral replication. In normal cells, not all of the viral proteins can be transcribed, rendering the infection inconsequential.
(Boviatsis et al., 1994). In addition, oncolytic viruses can be made to express immune-stimulating molecules like GM-CSF (Lei et al., 2008; Malhotra et al., 2007) or tumour-associated antigens (TAA) (Diaz et al., 2007) to recruit antitumour effector cells from the host immune system (Prestwich et al., 2008). With an abundance of candidate viruses and various mechanisms to retarget their tropism, oncolytic viruses present a promising therapeutic option for cancer treatment. The clinical application of oncolytic viruses is still in its infancy and lacks sufficient preclinical research. The first clinical trial took place only eleven years ago, and while a number of
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Issue 14
subsequent trials have been performed, few have made it to the later stages (Parato et al., 2005). Concerns of toxicity have alleviated since the vast majority of dose escalation trials with oncolytic viruses have failed to reach the maximum tolerable dose (MTD) (Parato et al., 2005). There are currently a number of viruses being tested in the clinic on various tumour types. Recently, an oncolytic adenovirus (H101) has been approved for clinical use in combination with chemotherapy (Yu & Fang, 2007), (Liu et al., 2007), providing a promising outlook for this treatment method (Garber, 2006). Over the next decade, it is likely that techniques for manipulating oncolytic viruses will continue to evolve, leading to successful clinical applications. It is quite possible that these viruses, which hold such great potential to yield high tumour-selectivity and limited therapeutic side effects, could ultimately fulfill the criteria of the ideal cancer treatment.
References Berk, A.J. (2005). Recent lessons in gene expression, cell cycle control, and cell biology from adenovirus. Oncogene. 24(52), 7673-7685. Boviatsis, E., Park, J., Sena-Esteves, M., Kramm, C., Chase, M., Efird, J., Wei, M., Breakefield, X., Chiocca, E. (1994). Long-term survival of rats harboring brain neoplasms treated with ganciclovir and a herpes simplex virus vector that retains an intact thymidine kinase gene. Cancer Research. 54(22), p. 5745-51. Canadian Cancer Society/National Cancer Institute of Canada: Canadian Cancer Statistics 2008, Toronto, Canada, 2008. Cattaneo, R., Miest, T., Shashkova, E., Barry, M. et al. (2008). Reprogrammed viruses as cancer therapeutics: targeted, armed and shielded. Nature Reviews Microbiology. 6(7), 529-40. Conner, J., Braidwood, L. & Brown S. M. (2008). A strategy for systemic delivery of the oncolytic herpes virus HSV1716: redirected tropism by antibodybinding sites incorporated on the virion surface as a glycoprotein D fusion protein. Gene Therapy. 15(24), 1579-1592. Diaz, R., Galivo, F., Kottke, T., Wongthida, P., Qiao, J., Thompson, J., Valdes, M., Barber, G., Vile, R. (2007). Oncolytic Immunovirotherapy for Melanoma Using Vesicular Stomatitis Virus. Cancer Research. 67(6), 2840-2848. Friedrich, I. Shir, A., Klein, S., Levitzki, A. (2004). RNA molecules as anti-cancer agents. Seminars in Cancer Biology. 14(4), 223-230. Garber, K. (2006). China Approves World’s First Oncolytic Virus Therapy For Cancer Treatment. National Cancer Institute. 98(5), 298-300. Goldman, L. & Goldman, A., eds. Cecil Medicine. 23 ed. 2008, Saunders Elsevier: Philadelphia. Grander, D. & Einhorn S. (1998). Interferon and malignant disease--how does it work and why doesn’t it always? Acta Oncologica. 37(4), 331-338. Harrison, L., Shasha, D., White, C., Ramdeem, B. (2000). RadiotherapyAssociated Anemia: The Scope of the Problem. Oncologist. 5(90002), 1-7. Janeway, C., Travers, P., Walport, M., Shlomochik, M., eds. Immunobiology. 6 ed. 2005, Garland Science Publishing: New York. Kim, J., Kim, J.H., Choi, K., Kim, P.H., Yun, C. (2007). E1A- and E1B-Double mutant replicating adenovirus elicits enhanced oncolytic and antitumour effects. Human Gene Therapy. 18(9), 773-786.
Figure 3 Selective infection based on deficiencies in antiviral pathways. Upon delivery, the oncolytic virus infects both normal (light) and cancer cells (dark). Shortly after infection, an antiviral response is initiated by the infected cell, which protects other normal cells in the vicinity from viral infection. Tumour cells, which often show impairments in their antiviral response, remain susceptible to viral infection and lysis. IFN = Interferon Lei, N., Shen, F., Chang, J., Wang, L., Li, H., Yang, C., Li, J., Yu, D. (2008). An oncolytic adenovirus expressing granulocyte macrophage colonystimulating factor shows improved specificity and efficacy for treating human solid tumours. Cancer Gene Therapy. 16(1), 33-43. Lichty, B., Power, A., Stojdl, D., Bell, J. (2004). Vesicular stomatitis virus: reinventing the bullet. Trends in Molecular Medicine. 10(5), 210-216. Liu, T.C., E. Galanis, & Kirn D. (2007). Clinical trial results with oncolytic virotherapy: a century of promise, a decade of progress. Nature Clinical Practice Oncology. 4(2), 101-117. Malhotra, S., Kim, T., Zager, J., Bennett, M., Ebright, M., D’Angelica, M., Fong, Y. (2007). Use of an oncolytic virus secreting GM-CSF as combined oncolytic and immunotherapy for treatment of colorectal and hepatic adenocarcinomas. Surgery. 141(4), 520-529. Mirow, D. & Nugent D. (2001). The effects of radiotherapy and chemotherapy on female reproduction. Human Reproduction Update. 7(6), 535-543. Parato, K., Senger, D., Forsyth, P., Bell, J. (2005). Recent progress in the battle between oncolytic viruses and tumours. Nat. Rev. Cancer. 5(12), 965-76. Prestwich, R., Harrington, K., Vile, R., Melcher, A. (2008). Immunotherapeutic potential of oncolytic virotherapy. The Lancet Oncology. 9(7), 610-612. Randall, R.E. & Goodbourn S. (2008). Interferons and viruses: an interplay between induction, signalling, antiviral responses and virus countermeasures. Journal of General Virology. 89(1), 1-47. Schliemann, C. & Neri D. (2007). Antibody-based targeting of the tumour vasculature. Biochemical Biophysics Acta. 1776(2), 175-92. Sova, P., Ren, X., Ni, S., Bernt, K., Mi, J., Kiviat, N., Lieber, A. (2004). A TumourTargeted and Conditionally Replicating Oncolytic Adenovirus Vector Expressing TRAIL for Treatment of Liver Metastases. Molecular Therapy. 9(4), 496-509. Thachil, J.V., Jewett, M.A. & Rider W.D. (1981). The effects of cancer and cancer therapy on male fertility. Journal of Urology. 126(2), 141-145. Vogelstein, B. & Kinzler K.W. (2004). Cancer genes and the pathways they control. Nature Medicine. 10(8), 789-799. Vongpunsawad, S., Oezgun, N., Braun, W., Cattaneo, R. (2004). Selectively receptor-blind measles viruses: Identification of residues necessary for SLAM- or CD46-induced fusion and their localization on a new hemagglutinin structural model. Journal of Virology. 78(1), 302-13. Yu, W. and Fang H. (2007). Clinical trials with oncolytic adenovirus in China. Current Cancer Drug Targets. 7(2), 141-8.
