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Heat Shock Proteins in Relation to Cancer
Currently, heat shock proteins suggest a new form of cancer treatment that could possibly create one of the first vaccines against cancer as well as a way of curing it that is much more effective and less damaging than chemotherapy. Certain types of HSPs have allowed for adaptive immunological functions which have been implicated in Ag presentation. Since HSPs react to stress like starvation and disease, their presence in the body are usually great indicators of something happening and this warning is sometimes noted by the t-cells which react to the problem.
The HSP known as gp96 has proven to be one of the most promising HSPs in this regard. This paper will discuss the roles of HSPs in immunology as well as cancer treatments. The question of whether or not gp96 has a specific immunogenicity has been studied extensively with some conclusions in place. What this means for cancer patients is the subject for this paper. I will focus on HSPs in their original job and then gp96 from which I will discuss the way this specific HSP can be used for cancer treatments. Already trials have begun for cancer patients in Stage I and Stage II with Stage III melanoma and renal cancer patients showing very positive results.
This paper will discuss the role of heat shock proteins in the human body before speaking specifically about the potential role of HSPs in the treatment and prevention of cancerous tumors.
Heat Shock Proteins
Heat shock proteins or HSP are proteins with an increased expression due to exposure to elevated temperatures or stress. (De Maio, January 1999) Research into HSPs has suggested some surprising results indicating that HSPs are more central to evolution and biology than previously believed. “In the past decade scientists have realized that HSPs…are integral to our immune defense against cancer and pathogens.” (Srivastava 2008) HSPs are considered escorts for the other proteins. They inhibit undesirable interactions and promote desirable ones, thus creating productive bonds between protein partners.
While investigating the effects of high temperatures on cells in regard to heat hardening, Ritossa reported that heat and dinitrophenol induced a state of chromosome “puffing” in Drosophilia flies (Ritossa, 1962) which led to the identification of heat-shock proteins. Since the 1980s, the studies in HSPs have grown considerably as scientists are learning new information about the way HSPs are formed and their potential benefits to living organisms. Members of the HSP family find themselves in all organisms because they have an essential role in protein maintenance. The benefits of HSP include cell monitoring, binding antigens before presenting them to the immune system, cardiovasculature and chaperone.
One of the keys to the HSP’s chaperone capability is its ability to interact and associate with a wide range of client proteins as opposed to regular proteins which only have a few proteins that they can interact with (such as the receptor and ligand being practically made for each other). This ability allows HSPs to perform many useful tasks like helping newly formed amino acid chains fold into their proper protein shapes, dismantling them after damage and escorting proteins to their intended mates (Srivastava 2008).
Under emergency situations like extreme heat, starvation or oxygen deprivation, heat shock proteins can mitigate the stress by rescuing essential proteins and getting rid of the damaged ones. Ritossa’s observation concerning the drosophilia apply here since the body produces these HSPs in order to protect itself from the damages of the external circumstances. The HSPs aren’t enough to save a life in lethal cases, but they do preserve the cells and in distressed environments.
Pramod Srivastava explains that the current research in regards to HSPs and cancer stems from studies in the 1940s that suggested that rats could be inoculated against cancer like humans can be inoculated against pathogens. Pathogens are recognized by the immune system as foreign and the immunization introduces the immune system to a non-lethal strain in order for it to fight the lethal strains. However, cancer is an effect on the patient’s cells so isolating cancer-specific antigens is a difficult task at best since the healthy cells and unhealthy cells seem virtually the same to the immune system.
As a member of the HSP90 family, the gp96 has been shown to elicit immune resistance to tumors. When HSP90 or HSP70s are taken from cancers, they bear peptides derived from cancer-specific antigens. Retaining peptides representative of origin cells gives the HSPs the role of recognizing cancerous cells. This helps the t-cells to recognize these MHC 1-peptide complex and destroy diseased cells. The antigen-chaperoning property of the peptide binding HSPs helps the HSP to immunize against the tumors.
