Infectious agents and cancer
10.29.09 by Sharmila Pejawar-Gaddy
Several cancers have been attributed to infectious agents. It is estimated that approximately 18% of all cancers worldwide are caused by infectious agents. 26% of these are in developing countries and 8% in developed countries. These figures and discrepancies between the developed and developing worlds point to differences in disease prevalence, either due to sanitary conditions or shortage of vaccines. Infectious agents can be classified as indirect or direct carcinogens. Indirect carcinogenic agents are those that cause chronic infection and thus chronic inflammation, which then leads to the advent of cancer. Examples of these include, Helicobacter pylori infection that is the an attributing factor to a majority of stomach/gastric cancers, as well as chronic hepatitis B and C infections that are causally linked to a majority of liver cancers. On the other hand, direct carcinogenic agents are those that can incorporate oncogenes into the cell’s genome. Examples of these are human papillomavirus that causes a majority of cervical cancers, as well as in some cases, penile cancer, vaginal cancer and genital warts; Epstein-Barr virus linked to a majority of Naso-pharengeal carcinomas and human herpes virus-8 linked to Kaposi’s sarcoma. This list grows every day. The good news is this: most of these infections, and thus the advent of several cancers, can be prevented by vaccination.
Adapted from Parkin, DM. 2006. Int J Cancer. 118:3030 and Dr. Douglas Lowy
Related articles
- Parkin, DM. 2006. The global health burden of infection-associated cancers in the year 2002. Int J Cancer. 118:3030.
- Campbell, K. 2006. The infectious causes of cancer. Nurs Times. 102(33):28.
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The Future of Brain Tumor Therapy
06.14.09 by Daniel Gaddy
A little over a year ago, the announcement that Senator Ted Kennedy was diagnosed with a malignant brain tumor brought a lot of attention to brain cancer research. Brain cancers are among the most perplexing types of cancers. Indeed, until now, it was not even known how brain cancers form. It was believed for many years that brain tumor metastasis, or the process whereby cancerous cells move from the location where a tumor has initially grown and spreads to other parts of the body, was the product of “brain-specific homing” of metastatic cancer cells from other areas of the body, followed by direct interactions of the cancer cells with neural tissues. However, recent research from Oxford University, published in the journal PLOS One, demonstrated that metastatic cancer cells in mouse and human tissue utilized “vascular cooption” for seeding brain tumors rather than invading and growing within the neural tissue. What this means is that cancer cells enter blood vessels, where they can then be transported throughout the body. This information is not new. What the Oxford researchers, led by Professor Ruth Muschel, showed is that once in the blood vessels, cancer cells can establish residence and begin to grow along the blood vessel walls. By thus co-opting blood vessels in the brain, tumors can utilize readily available nutrients and oxygen from the blood without having to grow their own blood vessels, which occurs via processes known as neovascularization and angiogenesis.
The normal course of treatment for malignant brain tumors is radiation and chemotherapy. The ability of newly established tumors to utilize existing vasculature may account for the resistance of some brain tumors to many chemotherapy drugs that target neovascularization and angiogenesis. Drug resistance, in part, leads to the poor prognosis for patients with malignant brain tumors. Because existing treatments are largely futile, novel therapies are always being investigated. The research of Dr. Muschel and her colleagues not only identified a novel mechanism of tumor metastasis to the brain, but also identified the integrin family of cellular adhesion proteins as the key molecules that mediate attachment of metastatic cancer cells to blood vessel walls. This discovery could, potentially, lead to novel brain tumor therapies.
Another novel therapy, which I have had the opportunity to work with, is the oncolytic virus, vesicular stomatitis virus (VSV). As a graduate student, I worked with a mutant VSV that had a preference for infecting and killing tumor cells, while sparing normal cells. A primary application for oncolytic VSV is in the treatment of brain tumors, because VSV naturally targets the brain. Many studies have successfully demonstrated the ability of VSV to kill brain cancer cells in vitro and in mouse models. To my knowledge, these studies have not been extended to human clinical trials, but the last I heard they were very close. Similar oncolytic (meaning they “lyse” or kill tumors) viruses have moved into clinical trials, with varying levels of success. Novel therapeutics such as oncolytic viruses, gene and cell therapies and immunotherapies offer the greatest promise for treatment, and potentially even cures, of some of mankind’s deadliest and most debilitating diseases. While these therapeutics are still met with some disdain in the United States (because genetically modified organisms are categorically evil!), other parts of the world are embracing them. These therapies are continuously being shown to be both safer and more effective than traditional therapies. While more research is certainly needed, the potential remains for these therapies to change the face of modern medicine.
