Radiofrequency ablation, heat shock protein 70 and potential anti-tumor immunity in hepatic and pancreatic cancers: a minireview

Li-Song Teng, Ke-Tao Jin, Na Han and Jiang Cao

Hangzhou, China

Radiofrequency ablation, heat shock protein 70 and potential anti-tumor immunity in hepatic and pancreatic cancers: a minireview

Li-Song Teng, Ke-Tao Jin, Na Han and Jiang Cao

Hangzhou, China

BACKGROUND:Radiofrequency ablation (RFA) is a minimally invasive surgical procedure which has widespread popularity in the treatment of hepatic and pancreatic cancers. Increased evidence indicates that RFA stimulates anti-tumor immunity, possibly through the induction heat shock protein 70 (HSP70) expression. HSP70 has the capacity to affect the immunogenicity of tumor cells, to chaperone antigenic peptides and deliver these into antigen presentation pathways within antigen-presenting cells, and to activate and regulate innate and adaptive immunity, which makes it useful in immunotherapeutic strategies for the treatment of cancers.

DATA SOURCES:An English-language literature search was conducted using MEDLINE (1991-2010) on anti-tumor immunity, heat shock protein 70, radiofrequency ablation, hepatic cancer, pancreatic cancer, and other related subjects.RESULTS:RFA has an increasing application in the surgical treatment of hepatic and pancreatic cancers. Increased evidence indicates that RFA can induce the expression of HSP70 which possesses properties that enable it to influence a variety of immunological processes. Tumor-derived HSP70 is regarded as a potent adjuvant facilitating presentation of tumor antigens and induction of anti-tumor immunity.

CONCLUSIONS:This review addresses the potential association of RFA, HSP70, and anti-tumor immunity in treatment of hepatic and pancreatic cancers. To establish direct evidence of a potential association of RFA, HSP70, and anti-tumor immunity in hepatic and pancreatic cancers, further investigations should be conducted.

(Hepatobiliary Pancreat Dis Int 2010; 9: 361-365)

anti-tumor immunity; heat shock protein 70; hepatic cancer; pancreatic cancer; radiofrequency ablation

Introduction

Radiofrequency ablation (RFA) is a minimally invasive surgical procedure which has been popular in the treatment of tumors. It is effective in the treatment of unresectable primary and metastatic hepatic tumors,[1,2]and promising results in pancreatic cancer have been reported.[3-6]Increasing evidence indicates that RFA might stimulate anti-tumor immunity through the induction of heat shock protein 70 (HSP70) expression.[7-9]HSP70 has the capacity to affect the immunogenicity of tumor cells,[10-17]to chaperone antigenic peptides and deliver them into antigen presentation pathways within antigen-presenting cells (APCs),[18-21]and to activate and regulate innate and adaptive immunity.[22-27]Thus HSP70 is useful in immunotherapeutic treatment of cancer.

Although there is no relationship between RFA and anti-tumor immunity, a potential mechanism for the initiation of anti-tumor immunity after RFA has been explored. In this review we discuss the potential association of RFA, HSP70, and anti-tumor immunity in the treatment of hepatic and pancreatic cancers.

RFA for treatment of hepatic and pancreatic cancers

RFA is a localized thermal technique designed to induce tumor destruction by heating tumor tissue to temperatures that exceed 60 ℃,[28]and is a minimally invasive, relatively low-risk procedure. RFA can be administered by open surgery, laparoscopic surgery, orpercutaneously.[29]After a radiofrequency electrode is passed into a tumor under sonographic, CT, or MR-guidance, the tumor is ablated by the thermal energy generated by the electrode.[28]RFA has the particular advantage of more predictable ablation areas and fewer treatment sessions.

RFA is currently widely accepted as an alternative to resection in small, unresectable liver malignancies, because it may prolong survival rates achieved with standard chemotherapy.[1,2]It has been applied for local ablation of liver malignancy since 1990[30,31]and is considered as a feasible option and standard local therapy in treating unresectable hepatic tumors that are either primary or metastatic. Long-term results of RFA of either primary or secondary hepatic neoplasms are scant because this is a fairly new technique. However, some published results are available on the short-term follow-up of patients treated with RFA. At least nine series document the results of RFA treatment of primary liver cancer.[32-40]RFA has also been used to treat tumors that have metastasized to the liver.[28,35-44]RFA of hepatic cancer is a promising technique and can be performed safely using percutaneous, laparoscopic, or open surgical techniques.

