Contrasting effects of heat shock proteins in cancer: resistance to cell death but facilitation to tumor cell destruction by the immune system

CIOCCA D. R.; CUELLO CARRIÓN F. D.; FRAYSSINET P.

Concepción, Chile

Workshop; 5th International Workshop on the Molecular Biology of Stress Responses; 2006

Cell Stress Society International

One of the first evidences involving HSPs with resistance to tumor cell death was reported when in in vitro experiments tumor cells were exposed to nonlethal elevated temperatures (heat shock) previously to the exposure to chemotherapy agents. In contrast, a more effective cell killing was reported when hyperthermia was combined with chemotherapy. These contrasting effects can now be explained by the induction of a HSP response due to the heat shock, then, the induced HSPs protect the tumor cells against damaging agents. Experiments performed with buman breast cancer cells showed that specific modifications (increased mRNA and protein expression and protein phosphorylation) in HSPs were associated with resistance to certain anticancer drugs. This study showed that Hsp70 and Hsp27 were involved in resistance to doxorubicin but not to other cytotoxic drugs, and that this mechanism of drug resistance was not associated with that conferred by the P170 (mdr-1 gene) multidrug resistance protein, in fact the level of protection conferred by the HSP response was of lower level than that produced by the P170. In line with this, elevated levels of Hsp27 has been found in human colon carcinoma cell lines expressing differential anthracycline sensitivity and similar levels of P170 glycoprotein. However, there rnight be connections between P170 and HSPs, like the presence of heat shock responsive elements in the promoter region of the mdr-1 gene. The associations between Hsp27 and drug resistance have been confirmed by transfection experiments in human breast, colon and testis cancer cells. At clinical level, high Hsp70 levels in recurrent breast tumors correlated with low response to radiation and hyperthermia treatments, while the disease free survival of patients concomitantly overexpressing Hsp27 and Hsp70 was significantly shorter in breast cancer patients treated with neoadjuvant chemotherapies. The molecular mechanisms underlying the resistance of the tumor cells overexpressing HSPs to cell death are: 1) the general properties of HSPs is to support the correct folding of nonnative or misfolded proteins and prevent their aggregation, 2) HSPs have been involved with resistance to apoptosis through a variety of molecular mechanisms, and 3) HSPs may contribute with the DNA repair function of the mismatch repair (MMR) and base excision repair (BER) systems. The study of these molecular mechanisms is of importance to the development of anticancer therapies directed against specific molecular targets. On the other hand, several HSPs can help to genera te specific T Iymphocytes against tumor antigens from the host, this is called active immunotherapy based on stimulation of T cells. Active immunotherapy is achieved cuIturing dendritic cells or another antigen presenting cells (APCs) in contact with the tumor antigen(s), or by presenting the antigens to the APCs in vivo. There are several approaches adrninistrating among others: a) tumor cells or tumor cell lysates, b) specific antigens and co-stirnulatory molecules, and c) HSPs as adjuvants rnixed with the tumor antigen(s). We have generated a therapeutic vaccine using self-antigens obtained from the tumor of the patient (autologous). The novel approach involved the purification of the tumor antigens using column chromatography with hydroxyapatite (HA) [Ca10(PO4)6(OH)2]. This allowed for the isolation of tumor antígens and adjuvants such as gp96, this rnixture was then combined with membrane antigens containing HSPs from the autologous tumor, and this rnixture was injected into the patients. The HA served both in the antigen isolation procedure and as a vector to present in vivo the tumor antigens and adjuvants to the patients APCs. Therefore, the HSPs can be utilized to generate a specific immune response useful to kill tumor cells.