Autoantibodies Against Oncoproteins

Proteins encoded by oncogenes and tumor suppressor genes are involved in the control of cell growth and differentiation and, if inappropriately expressed or mutated, in the genesis of tumors. Recently, AAb against oncoproteins and the tumor suppressor p53 have been reported in patients with malignant tumors. Such immune responses may be of special interest in the early diagnosis and therapy of cancer. There are a growing number of reports regarding p53 AAb, but only a few data about autoimmunity against oncogene products in tumor patients (summarized in Table 2) are available to date [7, 16-23]. AAb to the HER-

2/neu product, a 185-kDa transmembrane protein with extensive homology to the epidermal growth factor receptor have been found in 11-55% of breast cancer patients [7, 16]. The AAb response correlated with HER-2/neu protein overexpression in the patient's primary tumor, but could also be found in some women with HER-2/neu negative breast cancer, suggesting an active immunoselection for HER-2/neu negative variants [16]. This possibility is also underlined by the higher frequency and the higher titers of pl85HER-2/neu AAb jn the early stage of disease [16].

AAb against the p21ras protein, a member of the GTP-ase complex whose transforming activity evolves by point mutations, has been found in 32% of patients with colon cancer [17]. Although p21ras is activated

Table 2. Autoantibodies against proteins involved in the pathogenesis of malignant tumors

Autoantibody against Frequency in tumor patients

Remarks p]85HER-2/neu p21ras c-myc

L-myc c-myb

Breast cancer 11-55% [7]

Colon cancer 32% [17]

Colorectal cancer 57% [18] Hematological malignancies 2.7-5.2% [20] AIDS related lymphoma 15.4% [20]

Lung cancer 10% [21]

Breast cancer 43% [23] Colon cancer 40.5% [23] Ovary cancer 33.3% [23]

Frequency in healthy volunteers 0-5% [16] Frequency in healthy volunteers 3% [17]

Different results in healthy volunteers (1.1-17%) and SLE patients (0.8-35%) [18-20]; significantly higher titers in African Burkitt lymphoma patients and Ghanian normals compared to American normals [20]

No association to histology or staging; not detected in normal volunteers [21]; detectable in pleural effusions [22]

Not cancer-specific (24% in controls), but frequency significantly elevated in breast cancer patients compared to controls; not found in neuroblastoma patients [23]

by point mutations, most AAb detect epitopes near the carboxyl terminus of the wild-type protein [17]. In addition to these AAb directed against growth factor receptors (pl85HER-2/neu) or GTP binding proteins (p21ras), AAb to another group of oncoproteins have been described in patients with solid tumors (colorectal, breast, ovary, lung cancer) and patients with leukemias/lymphomas. These AAb are directed against nuclear regulatory proteins such as myb and myc [18-23]. However, with the exception of AAb to the L-myc protein, these antibodies have been shown to be relatively unspecific for tumors in some studies (see Table 2). Furthermore, the frequencies of c-myc AAb in healthy volunteers and SLE patients varied greatly in the different studies [18-20]. In general, different methods of AAb determinations and differences in the populations studied may account for varying results. The source and purification of autoantigens and the assays used for AAb determination may influence results dramatically. For example, c-myc AAb were determined with ELISAs using 31mer c-myc peptides [19] or human prokaryotically expressed recombinant c-myc protein [20] or with immunoblotting using the recombinant protein [18]. Furthermore, variations in the definition of standards of detectability led to different frequencies as has been shown for p185HER-2/neu AAb in breast cancer patients (1121%) and in healthy volunteers (0-1%) [16], But also ethnic differences and different influences of en-dogeneous and exogenous factors in the populations studied may be relevant for the variation in results.

For example, the frequency of pi85HER-2/neu AAb js highest in women with premenopausal breast cancer because there is also highest frequency of HER-2/neu protein overexpression [7], In conclusion, there is a further need for studies of the clinical and biological nature concerning humoral autoimmune responses to oncoproteins such as: (a) the evaluation of diagnostic relevance (diagnostic sensitivity and specificity) and the prognostic significance (correlation with the stage of the disease and survival) in defined patient groups using optimized and standardized methods; (b) the search for associations of antibody titers with disease progression or relapse and therapeutic effects; (c) the search for possible mechanisms of AAb induction (correlation with protein overexpression, mutations or presence of oncoproteins in the circulation); and (d) the search for possible effects of AAb on tumor cells.

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