HSPs in cancer and their possible relevance to prognosis

Heat shock proteins have been reported to exert a marked suppressive effect on cellular transformation. The suppressive effect could be a consequence of the formation of complexes between HSP and the transforming agents. For instance, transfection of HSP70 into cells transformed by mutant p53 and ras/myc oncogenes suppresses the process of transformation

(Yehiely and Oren, 1992). Complex formation between p53 and HSPs has also been shown to occur in several human tumours. Davidoff et al. (1992) demonstrated p53/HSP70 complexes in breast cancer. The tumours investigated in this series have been described as primary invasive breast carcinomas. Unfortunately, no information is available from this study by Davidoff et al. (1992) about the relationship between the detection of these complexes and the invasive nature of the carcinomas. Perhaps the value of this approach may be diminished because Iwaya et al. (1995) state that only a part of the p53 pool may enter into complex formation with HSPs. Nevertheless, it is noteworthy that the expression of HSP correlated positively with oestrogen receptor expression and inversely with epidermal growth factor receptor expression (Takahashi et al., 1994). This suggests that changes in HSP expression could be one of the events associated with the progression of breast cancer. Elledge et al. (1994) did not note any correlation between HSP detection and accumulation of p53- But patients with p53-/HSP+ tumours showed better overall survival than those with p53-/HSP- tumours.

HSP expression has also been examined in other forms of human cancer. The expression of high molelcular weight (60-90 kDa) HSP levels are said to be significantly higher in circulating cells of patients with acute myeloid leukaemia than in cells from patients with chronic myeloid leukaemia, and in both these cases HSP levels were higher than in mononuclear cells of normal peripheral blood (Chant et al., 1995). The occurrence of high molecular weight HSPs has also been described in lung cancers (Bonay et al, 1994). Prostate cancers have been reported to show positive cytoplasmic staining for both p53 and HSP72/73 (van Veldhuizen et al, 1993). The median intensity of immunochemical staining for HSP70 did not differ markedly between oral squamous cell carcinoma, epithelial dysplasia and benign oral mucosal lesions (Sugerman et al, 1995). In summation, it may be premature to judge the value of HSP expression as a marker of cancer progression and as a tool for predicting prognosis.

Postulated functions of HSP complexes

Several functions have been attributed to protein complexes involving heat shock proteins. The function of translocating proteins has been of particular interest with the implication that HSPs might ferry proteins across intracellular membranes and enable efficient antigen presentation for eliciting immunological responses (Chirico et al., 1988; Deshaies et al., 1988; van Buskirk et al., 1991). This view is supported by the observation that wherever immune response to p53 was encountered in breast cancer patients p53 protein was found to be complexed with HSP70. In contrast, patients who had no detectable anti-p53 antibodies contained no p53/HSP70 complexes (Davidoff et al., 1992). p53 protein is known to form complexes with SV40 large T antigen and tubulin and this may be an event associated with the intracellular translocation of these proteins (Maxwell et al., 1991). Although p53/HSP complexes have not been proven to involve the translocation of p53 to the plasma membrane, this seems to be a possible explanation for the detection of higher anti-p53 antibody titres in patients where p53 occurs in a complex with HSP70.

HSPs may be involved in the translocation of cellular protein, which may be crucial in maintaining the integrity of cell shape, and in cell mobility and intercellular adhesion. HSP70, for instance, has been reported to bind to actin microfilaments (Tsang, 1993). It is also involved in the folding and dimerisation of tubulin (Paciucci, 1994). It has been suggested that proteins such as the 18A2/mtsl which appear to possess the property of promoting cytoskeletal depolymerisation may be recruited to the sites of microtubule assembly by HSPs (Sherbet and Lakshmi, 1997). This is supported by much circumstantial evidence. For example, S-100j?, a Ca2+-binding protein closely related to the 18A2/mtsl protein, also shows association with tubulin (Donato, 1991). HSP70 has a calmodulin-binding site and is known to form a complex with calmodulin (Stevenson and Calderwood, 1990). By anology with these proteins, it is conceivable that HSPs form complexes with 18A2/mtsl protein.

Weinberg (1991) has suggested a further function for the formation of p53-HSP complexes, that they may provide the machinery by which the aberrant p53 is trapped and rendered ineffective. HSP70 (HSC70) has, in fact, been reported to suppress transformation of rat embryo fibroblasts by mutant p53. However, HSP does not form complexes exclusively with mutant p53, although early studies may have suggested a selective, or even a preferential process (Hainaut and Milner, 1992). The C-terminal domain of p53 is essential for p53 oligomerisation (Milner et al,, 1991) and it is also required for its interaction and binding with HSP which is dependent upon the tertiary structure of p53 (Hainaut and Milner, 1992).

0 0

Post a comment