Pancreatic cancer is one of the most aggressive human malignancies. Despite the advances in diagnostic and therapeutic mordalities, the outcome for these patients remains poor. RFA of solid pancreatic tumors sounds logical but also seems to be risky because of the friable pancreatic parenchyma and the fear of pancreatitis. Several studies indicated that RFA might also be a valuable treatment option for locally advanced pancreatic cancer. Matsui et al[3]reported that RFA is relatively safe and could be useful to treat patients with unresectable tumors without metastasis or those with benign pancreatic tumors such as insulinomas and glucagonomas. Goldberg et al[4]reported that endoscopic ultrasound-guided RFA can be used safely to create discrete zones of coagulation necrosis in the pig pancreas. Girelli et al[5]reported that RFA for treatment of locally advanced pancreatic cancer is feasible and relatively well tolerated. Hadjicostas et al[6]reported that RFA seemed to be a feasible, potentially safe and promising option for the treatment of patients with locally advanced and unresectable pancreatic cancer. The application of RFA in solid pancreatic tumors is still at a very early stage and is still under investigation for safer results.

HSP70 and anti-tumor immunity

The expression of this protein is induced following exposure of cells to elevated temperatures, hence the name HSP.[45,46]Other factors, such as ultraviolet and gamma-radiation, bacterial and viral infection, certain chemicals, drugs, and hypoxia also induce the expression of HSP70.[47]HSPs are regarded as chaperones, assisting protein folding and translocation.[48]They can act as cytoprotective agents by binding to misfolded proteins and thus protecting them from denaturation under conditions of cellular stress.[49]They can also serve as cytokines that can stimulate dendritic cells (DCs) and macrophages to produce proinflammatory cytokines and chemokines.[50-54]It is important that tumor-derived HSP is capable of chaperoning tumor antigens to DCs and then cross-presenting the antigens to T cells.[10]HSPs are released from various cells via passive and active pathways.[52-54]The most conserved class of HSPs includes the constitutively expressed cognate HSP70 (HSC70 or HSP73), the stress-inducible HSP70 (HSP70i or HSP72), and the mitochondrial HSP70 (HSP75).

It has been reported that tumor-derived HSP70 may contain tumor antigens and can present the associated antigens to APCs, which finally result in the induction of antigen-specific cytotoxic CD8+ T cells (CTLs).[10]HSP70 might influence the immunogenicity of dying tumor cells in a number of ways. Somersan et al[11]reported that tumor cells express higher levels of cytoplasmic HSP70 than their non-malignant counterparts, and lysates of these cells efficiently induce the maturation of DCs. Melcher and colleagues[12]reported a correlation between the expression and release of HSP70 and nonapoptotic forms of cell death. Other investigators[13-17]found that cell death which occurs concomitant with HSP gene expression is highly immunogenic. Tumor immunogenicity is also enhanced when HSP70 is over-expressed in engineered tumor cells,[12]induced by heat shock.[16]Todryk et al[14]reported that tumors over-expressing HSP70 induce more marked Th1-type immune responses. Until now, the precise influence that HPS70 has on the immunogenicity of tumor cells has yet to be fully elucidated, and might be exerted at a number of different levels.

Panjwani et al[19]reported and their findings were confirmed by Pierce[18], that expression of HSP70 influences the presentation and processing of antigen to CD4+ T cells by APCs. Wells et al[20]reported that increasing the expression of HSP70 in tumor cells promotes the presentation of peptides on the tumor cell surface via an enhancement of MHC classiexpression. Dressel et al[21]found HSP70 expression in tumor cells also enhances their recognition by T cells.

Tumor-derived HSP70 can activate DCs and hasbeen regarded as a potent adjuvant facilitating the presentation of tumor antigens and induction of antitumor immunity. As an intracellular chaperone, HSP70 binds a large number of peptides derived from the cells from which they are isolated.[22,23]HSP70 can act as a carrier of protein antigens from the cell from which it is derived. It is known that immunization of animals with a purified form of HSP70 from tumor cells elicits effective anti-tumor immunity and protects the animals from subsequent challenge with the same tumor cells.[24]This approach may also be used to generate effective immunity against established tumors.[25]The specificity of immunization leading to the generation of tumorspecific CTLs is defined by the peptides associated with HSP rather than by the HSP itself.[26,27]Previous reports indicated that HSP immunization is able to generate anti-tumor CTLs by transferring the antigenic peptides with which they are associated into the MHC classiantigen presentation pathway within APCs. This kind of antigenic cross-presentation is now considered to be a key process in the action of HSPs.[55,56]

RFA-induced upregulation of HSP70 and antitumor immunity: direct and indirect evidence