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The Kanzius Machine The topic of a “magic bullet” that only targets cancerous cells is a recurring one. What follows is a comprehensive summary of the principal mechanism for one of the most promising non-invasive cancer treatments to be pioneered in modern times. Michael Herman
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ohn Kanzius is a radio engineer from Pennsylvania who, after being diagnosed with leukemia, designed a device that may have implications for the future of cancer therapy. The instrument has been dubbed “The Kanzius Machine”, and is currently undergoing extensive research and development under the leadership of Dr. Steven Curley, a hepatic cancer surgeon of the University of Texas (Curley, 2009). The concept of this therapy is predicated on the insertion of metallic nanoparticles into cancerous cells, which are then excited with the use of electromagnetic radiation in the form of radio waves. Radio waves excite the particles, causing their electrons to become elevated to higher energy levels. As these electrons “fall back down” to their stable energy levels, they emit the energy in the form of highly localized bursts of heat, which destroy the cell. The type of wave used is radio frequency (RF), a label encompassing all electromagnetic radiation of frequency 9 KHz – 1990 MHz (Petrucci et al., 2007). Since exposure to radio waves in their usual form is harmless, the Kanzius machine increases the intensity of these waves, thereby generating sufficient energy to produce an effect, but not enough to cause radiation poisoning (Klune et
al., 2007). At first, the machine relied on radio waves generated by a device that required a ‘dispersal pad’ placed against the patient’s skin. This was the a cause for some concern about the skin possibly being burned when the pad became hot during treatment. Kanzius subsequently developed a system to generate higher energy waves without the need for equipment in contact with the skin (Klune et al., 2007). Since this
“...ability to target and kill only cancerous cells in the body...” is done at a current that is considered safe, the development increases the plausibility of further use of the machine in in vivo cancer therapy. The nanoparticles being used are called Single Walled Carbon Nanotubes (SWNTs), that are tiny carbon structures that measure a maximum of 25 nm in length (Chen & Haddon, 1998). In order for treatment to be effective, it is estimated that the temperature of the cells must be raised to approximately 50 degrees Celsius (Klune et al., 2007). It was originally thought that these particles were too
small to respond to the radiation and therefore not generating enough heat to make the therapy effective; however, it has since been shown that exposure to intensified RF waves causes them to spontaneously self-arrange into linear structures that are capable of achieving adequately high temperatures (Klune et al., 2007). Although not directly related to cancer therapy, it is notable that the Kanzius machine is one of the first experimental ventures to bring this property to light (Curley et al., 2007). Because of the use of heat in this cancer treatment, it is commonly called Thermotherapy. It is this ability to target and kill only cancerous cells in the body -- unlike other cancer treatments like chemotherapy -- that makes the Kanzius Machine so attractive as a possible treatment. As it stands, the Kanzius treatment will only be applicable to localised tumours, which must be injected with nanoparticles and irradiated. Though this is valuable, Dr. Steven Curley, one of the leading researchers in this new form of treatment, claims, the current approaches are simply insufficient and “if we can’t target the microscopic cells this is not going to be a cure” (Simon, 2008). Cancer is most dangerous after metastasis, but the therapy currently has no mechanism for treating cells www.meducator.org
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Figure 1 Gold-polymer nanorods can assemble into spheres and be used to deliver drugs (Weiss, 2008).
that have metastasized throughout the body. The next step is to develop a mechanism for specific targeting of cancerous cells. Achieving target specificity would pose difficulties given that cancer cells are essentially like any other cell in the body, except that they proliferate ectopically and at increased rates. Therefore, most of the antigens expressed by cancer cells are also expressed by other body cells. These self-antigens are not normally recognized as harmful by the immune system, and this unchecked disease progression is the hallmark of cancer (Egeblad &Werb, 2002). The goal of scientists today is to find tumour specific antigens to target for nano-particle delivery. Fortunately, the variety of differentiation states in cancer cells provides multiple investigative pathways to look for tumour specific antigens. The hope is that the therapy will permit the conjugation of a nano-particle to an antibody specific for cancerous cells. The problem with this is that most of the antigens that a cancer cell will present can also be found on other somatic cells. These self-antigens are not normally recognized by the immune system. Current studies suggest that there will be a need to tag the metal particles with eight to ten antigens that correspond to receptors on the cell surface that may be overexpressed in some cancers, but these trials remain in the early stages (Klune et al., 2007). Theoretically, overexpression by cancer cells would render them more likely to bind to the metal, though this targeting method is not entirely specific. Unfortunately, there is little data regarding the toxicity of the metallic compounds. It has been suggested that the cells may instigate a severe inflammatory response in attempt to oxidize the foreign compounds. Some research
Issue 14 suggests that gold (Figure 1) may be a suitable alternative, because it has similar properties but has already been approved for treatment of other conditions, most notably rheumatoid arthritis (Klune et al., 2007). Further investigation is also required due to possible side effects, one of which is that metallic particles will end up in the blood stream and eventually in the lymphatic vessels after cell death (Klune et al., 2007). These vessels may be damaged as RF therapy continues, causing significant harm to the patient. Current testing has been done via insertion of metallic particles in solution, then insertion in cultured cells, and finally on rats to simulate an in vivo situation. Presently, it appears that viable treatment may be limited to tumours at least five cm in diameter. Twenty-four hours after exposure in vivo, researchers noted increased neutrophils and tissue necrosis (Klune et al., 2007). This again highlights the need for target specificity if this therapy is to ever become viable. Both Kanzius and Curley, as well as their research teams and other experts reviewing the data admit that human clinical trials are still years away. NB: The results of the most current research are awaiting peerreview.