Citation: Carbonell WS, Ansorge O, Sibson N, Muschel R (2009) The Vascular Basement Membrane as “Soil” in Brain Metastasis. PLoS ONE 4(6): e5857. doi:10.1371/journal.pone.0005857
Cancer vaccines: a brief introduction
05.8.09 by Sharmila Pejawar-Gaddy
From the time of the first documented vaccine against smallpox by Edward Jenner, developing an effective vaccine to prevent deadly disease caused by existing or newly emerging pathogens has been the goal of many microbiologists and immunologists. With a single exception, that of the rabies vaccine, all vaccines developed previously have been prophylactic, meaning that they are administered in order to prevent the onset of disease. The concept of a vaccine has slowly evolved to currently include a therapeutic vaccine, meant to ameliorate an existing disease state by potentially strengthening an ongoing but not fully effective immune response against a pathogen. Further broadening of the concept of a vaccine has come about with the realization that in addition to eliciting an immune response where there was none, a vaccine could also be designed to change an existing immune response from one type to another. Most recently, vaccines are being considered not only for elicitation of immunity but also potentially for induction of tolerance [1, 2]. This concept has also increased potential targets of vaccines from diseases caused by pathogens to any disease that involves the immune system, such as cancer, autoimmunity and graft rejection. [3-6].
Challenges facing cancer vaccines
Choosing the right antigen and adjuvant are the sine qua non of an effective vaccine.
The “right” antigen: Antigens used in cancer vaccines should preferably be molecules that are different between normal cells and tumor cells ensuring that the immune response generated by vaccination will target for destruction antigen-bearing tumor cells and not normal cells [7, 8]. This requirement is satisfied more easily in the case of vaccines against pathogens because their antigens are all foreign to the host and thus immunity generated against them, in most instances, does not cross-react with normal host tissues. In cancer, most antigens are derived from mutated or modified self-proteins against which there is often a certain level of immune tolerance. This creates particular challenges for the appropriate design of vaccines that have to overcome this tolerance in order to elicit anti-tumor immunity without autoimmunity [9].
The “right” adjuvant: Adjuvants are diverse molecules that can activate antigen presenting cells (APC) to stimulate a potent and robust cellular immune response (T cells). Adjuvants can also activate natural killer cells or other cells of the innate immune system to produce cytokines that can promote survival of antigen-specific T cells [10]. Although at the present time, there are only two adjuvants approved worldwide for clinical use – aluminium-based salts (alum) and a squalene-oil-water emulsion (MF56) – many other molecules, such as cytokines, bacterial products (toll-like receptor (TLR) agonists), heat-shock proteins [11-13], microspheres [14, 15], virus-like particles [16, 17] and immunostimulatory complexes (ISCOMs) are being tested [18].
The “right” immune response: An effective vaccine must be able to generate and sustain a potent immune response that would ensure eradication and prevent recurrence of existing tumors, in the case of a therapeutic vaccine, or in the case of a prophylactic vaccine, prevent de novo tumor formation [19]. Thus the immune response generated must result in long-term memory to provide life-long protection from cancer. It is now clear that the generation of an immune response that can eliminate the tumor depends on the ability of a vaccine to activate both the innate and the adaptive immune system [20]. More importantly, the end result of this activation should be an immune response that is the “right” type for the tumor that is being treated. Different types of immune responses include systemic versus mucosal immunity, T-helper 1 (Th1) versus T-helper 2 (Th2), [21, 22] or primarily antibodies versus primarily cytotoxic T lymphocyte (CTL). Recent realization that every vaccine is capable of simultaneous induction of effector cells as well as regulatory T cells [23](reviewed in [24] has added another requirement, that of preferential induction of effector T cells.
Tumor antigens, candidates for cancer vaccines
Since the pioneering work of Boon and Rosenberg leading to the isolation of the first human melanoma antigens [25-27], work on the discovery of tumor antigens has been pursued by many researchers employing many different methods [28-31].
Tumor antigens can be broadly classified into two categories: shared tumor antigens and unique tumor antigens. Shared tumor antigens are expressed by many tumors and either not on normal tissues or expressed by normal tissue in a quantitatively and qualitatively different form. Examples of such shared tumor antigens are the cancer testes antigens (MAGE, GAGE and NY-ESO1) (reviewed in [32]). Unique tumor antigens, on the other hand, are products of random mutations induced by physical or chemical carcinogens, and therefore expressed uniquely by individual tumors [33]. These include specific mutations in oncogenes, such as p53 and Kras (reviewed in [32]). An interesting variation on this theme are tumor-derived heat shock proteins that are being developed as cancer vaccines [34, 35]. The heat shock proteins themselves are conserved proteins but the tumor peptides bound to them are derived from both shared and unique tumor antigens.
Undefined tumor antigen-based vaccines
A recent report shows that colon and breast cancers contain on an average at least 11 different mutations in proteins involved in a wide range of cellular functions, including transcription, adhesion and invasion [36]. Many of these mutations are candidates for tumor antigens. This supports a long-held notion that one way to expose the immune system to many potential tumor antigens is to immunize with whole tumor cells. This approach mimics many vaccines against infectious diseases that use the whole, attenuated forms of the pathogens. The benefit of such vaccines is that it allows the immune system rather than the vaccinologist to select most immunogenic tumor specific antigens. The danger is that in the presence of adjuvants, tolerance to normal molecules might be broken resulting in autoimmunity.
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