The gp96 molecules have been under scrutinized as only one particular variable in a highly complex system. However, studies have suggested that the gp96 is the best theory concerning chaperoned antigenic peptides. According to Binder’s article:
“The possibility that gp96 molecules are not associated with endogenous peptides was first raised from experiments that showed that truncated gp96 molecules lacking the carboxyl terminus…could still confer protective immunity. While this article was under publication, a second peptide binding site of gp96 was identified on the amino terminus of gp96. The presence of this second, N-terminally located peptide binding site invalidated the conclusion that the immunogenicity of gp96 is peptide independent…the single study that purported to show evidence of the peptide independence of immunogenicity of gp96 could not be upheld after the identification of this second peptide binding site.” (Binder 2007)
Srivastava describes the gp96 as a sentinel to the immune system in which antigen-presenting cells sample their surroundings and present their findings to the T cells. Antigen-presenting cells carry receptors on their surface for the peptide-binding chaperones. When the cells encounter an HSP-peptide complex, they internalize it through the receptor. When HSPs chaperone the cancerous cells to the t-cells, it alerts the t-cells which understand that there is something wrong and take action against the cancerous cells.
“Gp96 was shown to directly stimulate dendritic cells to mature to competent antigen-presenting cells and to induce anti-tumor immune responses even when the peptide binding domain had been deleted. The a2-macroglobulin receptor was shown to be the receptor for gp96 involved in these processes. All of these observations suggest that gp96 plays an important role in the cellular immune response.” (Demine, February 2, 2005)
Just exposing antigen-presenting cells to HSP70 and HSP90 family members causes the cells to change in a wide variety of ways. The initiation of signals that cause inflammation which causes a strong immune defense is one of the effects. Most of the time HSPs work within cells and keep their primary role as a carrier and source of stabilization. However, cells under stress release HSPs and activate antigen-presenting cells by their mere presence. This activity suggests that the very appearance of the HSPs outside cells acts as a mechanism that needs to alert the rest of the immune system to potential dangers.
In his experiments, Srivastava has been utilizing HSP-peptide complexes purified from cancers to elicit tumor rejection. This work is based upon the immunizing function. Srivastava is going on the assumption that every tumor is antigenically unique. Since tumors are unique antigens, they are not treatable in all cases. This is why chemotherapy is the most popular solution to cancer since it destroys everything without discrimination. With an HSP-based immunization system, the treatment of the tumors is infinitely more subtle and individual.
The program suggested by Srivastava involves extracting HSP-bound peptides from the individual patient and then introducing them in a purified form which releases inflammatory signals to recruit other immune cells. This individual process creates a vaccine that stimulates the immune system in order to fight the tumors.
Already, this process has been tested in the U.S. and Europe in a series of early human trials. More advanced tests for Phase III cancers have been conducted for patients in the U.S., Europe, Australia and Russia. These particular tests have focused on melanoma and renal cancers. In the renal cancer trials, the vaccine extended recurrence free survival time to more than a year and a half.
Due to these results, the Russian government has approved this as a treatment, thus creating the first cancer vaccine to enter actual clinical use. In Europe and the U.S. there are applications on the waiting list for approval. The Food and Drug Administration is currently waiting for more data on the test patients’ long term survival rate.
This particular paper focused on the method of amplifying the HSPs on the immune system and using them as vaccines. The HSP can definitely have a positive effect on tumors and t-cells in relation to tumors. However, there are several other uses for the HSP and studies have shown that HSPs perform their core job of mitigating stressful cell conditions. When HSP90 functions were suppressed in fruit flies, several preexisting mutations came to light. The HSP managed to keep these mutations from overwhelming the host. With the presence of the HSP, the evolutionary activities of the body are slowed to the point where they are beneficial. Furthermore, the HSP helps the body to resist certain drugs and medicines that would otherwise be harmful. Even more importantly, HSP can considerably weaken certain cancerous cells in order to make them more vulnerable to chemotherapy.
The diverse roles of HSPs make for attractive agents for treating many diseases. However, the universality of the HSP treatments could cause more problems down the world. The HSPs are essential in the basic structure of life and this is the same kind of building block that causes the cancer in the first place. Still, the HSP trials are currently showing some very beneficial and promising results.
Binder, Robert J. et al. (2007) “Specific immunogenicity of heat shock protein gp96 derives from chaperoned antigenic peptides and not from contaminating proteins.” Journal of Immunology. 179: 7254-7261
Demine, Rodion and Peter Walden (February 2, 2005). “Testing the role of gp96 as peptide chaperone in antigen processing.” The Journal of Biological Chemistry.280 (18).
De Maio A (January 1999). "Heat shock proteins: facts, thoughts, and dreams". Shock (Augusta, Ga.) 11 (1): 1–12
Ritossa, F (1962) “A new puffing pattern induced by temperature shock and DNP in drosophilia.” Cellular and Molecular Life Sciences (CMLS). 18 (12): 571-3.
Srivastava, Pramod. (July 2008). “New jobs for ancient chaperones.” Scientific American. (Washington DC.). 50-56.
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