References Chen, J., & Haddon, R. C. (1998). Solution properties of single-walled carbon nanotubes. Science, 282, 95-98. Curley S. et al. (2007). Carbon Nanotube-enhanced Thermal Destruction of Cancer Cells in a Noninvasive Radiofrequency Field. Cancer, 110, 2654- 65. Egeblad, M., Werb, Z. (2002). New functions for the matrix metalloproteinases in cancer progression. Nature Reviews, 2(3), 161-174. Klune, J. R., Jeyabalan, G., Chory, E. S., Kanzius, J., & Geller, D. A. (2007). P64: Pilot investigation of a new instrument for non-invasive radiofrequency ablation of cancer. Journal of Surgical Research, 137(2), 263-263. Petrucci, Ralph H., Harwood, William S., Herring, F Geoffrey., Madura, Jeffrey D. (2007). General chemistry: Principles & modern applications (9th ed.). New Jersey, USA: Pearson Education Inc. Simon, T. (Producer). (2008, April 13). 60 Minutes [Television Broadcast]. CBS Interactive Inc. The University of Texas M. D. Anderson Cancer Center. (2009). Steven A. Curley, M.D., F.A.C.S. Retrieved 02/03, 2009, from http://www. mdanderson.org/departments/ltsg/display.cfm?id=93c874fa8ae1-47a0-8c7134cb276d0b59&method=displayfull&pn=4c668 621-bcb9-11d4-80fb00508b603a14. Weiss, R. (2008). Time to sweat the samll stuff. Retrieved 02/11, 2009, from http://www.scienceprogress.org/2008/07/time-to-sweatthe-small-stuff/.
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Ethical Dilemmas in Palliative Surgery for Cancer Patients Palliative care is common in treating terminally ill patients. One important aspect is treating cancer patients with surgical interventions. Such interventions for cancer patients puts palliative care at the forefront of ethical debates. This article will explore some of the principles of biomedical ethics with respect to palliative
Rohan Kehar
interventions in patient care.
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ne possible route of palliative treatment available to cancer patients is surgery. However, the ethical implications of palliative surgical treatment are under continuous debate. Issues involved in the practice and research of palliative surgery will be explored using the four principles of biomedical ethics.
What is Palliative Care? According to the World Health Organization, “palliative care” differs from conventional medical care by promoting the quality of life in those patients with non-curable diseases (Cimino, 2002). Palliative care is common in treating terminally ill patients. Its purpose is to alleviate symptoms with minimal impact on the patient’s survival without worsening the patient’s condition. Techniques such as radiotherapy, chemotherapy, and surgery in addition to a support system are used to help the patient cope with the illness (Cimino, 2002).
Principles of Biomedical Ethics Beauchamp and Childress provided the impetus to develop the four principles of biomedical ethics: beneficence, nonmaleficence, respect of autonomy, and justice (Hofman, 2005). Beneficence and nonmaleficence mean ‘doing good’ and ‘doing no harm’ on the part of the clinician. Both served as
“...principles of biomedical ethics: beneficence, nonmaleficence, respect of autonomy, and justice.”
the foundation for those traditional and paternalistic beliefs which maintains ‘doctor knows best’. Patient autonomy means that the patient has the right to informed consent and to input in decision-making (Hofman, 2005). ‘Justice’ is a principle that entitles each patient to an equal level of attention from clinicians. The application of these principles is important in understanding the ethical concerns of palliative surgery for cancer patients.
Ethical Issues in Patient Care To discern the prevalent ethical concerns, McCahill et al. (2001) devised a 110-item survey. Its purpose was to determine the extent that palliative surgery was practiced and to identify ethical concerns involved in their decision making. The most frequent ethical dilemmas reported include: ‘providing honest information without destroying hope’, ‘uncertainty about the patient’s prognosis’, ‘preserving patient choice’, and ‘withholding/withdrawing life-sustaining treatments’ (McCahill, 2001). Patients are entitled to informed consent and full disclosure, but a balance must be achieved between informing the patient and maintaining hope. If a clinician reveals the truth, especially in a manner that is not sensitive to the patient’s state, the bad news may worsen the patient’s condition. On the other hand, it is unethical to withhold information that is pertinent to future treatment plans. In doing so, the clinician can influence the patient’s decision and compromise their autonomy. For example, if an oncologist believes major surgery is the best option for a patient with Stage IV breast cancer, it would be unethical according to the principle of autonomy to withhold information about alternative treatments such as chemotherapy or radiotherapy. Therefore, it is recommended in palliative care to make the patient aware of the severity of
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Issue 14 refusing a patient’s request also conflicts with a physician’s ‘duty to help’ (Krouse, 2005). The physician may wish to help the patient and adhere to their requests, but this may lead to futile treatment.
Ethical Issues in Clinical Research
the illness in a manner that gives the patient the opportunity to make decisions, while preserving their hope (Krouse, 2002). It is recommended that a paternalistic model be avoided. Information about treatment options should be made known to the patient, as the patient has the right to informed consent. However, uncertainty with the patient’s prognosis results in ambiguity, in which case, how much detail should be elucidated to the patient if doubt exists with respect to the prognosis? Concerns about the quality of life should take precedence over informed consent as physicians have a duty to do no harm to the patient. Preserving patient choice is an important principle to uphold, but its application should consider individual circumstances. One could argue that patients should be tested to ensure impaired thinking is not impacting the decision making process (Davies, 1995). Suggestions in the medical literature contend that patients should undergo mental health examinations to determine if they can make adequate choices (Krouse, 2002). If the patient is incapable of making decisions regarding one’s health, a substitute decision maker should be delegated. Otherwise, an incapacitated patient may decide to refuse promising treatment. Another issue is whether or not it is ethical to withhold a treatment, even if it is demanded by a patient. In their Code of Medical Ethics, the American Medical Association discusses this concept and claims that “physicians are not ethically obligated to deliver care that, in their best professional judgment, will not have a reasonable chance of benefitting their patients. Patients should not be given treatments simply because they demand them” (Davies, 1995). Thus, while the patient may demand surgery, the physician is entitled to refuse such a request. However, what if this lack of adherence negatively impacts the doctor-patient relationship? Some clinicians argue that questionable therapy is justified on the grounds of maintaining the trust and cooperation of the patient (Krouse, 2005). But
Another ethical concern is the lack of reliable and valid scientific evidence in support of palliative surgical treatments. Many surgical cancer treatments have not been subjected to a randomized controlled trial (RCT), resulting in a possible placebo effect (Hofman, 2005). Although this is not necessarily a negative outcome when it comes to palliative care, it is still in the practice of good science to discern the effect of treatment from a given intervention. However, there is an insufficient number of RCTs because it is unethical to use placebos to randomize control patients in a surgical trial. Many operations that are medically futile, or even detrimental in terms of patient risk, continue to be employed, such as palliative nephrectomy for radiating pain (McCahill, 2001). According to Hofman et al. (2005) these widely accepted surgical procedures require ethical consideration. In context of Beauchamp’s and Childress’ principles of biomedical ethics, it is a physician’s duty to do no harm. Performing a procedure that is known to be detrimental is an unethical practice. There is a responsibility among clinicians to help individuals with non-curable disease such as cancer, and surgery provides an important option to palliate symptoms. But despite the desire to adhere to patient needs, if there is insufficient scientific evidence for a surgical option, alternative methods should prevail. Otherwise, a surgical option becomes unethical.