It was demonstrated that RFA induces the up-regulation of HSP70 expression. Rai et al[7]studied the cellular injury induced by RFA in the area surrounding the ablated tissue and found that it induces sublethal injury in the zone of transition causing an increase in HSP70 expression, which enhances the immunogenicity of these cells that can have therapeutic implications. Their study indicated that HSP70 is a potential target for enhancing the efficacy of RFA.[7]

Increasing evidence suggests that anti-tumor immunity is initiated after hyperthermia treatment. Importantly, RFA relies on hyperthermia to affect tumor killing. Hyperthermia has been reported to enhance the immunogenecity of cancer cells concomitantly with the expression of HSP.[57,58]Various HSPs are released from tumor cells upon heat stress treatment.[52-54]HSP70 may be the major HSP responsible for the autocrine induction of chemokines by tumor cells.[9]Recent reports demonstrate that heat stress induces the cell surface expression and release of HSP70.[50-54]

Fig. Two ways to describe the potential relationship between RFA and anti-tumor immunity. A: RFA may cause anti-tumor immunity by inducing the up-regulation of HSP70 expression, which influences a variety of immunological processes; B: RFA results in hyperthermia, which induces anti-tumor immunity by inducing the up-regulation of HSP70 expression.

Chen et al[9]suggested a potential mechanism for the initiation of anti-tumor immunity during hyperthermia treatment. They demonstrated the important roles of releasable HSPs from heat-stressed tumor cells in the initiation of anti-tumor immunity. They pointed out that hyperthermia might induce the release of HSP70 from tumor cells, which could activate tumor cells in an autocrine manner for chemokine production and simultaneously activate the chemo-attracted DCs in a paracrine manner, leading to the uptake of tumor antigens chaperoned by HSPs and the subsequent presentation of tumor antigens to naive T cells in the spleen and lymph node as soon as the DCs mature and migrate to the spleen and lymph nodes. Considering that local hyperthermia treatment is administered repeatedly, they suggested that the autocrine and paracrine actions of releasable HSP70 might be positively augmented, leading to the observed inhibition of tumor growth and induction of anti-tumor immunity.[9]In the same study, they further demonstrated that HSP70 activates DCs via the TLR4 signaling pathway. Their data provided direct evidence for the important roles of releasable HSP70 in the initiation of anti-tumor immunity during local hyperthermia.[9]

Though there is no direct evidence of a relationship between RFA and anti-tumor immunity, a potential mechanism for the initiation of anti-tumor immunity after RFA has been hypothesized (Fig.). There may be two ways to describe the potential relationship between RFA and anti-tumor immunity. First, RFA may cause anti-tumor immunity by inducing the up-regulation of HSP70 expression, which has properties that enable it to influence a variety of immunological processes. Second, RFA results in hyperthermia, which induces anti-tumor immunity by inducing the up-regulation of HSP70 expression. To test this hypothesis, further investigations should be conducted.

Conclusion

RFA has widespread popularity in the surgical treatment of hepatic and pancreatic cancers. Increased evidenceindicates that RFA induces the expression of HSP70 which influences a variety of immunological processes. Tumor-derived HSP70 is regarded as a potent adjuvant facilitating presentation of tumor antigens and induction of anti-tumor immunity. To establish direct evidence of an association between RFA, HSP70, and anti-tumor immunity in hepatic and pancreatic cancers, further investigations are needed.

Funding:This study was supported by grants from the State Key Development Program for Basic Research of China (973 Program) (2009CB521704) and the National High Technology Research and Development Program of China (863 Program) (2006AA02A245).Ethical approval:Not needed.

Contributors:TLS, JKT and HN wrote the main body of the article. CJ provided advice on medical aspects. TLS is the guarantor.

Competing interest:No benefits in any form have been received or will be received from a commercial party related directly or indirectly to the subject of this article.

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（3）郎格系數(shù)法。該方法是將建設(shè)項(xiàng)目過程中的直接費(fèi)用和間接費(fèi)用進(jìn)行匯總，兩者相加得到整體工程的預(yù)估費(fèi)用。但是該方法有忽略建造過程中一些其他因素的干擾，如材料類型、設(shè)備規(guī)格等，這些因素也會對造價(jià)成本產(chǎn)生一定波動影響。

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February 22, 2010

Accepted after revision May 26, 2010

Author Affiliations: Cancer Center, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China (Teng LS and Jin KT); Sir Run Run Shaw Institute of Clinical Medicine, Zhejiang University, Key Laboratory of Biotherapy of Zhejiang Province, Hangzhou 310016, China (Han N and Cao J)

Li-Song Teng, MD, PhD, Cancer Center, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China (Tel: 86-571-86006336; Fax: 86-571-86960497; Email: lsteng@ zju.edu.cn)

? 2010, Hepatobiliary Pancreat Dis Int. All rights reserved.