“Prognostic Significance of Heat Shock Protein 70 (HSP70) in Patients with Oral Cancer,” published just two months ago, seemed two purport the idea that heat shock proteins do play a role in preventing cancer deaths. The experiment took 61 tumors from oral cancer patients and performed immunohistochemistry—a method for detecting proteins and antigens, in this case HSP70, by staining them [1]. For tumors that stained 20% or more for HSP70, it meant that they were HSP70+, and those that did not were HSP70-[1]. Scientists found the “the survival of patients suffering from T2 tumors [tumors of sizes 2-5 cm] with positive HSP70 expression was 8 times higher than that for patients with negative HSP70 expression”[1], as illustrated in the Kaplin-Meyer plot below. In essence, HSP70 plays a role in tumor control; however, the paper also concluded by suggesting that that HSP70 is most effective in early stages (T2) of tumor growth [1].
I thought my question was answered by the findings from the above paper, until I found a second article. Interestingly, this latter article, “Epigallocatechin-3-Gallate Suppresses the Expression of HSP70 and HSP90 and Exhibits Anti-Tumor Activity in vitro and in vivo,” claims that HSP70 and HSP90 add to tumor growth while their inhibition stops tumor growth. The experiment involved two parts. The first cultured and transfected MCF-7 (human breast cancer) cells with transfected plasmids containing HSP70 promoters; heat shocked the cells at 44°C for 1 hour; then added different concentrations of Epigallocatechin-3-gallate (EGCG). The second injected CT26 (mouse colon carcinoma) cells into mice; allowed tumors to form; then injected EGCG into mice for several days. In summary, results from the first part of the experiment showed that EGCG inhibited HSP70 and HSP90 production, while the second part showed that inhibition of HSP70 and HSP90 production reduces tumor volume by about 70%, as illustrated on the figure below.
Clearly and interestingly, the experimental results of the two studies contradicted and clashed with each other. Which one is correct? Does HSP70 act as a tumor promoter or a tumor inhibitor?
When I did some further research, I found that HSP70 was not only involved in protecting from protein denaturation; rather HSP70 also inhibits apoptosis. Overproduction of HSP70 causes cells to be resistant against “apoptosis-inducing agents” and leads to increased malignancy and therapy resistance [3]. On the other hand, down regulation of HSP70 causes increased cell death [3]. This information seems to support the conclusion reached by the second research—that HSP70 causes tumor growth. But, once again, why did results of the first experiment prove otherwise?
In my opinion, neither experiment could really answer my original question. The first did not really test for HSP70 production as a result of external stimulus, heat stress; it only looked for presence and abundance of HSP70 in tumors. It could very likely be that certain individuals produce more HSP70 than others. It could also be the different states of the human body during tumor removal. The experiment only showed a correlation between high HSP70 abundance and increased survival rates. This correlation does not necessarily indicate a causal relationship, which is why I do not find the results too convincing. Regarding the second experiment, heat stress was tested for; yet, like the first, there was no evidence that decrease in HSP70 and HSP90 led to anti-tumor activity. It is known that EGCG “produces anit-cancer effects”[2]. It could be that anti-tumor activity was actually caused by the EGCG; EGCG may halt heat shock protein production, but this does not mean that HSP’s cause tumor growth.
A better way to directly test for HSP70 effect on tumor growth can involve simpler methods. NIH3T3 cells can be transfected by DNA from tumor cells and then injected into nude mice. Tumors should be grown for different time periods—one group of mice with tumors grown for 2 weeks, another for 3 weeks, and another for 4 weeks. Each group of mice should then be treated with heat stress at different stress levels for several days. For example, mice with 2 week old tumors can be further divided into groups where one group receives 38C heat shock for 1 hour several times during the day; another group receives 40C; and another receives 42C. Through experiments like this, scientists can measure the amount of HSP proteins produced as a result of different degrees of stress and their effects on tumor growth and size. This proposal has possible faults as it does not account for other possible mechanisms that can effect tumor growth; however, in putting mice through heat stress and measuring HSP’s, there is a more direct and simple pattern can be observed.