References Cimino, J.E. (2002). A clinician’s understanding of ethics in palliative care: an American perspective. Critical Reviews in Oncology/ Hematology, 46, 17-24. Davies, B., Reimer, J.C., Brown, P., and Martens, N. (1995). Challenges of conducting research in palliative care. Omega, 31, 263-73. Hofman, B., Haheim, L.L., & Soreide, J.A. (2005). Ethics of palliative surgery in patients with cancer. British Journal of Surgery, 92, 802-819. Krouse, R.S. (2002). Palliative care for oncological patients. Journal of American College of Surgeons, 198,311-319. McCahill, L.E., Krouse, R.S., Chu, D., Juarez, G., Uman, G.C., Ferrell, B.R., &Wagman, L.D. (2001). Decision making in Palliative Surgery. Journal of American College of Surgeons, 195, 411-423.
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Paradigm Shift: Cancer Stem Cells
Kevin Wang
Despite rapid technological advancements, cancer remains to be one of the leading causes of mortality. Since the introduction of chemotherapy and radiation nearly half a century ago, there has been little advancement in cancer treatment. The present article will examine the cancer stem cell hypothesis, which is proving to be a promising model that may lead to novel therapy targets.
“We have to find something that walks like cancer, talks like cancer, but isn’t cancer.” “Cancer stem cells are real!”
S
uch were the words of Dr. Gregory House (from popular TV series, House) as he elucidated the presence of cancer stem cells. It has long been known that cancers originally develop from one or a few normal cells that acquire the ability to proliferate and metastasize. Yet, the origin of these tumours remains a mystery. Only recently has the discovery of cancer stem cells begin to shed light on the underlying mechanisms of oncogenesis. This potential paradigm shift in cancer biology may one day lead to the development of new treatment strategies that target the heart of a tumour by attacking the cells that initiate them.
In normal tissues, these self-renewing stem cells can differentiate into progenitor and mature cells depending on their microenvironment (Bjerkvig et al., 2005). Unregulated proliferation is prevented by restricting the stem cells’ ability to self-renew. Cancer stem cells have similar self-renewal and differentiation ability as stem cells, except its growth is unregulated.
Evidence of Cancer Stem Cells The stochastic theory of oncogenesis fails in its inability to explain two important observations in cancer growth (Lobo et al., 2007). For decades, scientists have observed that most tumours arise from a single cell, but not all the cells within the
Properties of Stem Cells In order to understand the Cancer Stem Cell (CSC) hypothesis, we must first revisit the basics of stem cell biology. In the early stages of human life, a totipotent pool of cells differentiate into the germ layers, each of which further develop into tissue types in the body. The genesis of new cells occurs through a small pool of somatic stem cells that are responsible for the development and maintenance of tissues throughout one’s lifetime. These somatic stem cells have the capacity to selfrenew and differentiate into one or more mature cell types (Figure 1). Each division gives rise to two daughter cells, a stem cell and a progenitor cell. The stem cell renews the stem cell pool and the progenitor cell loses the power to selfrenew but acquires the ability to differentiate into mature cell types (Lobo et al., 2007).
Figure 1 Normal stem cell differentiation to different lineages of nerve cells (NINDS, 2005).
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14 tumour are identical, a concept known as tumour heterogeneity (Heppner, 1984). This diverse morphology cannot be explained by a somatic cell that has acquired the ability to proliferate as it cannot differentiate into different cell types. The CSC hypothesis, on the other hand, is able to explain this anomaly through the generation of a pool of progenitors, each of which, depending on its cellular niche, can differentiate into the desired cell type (Calvi et al., 2003). In many cancers, portions of the tumour are cancerous, while others are “normal” cells that support the growth of the tumour. The second observation stems from the observation that, despite the stochastic model suggesting that a single cell can generate a tumour, at times even large numbers of cancerous cells fail to do so (Lobo et al., 2007). If all the cells within a tumour have the same proliferative potential, one would assume that even a few cells can recapitulate the original tumour, yet this has not been demonstrated in the lab. The CSC hypothesis postulates the existence of a cellular hierarchy whereby only a small population of the tumour is capable of self-renewal and thus generating a new tumour. As the cancer stem cells proliferate, a large pool of progenitors is responsible for the bulk of the tumour, yet these cells only have a limited capacity to replicate and cannot initiate tumour formation de novo. Another observation stems from mutations that give rise to cancers. Despite rigorous regulatory mechanisms, mutations that result in aberrant proliferation during mitoses do occur. Many of the tissues in which malignancies originate are composed of short-lived cells such as skin, or blood. Many cancers require a specific series of mutations involving signal transduction, cellular control,
Issue 14
Figure 2 Hypothesized cellular origins of cancer stem cells: a) stem cell, b) progenitor cell, c) differentiated cell (Bjerkvig et al., 2005)
and DNA repair mechanisms. These differentiated progenies are often protected from genotoxic stresses due to their relatively shorter life-span. Stem cells may be preferential targets of initial oncogenic mutations, as they are maintained throughout a person’s lifetime, thus have many opportunities to accumulate mutations (Lobo et al., 2007).
Cancer Stem Cells in Different Tissues Leukemia The existence of stem cells began with the discovery of hematopoietic stem
cells by Till and McCulloch in 1961. They were able to demonstrate clones that could give rise to multilineage colonies consisting of different blood cells (Till & McCulloch, 1961). Fittingly, the first discovery of cancer stem cells also took place in hematology. John Dick’s group at the University of Toronto was the first to isolate a population of primitive hematopoeitic stem cells in acute myeloid leukemia (AML) in 1997 (Bonnet & Dick, 1997). This small population of tumour cells, characterized by surface markers CD34+CD38-, when transplanted into recipient mice, was able to recapitulate the phenotypic profile of the original cancer.
February 2009
Breast Cancer In order to substantiate the CSC theory, it became critical to isolate stem cell populations in other cancer types. To find CSCs in solid tumours became the Holy Grail in the field as the surface markers required to isolate CSCs were still unknown. In 2003, Michael Clarke’s lab succeeded in finding CSCs in breast tumours. In a mouse model, as few as 100 breast cancer stem cells (CD44+CD24-) injected into the breast of healthy mice formed tumours, whereas tens of thousands of other cancer cells isolated from the same original tumour were unable to do so (Al-Hajj et al., 2003; Dontu et al., 2003).
Brain Cancer CSC in the central nervous system was another hard-sought trophy due to the long-held dogma that brain tissue becomes quiescent in adulthood. In 2004, Sheila Singh, formerly at the University of Toronto (now a scientist at the McMaster Stem Cell and Cancer Research Institute), identified similar stem-like cells in human brain tumors.
