Introduction

Stress proteins or heat shock proteins (HSP) belong to the most conserved proteins. Members of stress protein families are expressed in prokaryotic and eukary-otic cells. The conservation of stress proteins stems from their basic and vital role in cells: prevention of protein aggregation under stress and physiological conditions. Under stress, HSP prevent aggregation of partially denatured and misfolded proteins. Under physiological conditions, they prevent immature folding of nascent proteins, assist intracellular protein transport through membranes, guide the assembly of protein complexes and regulate the function and degradation of cellular proteins [1-4], An additional role for members of the HSP 70 and 90 families has emerged recently—peptide binding chaperones possibly involved in antigen presentation [5-8].

Stress proteins are discussed as important target antigens in autoimmune diseases and during certain bacterial infections [9, 10]. It is assumed that bacterial infections might trigger T-cell responses against conserved sequences of stress proteins, which can induce or inhibit autoimmune processes [11], The apparent immunogenicity of stress proteins in autoimmunity and immunity against infections leads to the question whether stress proteins of tumor cells are immunogenic as well. In the following article we will review and discuss whether tumor stress proteins can stimulate a T-cell response of the host and what implications this T-cell response will have for immunity against the tumor or autoimmunity. A major part of the article will focus on the T-cell response induced by tumor stress proteins of the HSP 70 and 90 family includ ing the endoplasmic HSP 90 homologue gp96. This T-cell response is strictly speaking not an autoreactive T-cell response because it is not directed against stress proteins themselves but against peptide antigens complexed with them. However, the tumor stress proteins seem to play a crucial role as carriers and strong natural adjuvants for these tumor peptide antigens.

2. OVEREXPRESSION OF STRESS PROTEINS IN TUMORS: TUMORIGENICITY VERSUS IMMUNOGENICITY

The expression of stress proteins in cancer can be altered. An overexpression of constitutively expressed or inducible stress proteins of the HSP 70 and 90 family in tumor tissue has been reported [12-14], Additionally, an aberrant expression of HSP 70, HSP 90 and gp96 stress proteins on the cell surface of tumor cells has been described constitutively or after induction [12, 15-17], A loss of stress protein expression has not been reported.

A hostile microenvironment with hypoxia, acidosis, glucose starvation will increase stress protein expression in tumors [18] and may confer tumor cells an increased resistance against stress factors and in consequence an increased tumorigenicity. This has been substantiated by several experimental studies and clinical observations. An increased HSP 70 and 60 stress protein expression by ovarian and breast cancer, respectively, has been correlated with an unfavourable prognosis [19, 20], In experimental tumor models increased stress protein expression correlated with increased tumorigenicity. Menoret and coworkers [21]

showed in a rat colon cancer model that tumorigenic-ity correlated with resistance to glucose starvation and to increased gp96 expression level. Additionally, an increased expression of grp78, the endoplasmic HSP 70 homologue, conferred mouse fibrosarcoma cells an increased resistance against lysis by CTL and TNF [22]. In vivo, HSP 70 and grp78 expression correlated with tumorigenicity of mouse fibrosarcoma cells [23, 24] and this was related with resistance against TNF [25],

However, in other mouse tumor models an inverse correlation between HSP 70 expression and tumorigenicity was found. In these cases expression of HSP 70 correlated with increased immunogenicity of tumor cells [26,27]. Transfection of mouse tumors with bacterial HSP 60 also led to increased immunogenicity [28],

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