Nuclear Antigens As Candidates For Oncogenic Proteins

In a growing number of reports, antibodies present in the sera of cancer patients have provided useful mole cular tools for the identification of the corresponding antigens [27-32]. These autoantigens are often either mutated or overexpressed in tumors [32], which strongly supports the idea that the immune response is indeed targeted against the tumor. Many of these autoantigens appear to be specific to an individual patient [33], However, we hypothesize that the proteins involved in tumorigenesis might comprise a class of autoantigens that would be more generally recognized by groups of patients. This hypothesis is based on the following reasoning. There is no rationale to suggest that the immune system should treat oncogenic proteins differently than any other cellular antigen. That is, abnormalities in important cell-cycle regulators that lead to unregulated cell growth and division may be as likely as any other tumor antigen to be recognized by the immune system. Thus, we postulate that a subset of autoantigens in cancer is likely to be made up of molecules known to play important roles in cell proliferation.

This is supported by reports of antigens recognized by cytotoxic T lymphocytes that are important regulatory molecules with potential roles in oncogenesis. In one case, a mutated version of the cell-cycle regulator CDK4 was identified as an autoantigen in a patient with melanoma [34], The particular mutant abolishes the interaction with the negative regulator pi6, and thus clearly has potential to play a causative role in cancer. A mutated form of /?-catenin, an extracellular matrix protein that participates in cell adhesion and growth, has also been identified as a T-cell autoantigen in association with melanoma [35] . Finally, an antigenic mutation in caspase-8, which may have a role in mediating apoptosis, has also been reported [36].

There is also evidence for a humoral response directed against potentially oncogenic tumor antigens.

Mutations in the tumor suppressor p53 have been found in tumor tissue but not in normal tissue from a patient who had anti-p53 antibodies [37]. Expression of p53 has also been reported to be elevated in tumor cells in cancer patients with anti-p53 antibodies [38], Cloning of autoantigens by screening autologous tumor cDNA libraries using patient sera has also identified two potentially oncogenic antigens, p53 isolated from a case of colon cancer and NY-LU-12 in lung cancer [39, 40] . In addition, we have recently cloned the 32 kDa subunit of replication protein A (RPA) [41] using autoantibodies from a breast cancer patient. By screening with recombinant antigen, we have found autoantibodies to this important replication and repair protein in 8% of cancer patient sera [42]. This antigen has been previously reported in the sera from patients with Sjögrens syndrome and systemic lupus erythematosus [43], but has not so far been described in cancer. We are presently asking whether this frequent autoimmune response to RPA is related to mutation in the gene or to abnormalities in expression or localization of the protein.

A second reason to suggest that oncogenic proteins may constitute a commonly recognized set of nuclear autoantigens is that our current knowledge on tumor suppressors and oncogenes suggests that there are a finite number of pathways to cause cancer. That is to say, all tumors are expected to have an abnormality in at least one of a limited subset of proteins that regulate the cell cycle, DNA repair and/or apoptosis. These proteins are likely candidates to be involved in the process of carcinogenesis. The majority of proteins in this subset defined to-date are nuclear during at least part of the cell cycle (e.g., transcription factors p53, Rb, cyclins, CDKs, DNA repair enzymes and cas-pases). Thus, it might be expected that some members of this subset will be found as nuclear autoantigens in multiple cancer patients. It is also possible that the particular oncogenic proteins that appear as autoantigens may be specific to cancer type, and/or to the nature of the mutagen. As tumor characteristics are in part defined by the underlying molecular changes that allow escape from normal growth regulation, we suggest that the presence or absence of autoantibodies to these particular nuclear proteins may also be useful predictors of prognosis and indicators of therapeutic outcomes.

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