15 These CSCs, composing a much smaller portion of the tumour were isolated using the marker CD133. In a mice xenotransplantation model, it was demonstrated CD133+ tumour cells were able to generate the original tumor even when 1000 fold increase in the CD133- population were unable to do so (Singh et al., 2004). Since this discovery, CSCs were identified in several other tissue malignancies including melanoma, bone, ovarian, prostate, and colon cancers (Fang et al., 2005; Gibbs et al., 2005; Bapat et al., 2005; Collins et al., 2005; O’Brien et al., 2007).
Cancer Stem Cell Biology Since the discovery of CSCs, one central question involves the cellular origin of these cells. As both CSCs and normal stem cells must renew themselves and induce differentiation, it is reasonable to assume some molecular mechanisms are shared. Even though researchers have been able to isolate CSCs from tumours, no one has been able to differentiate CSCs from their normal counterparts as they often share the
same molecular markers (Lobo et al., 2007). It remains to be elucidated whether it is the progenitors which have accumulated mutations and now can revert back to a CSC, or whether it is the normal stem cell transforming into a CSC (Figure 2). Recent evidence is showing that both are possible; however, the molecular pathways that lead to these transformations remain to be discovered (Bjerkvig et al., 2005). Regulation of stem cell functions has become a rapidly growing research field. Studies published in 2003 by Molofsky and Sauvageaou independently demonstrated the role of polycomb-group protein, Bmi-1, as crucial in the self-renewal of CSCs (Molofsky et al., 2003; Lessard & Sauvageau, 2003). In patients with AML, expression of Bmi-1 is much higher than in normal bone marrow, indicating a potential relationship in causing oncogenesis. Another important pathway that is associated with many types of cancer is the Wnt/βcatenin pathway. Although crucial in normal development, they have been implicated in the self-renewal of CSCs (Reguart et al., 2005).
Figure 3 Current versus prospective therapy targets (Bjerkvig et al., 2005).
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Clinical and Ethical Considerations Despite the vast amount of resources invested into cancer research, the prospect of a cure has long eluded scientists. The CSC hypothesis may one day provide the answer to a cure. From a clinical point of view, it becomes necessary to target CSCs while not harming the normal stem cells that are vital to tissue growth and repair. Many current chemotherapies target the bulk of the tumour mass, which may explain the high likelihood of relapse. Current therapies operate under the assumption that all cancer cells have equal malignant potential. Thus, in many cases, a small population of cells remains after treatment. In fact, recent reports have shown
References Al-Hajj, M., Wicha, M.S., Benito-Hernandez, A., Morrison, S.J., Clarke, M.F. (2003). Prospective identification of tumorigenic breast cancer cells. Proc. Natl. Acad. Sci. 100:3983–88. Bao, S., Wu, Q., McLendon, R.E., Hao, Y., Shi, Q., et al. (2006). Glioma stem cells promote radioresistance by preferential activation of the DNA damage response. Nature. 444:756–60. Bapat SA, Mali AM, Koppikar CB, Kurrey NK. 2005. Stem and progenitor-like cells contribute to the aggressive behavior of human epithelial ovarian cancer. Cancer Res., 65:3025–29.
that CSCs are more resistant to conventional therapies, including chemotherapy (Costello et al., 2000) and radiation (Bao et al., 2006). Future treatment strategies must focus on targeting and eliminating the CSCs which drive the growth of the tumour (Figure 3). The study of cancer stem cells have come under much scrutiny due to the use of embryonic stem cells (cells obtained from aborted fetuses). In Canada, there is a relative freedom in scientists’ access to rare stem cell samples, but this is not the case for many other nations including the United States (however this is rapidly evolving under the new Obama administration). Despite the promising new findings, many barriers remain to be overcome before these advances can be translated to patient care.
Fang D, Nguyen TK, Leishear K, Finko R, Kulp AN, et al. 2005. A tumorigenic subpopulation with stem cell properties in melanomas. Cancer Res., 65:9328–37. Gibbs CP, Kukekov VG, Reith JD, Tchigrinova O, Suslov ON, et al. 2005. Stem-like cells in bone sarcomas: implications for tumorigenesis. Neoplasia ,7:967– 76. Heppner GH. 1984. Tumor heterogeneity. Cancer Res., 44:2259–65. Lessard J, Sauvageau G. 2003. Bmi-1 determines the proliferative capacity of normal and leukaemic stem cells. Nature, 423:255–60. Lobo NA, Shimono Y, Qian D, Clarke MF. 2007. The Biology of Cancer Stem Cells. Annual Review of Cell and Developmental Biology, 23:675-99.
Bjerkvig R, Tysnes BB, Aboody KS, Najbauer J & Terzis AJA. 2005. The origin of the cancer stem cell: current controversies and new insights. Nature Reviews Cancer., 5: 899-904.
Molofsky AV, Pardal R, Iwashita T, Park IK, Clarke MF, Morrison SJ. 2003. Bmi-1 dependence distinguishes neural stem cell self-renewal from progenitor proliferation. Nature, 425:962–67.
Bonnet D, Dick JE. 1997. Human acute myeloid leukemia is organized as a hierarchy that originates from a primitive hematopoietic cell. Nat. Med., 3:730–37.
National Institute of Neurological Disorders and Stroke (NINDS) (2005). The Life and Death of a Neuron. National Institutes of Health. Retrieved January 25, 2009, from http://www.ninds.nih.gov/disorders/brain_basics/ninds_ neuron.htm
Calvi LM, Adams GB, Weibrecht KW, Weber JM, Olson DP, et al. 2003. Osteoblastic cells regulate the haematopoietic stem cell niche. Nature, 425:841–46. Collins AT, Berry PA, Hyde C, Stower MJ, Maitland NJ. 2005. Prospective identification of tumorigenic prostate cancer stem cells. Cancer Res., 65:10946–51. Costello RT, Mallet F, Gaugler B, Sainty D, Arnoulet C, et al. 2000. Human acute myeloid leukemia CD34+/CD38− progenitor cells have decreased sensitivity to chemotherapy and Fas-induced apoptosis, reduced immunogenicity, and impaired dendritic cell transformation capacities. Cancer Res., 60:4403–11. Dontu G, Al-Hajj M, Abdallah WM, Clarke MF, Wicha MS. 2003. Stem cells in normal breast development and breast cancer. Cell Prolif., 36(Suppl. 1):59– 72.
O’Brien CA, Pollett A, Gallinger S, Dick JE. 2007. A human colon cancer cell capable of initiating tumour growth in immunodeficient mice. Nature, 445:106–10. Pardal R, Clarke MF, Morrison SJ. 2003. Applying the principles of stem-cell biology to cancer. Nat. Rev. Cancer, 3:895–902. Reguart N, He B, Taron M, You L, Jablons DM, Rosell R. 2005. The role of Wnt signaling in cancer and stem cells. Fut. Oncol., 1:787–97. Singh SK, Hawkins C, Clarke ID, Squire JA, Bayani J, et al. 2004. Identification of human brain tumour initiating cells. Nature, 432:396–401. Till JE, McCulloch CE. 1961. A direct measurement of the radiation sensitivity of normal mouse bone marrow cells. Radiat. Res., 14:213–22.