Here are some miscellaneous thoughts I had during my research about HSP70 and tumor growth :
Clearly and interestingly, the experimental results of the two studies contradicted and clashed with each other. Which one is correct? Does HSP70 act as a tumor promoter or a tumor inhibitor?When I did some further research, I found that HSP70 was not only involved in protecting from protein denaturation; rather HSP70 also inhibits apoptosis. Overproduction of HSP70 causes cells to be resistant against “apoptosis-inducing agents” and leads to increased malignancy and therapy resistance [3]. On the other hand, down regulation of HSP70 causes increased cell death [3]. This information seems to support the conclusion reached by the second research—that HSP70 causes tumor growth. But, once again, why did results of the first experiment prove otherwise?
In my opinion, neither experiment could really answer my original question. The first did not really test for HSP70 production as a result of external stimulus, heat stress; it only looked for presence and abundance of HSP70 in tumors. It could very likely be that certain individuals produce more HSP70 than others. It could also be the different states of the human body during tumor removal. The experiment only showed a correlation between high HSP70 abundance and increased survival rates. This correlation does not necessarily indicate a causal relationship, which is why I do not find the results too convincing. Regarding the second experiment, heat stress was tested for; yet, like the first, there was no evidence that decrease in HSP70 and HSP90 led to anti-tumor activity. It is known that EGCG “produces anit-cancer effects”[2]. It could be that anti-tumor activity was actually caused by the EGCG; EGCG may halt heat shock protein production, but this does not mean that HSP’s cause tumor growth.
A better way to directly test for HSP70 effect on tumor growth can involve simpler methods. NIH3T3 cells can be transfected by DNA from tumor cells and then injected into nude mice. Tumors should be grown for different time periods—one group of mice with tumors grown for 2 weeks, another for 3 weeks, and another for 4 weeks. Each group of mice should then be treated with heat stress at different stress levels for several days. For example, mice with 2 week old tumors can be further divided into groups where one group receives 38C heat shock for 1 hour several times during the day; another group receives 40C; and another receives 42C. Through experiments like this, scientists can measure the amount of HSP proteins produced as a result of different degrees of stress and their effects on tumor growth and size. This proposal has possible faults as it does not account for other possible mechanisms that can effect tumor growth; however, in putting mice through heat stress and measuring HSP’s, there is a more direct and simple pattern can be observed.
Here are some miscellaneous thoughts I had during my research about HSP70 and tumor growth :
If heat shock proteins really do cause tumor growth, could they also be
partially responsible for causing melanomas when the skin is constantly
exposed to the sun’s heat or when the skin is frequently sun-burnt?
Could heat shock proteins play a role in cancers when our bodies accumulate
lots of oxidative stress due to lack of sleep?
What role would HSP’s play in radiation therapy? If they were beneficial, then HSP production during radiative stress could add to fighting tumor growth; however, if
HSP’s were harmful, then their production during radiation would be another
side-effect of the treatment.
Perhaps future research can answer them.
[1] Tavassol, Frank et al. (2011). Prognostic Significance of Heath Shock Protein 70 (HSP70) in Patients with Oral Cancer.Head and Neck Oncology, 3:10, 1-6.
[2] Tran, Phan et. al. (2010). Epigallocatechin-3-gallate Suppresses the Expression of HSP70 and HSP90 and Exhibits Anit-Tumor Activity in vitro and in vivo. BMC Cancer, 10:276, 1-9.
[3] Mayer, M.P. and Bukau, B. (2005). HSP70 Chaperones: Cellular Functions and Molecular Mechanism. Cell Molecular Life, 62:6, 670-684.
[2] Tran, Phan et. al. (2010). Epigallocatechin-3-gallate Suppresses the Expression of HSP70 and HSP90 and Exhibits Anit-Tumor Activity in vitro and in vivo. BMC Cancer, 10:276, 1-9.
[3] Mayer, M.P. and Bukau, B. (2005). HSP70 Chaperones: Cellular Functions and Molecular Mechanism. Cell Molecular Life, 62:6, 670-684.