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Stress in the Lives of Cancer Patients Current
advancements in cancer therapy are quick to capture the attention
of society.
However, with no real cure, patients must struggle to live with the effects of cancer - beyond its biological consequences. This article introduces some of these factors and the stresses that patients face. Crystal Chung
B
ecoming ill with cancer is a frightening thought. Amidst the brouhaha of emerging cancer therapies and endless risk factors, other implications of cancer are often unnoticed. Most understand that it can be devastating, but never truly recognize the depth at which this disease affects its patients. Not only does it have severe biological consequences in a human host, there are several other dimensions in which cancer can affect quality of life. While some factors are consistently found with each cancer, others define the specific characteristics of the disease. By looking at the psychological, physical, and familial implications of one specific cancer, such as breast cancer, we can begin to form a comprehensive understanding of the hardships that cancer patients face beyond their biological struggles. Breast cancer is the most common cancer among women worldwide, apart from non-melanoma skin cancers (World Health Organization, 2004). According to the Canadian Cancer Society, one in nine Canadian women will develop some form of breast cancer in her lifetime. What follows is an overview of breast cancer literature on select issues pertaining to the lesser known effects of this prevalent disease.
Psychological Implications A study in London, England, continually interviewed 170 women with early staged breast cancer for five years after initial diagnosis. It was found that, within the five year period, 60% of women reported episodes of anxiety and/ or depression (Burgess et al., 2005). It is not difficult to understand why these women experience feelings of distress. Apart from the obvious health concerns, there are difficult decisions that need to be made about treatment options and uncertainties regarding the future.
“...1 in 9 Canadian women will develop some form of breast cancer...”
Unfortunately, this stress can exacerbate or be the result of pain and fatigue; these are the two most prevalent symptoms in cancer patients (Kurtz et al., 2008). Not only can these interfere with the patient’s daily activities and motivation to exercise – a very important part of the healing process (Holmes et al., 2005) – but it can lead to catastrophizing. Catastrophizing is exhibited when patients display negative thoughts about themselves or the future, and do not possess a “fighting spirit” (Jacobson et al, 2004). In general, there is a strong association between depression and fatigue in breast cancer patients (Reuter et al., 2006) which can have a broad effect on many aspects of their lives during recovery. Given these psychological effects after cancer diagnosis, research on coping mechanisms and social support has become increasingly important. In general, those who cope best with stress after diagnosis demonstrate higher psychological and physical quality of life throughout their treatment and recovery (Golden-Kreutz et al., 2005). The quality of life scores were assigned using the Medical Outcomes Study-Short Form (SF-36), a questionnaire www.meducator.org
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that evaluates several categories, including physical and mental health, pain, and health perception (Ware et al., 1993). Additionally, women with more significant social support systems have lower mortality rates in some studies (Kroenke et al., 2006). These networks, formed by a collection of family, friends, and confidants, serve as an important avenue for emotional release. Therefore, it may be necessary to address the social and psychological issues facing patients throughout the course of recovery.
Physical Effects The physical appearance of cancer patients can change dramatically over the course of illness. Hair loss is a side effect of some chemotherapy regimes. Since, traditionally, hair was sometimes viewed as a symbol of culture or identity, many patients lose their self-confidence (Mßnstedt et al., 1997). However, nowadays, the effect of hair-loss depends on the patient’s disposition: while one person may see hair-loss as a representation of their disease progression, others see it as a sign of pride and bravery (Batchelor, 2001). Women with breast cancer face another body image problem that can especially affect their sexuality. Women report less satisfaction with themselves, due to factors such as weight gain, breast surgeries, hair loss, and problems with sexual activity. The latter issue is compounded if they feel that their partners do not understand the sexual implications of the disease (Fobair et al., 2006). Mastectomies (removal of the breast) and lumpectomies (removal of an isolated part of the breast) adds another dimension of fear and anxiety about rejection from a partner or suppressed self image. In one study, 41% of mastectomy patients felt uncomfortable and unhappy with their bodies six months after surgery. Of lumpectomy patients, 8% felt a similar way. In general, perceived body image after breast surgery becomes less of a problem over time (Schain et al., 2006). However, it plays a large part in treatment decisions as the outcome is often irreversible, except in the case of breast reconstruction. Yet, even with reconstruction, relationships may not revert back to their original charm since some become fearful of hurting their partners or reopening scars when intimate (Sandham & Harcourt, 2006).
Familial Concerns While there are considerable personal issues to face during cancer recovery, many patients often think of the disease implications on their loved ones. Due to the nature of genetics, some cancers have a familial component, which
naturally places relatives at an elevated risk compared to the general population. For example, the risk of breast cancer in women increases as the number of first-degree relatives with breast cancer increases (Collaborative Group on Hormonal Factors in Breast Cancer, 2001). The familial links between patients with breast cancer has spurred much research into mutated genes that may predispose cancer. The BRCA1 and BRCA2 genes have been heavily studied within populations of people with breast and ovarian cancer. In one study, it was found that approximately 25% of patients who were identified within families at risk of breast cancer carry a mutation in either gene (Shih et al., 2002; Simard et al., 2007). However, the actual population prevalence of mutations in the BRCA1 and BRCA2 genes is low within those affected by breast cancer (Risch et al., 2001). Given the more sensitive methods of detecting genetic mutations and earlier detection of cancer risks, women are becoming more stressed with genetic consultation. Patients and professionals feel that at the time of diagnosis, cancer patients would rather avoid the extra anticipation of genetic testing unless it played a role in altering treatment decisions (Ardern-Jones, 2005). Additionally, the joint occurrence of cancer diagnosis and positive cancer gene screening can result in perceived urgency from the patient, thereby giving them less time for rationalization of treatment options. This can lead to major changes, as in the case of mastectomies, and overtreatment (Ardern-Jones, 2005). The impact of genetic testing becomes even more important as studies have found an increase in post-traumatic stress disorder in mutated BRCA1/2 carriers when compared to those who do not have the mutation (Hamann et al., 2005). Closing Remarks While the example of breast cancer has been used to explore some of the difficulties that patients face, it is important to keep in mind that many of these hardships are applicable to patients with other types of cancer. The variety of stresses experienced by patients is by no means limited to the factors introduced here. One must also be cognizant of specific complications arising from different therapies, the effect on one’s career, as well as the implications for those who consider having children. Financial burden can be disheartening, while religious obligations may also add pressure to the patient. By understanding the multifaceted effects of cancer, support networks and health providers can better assist patients with their struggles. In realizing that cancer therapy is not just a battle against rogue cells, society can play a role in helping to maintain quality of life and happiness in the infirm. .
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References Ardern-Jones, A., Kenen, R., Eeles, R. (2005). Too much, too soon? Patients and health professionals’ views concerning the impact of genetic testing at the time of breast cancer diagnosis in women under the age of 40. European Journal of Cancer Care. 14(3):272-281. Batchelor, D. (2001). Hair and cancer chemotherapy: Consequences and nursing care—A literature study. European Journal of Cancer Care. 10:147–163. Burgess, C., Cornelius, V., Love, S., Graham, J., Richards, M., Ramirez, A. (2005). Depression and anxiety in women with early breast cancer: five year observational cohort study. British Medical Journal. 330:702. Canadian Cancer Society/National Cancer Institute of Canada: Canadian Cancer Statistics 2008, Toronto, Canada, 2008. Collaborative Group on Hormonal Factors in Breast Cancer. (2001). Familial breast cancer: collaborative reanalysis of individual data from 52 epidemiological studies including 58 209 women with breast cancer and 101 986 women without the disease. The Lancet. 358(9291):1389-1399. Fann, Jesse, Thomas-Rich, A., Katon, W.,Cowley, D., Pepping, M., McGregor, B., Gralow, J. (2007). Major depression after breast cancer: a review of epidemiology and treatment. General Hospital Psychiatry. 30(2): 112-126. Fobair, P. Stewart, S., Chang, S., D’Onofrio, C., Banks, P., Bloom, J. (2006). Body image and sexual problems in young women with breast cancer. PsychoOncology. 15:579-594. Golden-Kreutz, D., Thornton, L., Wells-Di Gregorio, S., Frierson, G., Jim, H., Carpenter, K., Shelby, R., Andersen, B. (2005). Traumatic Stress, Perceived Global Stress, and Life Events: Prospectively Predicting Quality of Life in Breast Cancer Patients. Health Psychology. 24(3):288-296. Hamann, H., Somers, T., Smith, A., Inslicht, S., Baum, A. (2005). Posttraumatic Stress Associated With Cancer History and BRCA1/2 Genetic Testing. Psychosomatic Medicine. 67:766-772. Holmes, M., Chen, W., Feskanich, D., Kroenke, Colditz, G. (2005). Physical Activity and Survival After Breast Cancer Diagnosis. Obstetrical & Gynecological Survey. 60(12): 798-800.
Jacobsen P., Andykowski, M., Thors, C. (2004). Catastrophizing among women receiving treatment for breast cancer. Journal of Consulting and Clinical Psychology. 72(2): 355–361. Münstedt, K., Manthey, N., Sachsse, S., Vahrson, H., (1997). Changes in selfconcept and body image during alopecia induced cancer chemotherapy. Support Care Cancer. 5:139–143. Reuter, K., Classen, C., Roscoe, J., Morrow, G., Kirshner, J., Rosenbluth, R., Flynn, P., Shedlock, K., Spiegel, D. (2006). Association of coping style, pain, age, and depression with fatigue in women with primary breast cancer. PsychoOncology. 15:722-779. Risch, H., McLaughlin, J., Cole, D., Rosen, B., Bradley, L., Kwan, E., Jack, E., Vesprini, D., Kuperstein, G., Abrahamson, J., Fan, I., Wong, B., Narod, S. (2001). Prevalence and Penetrance of Germline BRCA1 and BRCA2 Mutations in a Population Series of 649 Women with Ovarian Cancer. The American Society of Human Genetics. 68(3):700-710. Sandham, C. & Harcourt, D. (2006) Partner experiences of breast reconstruction post mastectomy. European Journal of Oncology Nursing. 11(1):66-73. Schain, W., d’Angelo, T., Dunn, M., Lichter, A., Pierce, L. (2006). Mastectomy versus conservative surgery and radiation therapy. Psychosocial consequences. Psycho-Oncology. 73(4):1221-1228. Shih, H., Couch, F., Nathanson, K., Blackwood, A., Rebbeck, T., Armstrong, K., Calzone, K., Stopfer, J., Seal, S., Stratton, M., Weber, B. BRCA1 and BRCA2 Mutation Frequency in Women Evaluated in a Breast Cancer Risk Evaluation Clinic. Journal of Clinical Oncology. 20(4):994-999. Simard, J., Dumont, M., Moisan, A., Gaborieau, V., Vézine, H., Durocher, F., et al. (2006). Evaluation of BRCA1 and BRCA2 mutation prevalence, risk prediction models and a multistep testing approach in French-Canadian families with high risk of breast and ovarian cancer. Journal of Medical Genetics. 44:107-121. Ware, J., Snow, M., Kosinski, B., (1993). SF-36 Health Survey: Manual and interpretation guide. Lincoln, RI: Quality Metric Incorporated. World Health Organization Department of Measurement and Health Information. (2004). Mortality and Health Status: Causes of Death. Geneva: World Health Organization.
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Cancer and Nanotechnology Nanotechnology
is a rapidly growing field in biomedical research with
promising implications in the development of novel methods to target cancerous cells.
With
a diverse repertoire of potential functions
imaging to drug delivery
–
from prophylactic
– such nano-sized agents are currently the subject
of much investigation.
The following article explores the properties of various nanovector devices, the mechanisms through which they elicit their effects, as well as recent findings from both in vitro and in vivo studies.
Michael Chan & Stephanie Dreckmann
T O
O
O O O
O
O
O O
O
O
Core
O O
O O
O O
O O
OH
O O
Nanovectors
O
O O O
O
End Groups
O O
O
he past few decades have seen great progress in basic cancer biology research; however, this progress has failed to translate into comparable advancements in clinical applications. One challenge accounting for this discrepancy involves the difficulty to develop agents that can evade biological barriers, and selectively target malignant cells with minimal side effects (Duncan, 1998; Ferrari, 2005). The emerging field of nanotechnology is a promising solution to this challenge. Nanotechnology is a multidisciplinary field involving the use of exceptionally small devices – at the scale of 1-100 nm – for selective delivery of drugs and imaging agents to cancer cells. This paper will discuss several of these nanotechnology platforms including nanovectors and nanoshells.
O
Figure 1 Generation 4 poly(benzyl) ether dendrimer consisting of OH core and end groups (Hawker, 1990).
Nanovectors are multifunctional devices usually comprising three components: (1) a core material, (2) a therapeutic or imaging agent, and (3) biological surface modifiers with or without a targeting group. The core material, which is usually made of biodegradable polymers, may carry one or more therapeutic agents. Biological surface modifiers are designed to increase the half-life of drugs in the body, protect drugs against enzymatic degradation, as well as avoid other obstacles. For example, polyethylene glycol (PEG) is a biological surface modifier that has been shown to prevent uptake of nanovectors by macrophages or other cells of the reticulo-endothelial system. In addition, nanovectors are designed to selectively deliver therapeutic
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agents to cancer cells. This can be achieved by attaching ligands or antibodies to the surface of nanovectors that recognize certain epitopes on the diseased tissue or organ. This process is termed targeted delivery-active transport. Nanovectors can also be delivered passively through enhanced permeation and retention effect (EPR) due to their long circulation half-life (Matsumura, 1986; Ferrari, 2005). The EPR mechanism takes advantage of the increased fenestrations in vasculature that allows for the extravasation and accumulation of nanovectors in tumours (Ferrari, 2005; O’Neal, 2004). Another targeting method involves externally activating nanovectors in certain parts of the body to prohibit systemic cytotoxicity (O’Neal, 2004; Yan, 2003).
Figure 2 Generation 5 dendrimer linked to a cancer drug (methotrexate), a targeting agent, and an imaging agent. Another optional attachment not pictured above includes a high density contrast agent, such as gold, which would be useful for MRI detection (Kukowska-Latallo, 2005).
Dendrimers A novel approach to cancer therapy involves the use of dendrimers as nanovectors (Hawker, 1990). These are repeatedly branched symmetrical molecules, consisting of a polyfunctional core bound to multiple end groups (Figure 1) (Hawker, 1990). A large number of dendrimers with different properties can be synthesized due to variations in their size, shape, and reactivity (Tomalia, 1995). One such property is the ability to target, detect, and destroy cancer cells (Majoros, 2006). Studies conducted at the Michigan Nanotechnology Institute showed that dendrimers could effectively detect and eliminate cancerous cells when linked to therapeutic, fluorescent, targeting, and contrast agents (Figure 2) (Majoros, 2006).
Cancer Cell Detection and Internalization As previously described, there are several ways to target cancer cells. One method involves conjugating cancer-specific receptor ligands to drug-carrying dendrimers. For example, the unregulated proliferation of cancer cells increases the cell’s requirement for folate, a water-soluble vitamin. Consequently, folate receptors are upregulated in different carcinomas, including cancers of the ovary, kidney, uterus, testes, brain, colon, blood, and lung. By conjugating folic acid to a drug-carrying dendrimer, these cancers are preferentially targeted. The dendrimer internalizes into lysosomes through folic acid receptors and releases chemotherapeutic drug into the cell, resulting in cell death (Majoros, 2006). Another example involves the overexpression of human epidermal growth factor receptor 2 (HER2) in many breast carcinomas. By coupling a dendrimer to herceptin (a HER2 ligand), these cancers can also be eradicated (Shukla, 2006).
Studies to Date Successful dendrimer testing has occurred both in vitro and in vivo (Majoros, 2006; Navarro, 2008). The dendrimer was conjugated to folic acid, and the final product has successfully killed cancer cells (Majoros, 2006). In another study by O’Neal et al. (2004), nanoshells that are composed of a silica core and a thin metallic gold shell were shown to be effective against subcutaneously implanted tumours in mice. These nanoshells were designed to become activated at near infrared (NIR) wavelengths, an optimal wavelength for light to penetrate into deeper tissues (Weissleder, 2001). Nanoshells were systemically introduced and externally activated by a laser.The resulting increase in temperature caused irreversible damage to surrounding cancer cells. Results indicated that there was a selective accumulation of nanoshells in tumours, as opposed to in healthy tissue, which could be attributed to the EPR effect. In addition, nanoshell-treated mice exhibited complete destruction of the tumour within ten days of beginning treatment, while all control group animals exhibited uncontrolled tumour growth and had to be euthanized according to study protocols.
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Issue 14
The Future The use of nanotechnology in cancer research is an exciting field that is receiving increasing international recognition. Through careful design of nano-devices, scientists will be able to use various combinations of therapeutic agents that specifically target cancer cells, avoid biological barriers, and eliminate tumours without damaging healthy cells. In addition, these devices may also be used for early detection of cancer cells even before they develop into the disease. Nevertheless, there could be some safety issues associated with the use of these devices. Are they compatible with humans? How reliable are the production protocols of these agents? Due to their nature, nanoparticles will fall under several categories such as drugs, medical devices, and biological agents. Thus, the time required for regulatory approval may be lengthy. Despite all of these challenges, it is clear that the future holds countless possibilities for nanotechnology research.
References Duncan, R. (2003). The dawning era of polymer therapeutics. Nature Review Drug Discovery, 2, 347-360. Ferrari, M. (2005).Cancer nanotechnology: opportunities and challenges. Nature Reviews 5, 161-171. “Golden slingshot: The next generation of cancer treatments may be delivered by nanoparticles.” The Economist 6 Nov 2008 25 Nov 2008 <http:// www.economist.com/science/displaystory.cfm?story_id=12551598>. Hawker, C.J., Fréchet, J.M.J. (1990). Preparation of polymers with controlled molecular architecture. A new convergent approach to dendritic macromolecules. Journal of the American Chemical Society, 112, 7638-7647. Kukowska-Latallo, J., Candido, K.A., Cao, Z., Nigavekar, S.S., Majoros, I.J., Thomas, T.P., Balogh, L.P., Khan, M.K., Baker, J.R. (2005). Nanoparticle targeting of anticancer drug improves therapeutic response in animal model of human epithelial cancer. Cancer Research, 65(12), 53165324. Majoros, I.J., Myc, A., Thomas, T. Mehta, C.B., Baker, J. (2006). PAMAM dendrimer-based multifunctional conjugate for cancer therapy: synthesis, characterization, and functionality. Biomacromolecules, 7(2), 572-579. Matsumura, Y. & Maeda H. (1986). A new concept for macromolecular
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therapies in cancer chemotherapy: mechanisms of tumortropic accumulation of proteins and the antitumor agents SMANCS. Cancer Res. 6, 6397–6392. Navarro, G., Tros de ILarduya, C. (2009). Activated and non-activated PAMAM dendrimers for gene delivery in vitro and in vivo. Nanomedicine, 10: 1016. O’Neal, D.P., Hirsh L.R., Halas N.J., Payne, J.D. & West, J.L. (2004). Photothermal tumor ablation in mice using near infrared-absorbing nanoparticles . Cancer Letters. 209(2), 171-176. Shi, X., Wang, S., et al. (2007). Dendrimer-entrapped gold nanoparticles as a platform for cancer-cell targeting and imaging. Small, 3: 1245-1252. Shukla, R., Thomas, T.P., Peters, J.L., Desai, A.M., Kukowska-Latallo, J., Patri, A.K., Kotlyar, A., Baker, J.R. (2006). HER2 specific tumor targeting with dendrimer conjugated anti-HER2 mAb. Bioconjugate Chemistry, 17(5), 1109-1115. Tomalia, D.A. (1995). Dendrimer molecules. Scientific American, 272(5), 62-66. Weissleder, A. (2001). Clearer vision for in vivo imaging. Nat. Biotechnol. 19, 316–317. Yan, F. & Kopelman, R. (2003). The embedding of meta-tetra(hydroxyphenyl)chlorin into silica nanoparticle platforms for photodynamic therapy and their singlet oxygen production and pH-dependent optical properties. Photochem. Photobiol. 78, 587–591.
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