Abstract
We hypothesized that cancer tissue immunogens – antigens capable of inducing specific antibody production in patients – are promising targets for development of precision diagnostics and humoral immunotherapies. We developed an innovative immuno-proteomic strategy and identified new immunogenic markers of colon cancer.Proteins from cancers and matched normal tissues were separated by 2D gel electrophoresis and blotted with serum antibodies from the same patients. Antibody-reactive proteins were sequenced by mass spectrometry and validated by Western blotting and immunohistochemistry.170 serum antibody-reactive proteins were identified only in cancerous but not matched normal. Among these, proteasome subunit alpha type 1 (PSA1), leucine aminopeptidase 3 (LAP3), annexin A3 (ANXA3), and maspin (serpin B5) were reproducibly found in tissues from three patients. Differential expression patterns were confirmed in samples from eight patients with various stages of colon adenocarcinoma and liver metastases.These tumor-resident proteins and/or their associated serum antibodies may be promising markers for colon cancer screening and early diagnosis. Furthermore, tumor tissue-specific antibodies could potentially be exploited as immunotherapeutic targets against cancer. More generally, proteomic profiling of antibody-inducing cancer-associated immunogens represents a powerful generic method for uncovering the tumor antigen-ome, i.e., the totality of immunogenic tumor-associated proteins.
Highlights
Colon cancer is amongst the most common cancers and poses a major health burden worldwide [1]
From proteins extracted from each tissue sample, triplicates of high quality 2D gels were prepared: one gel was used for sequencing of differentially expressed proteins by mass spectrometry (Figures 1-2, top row), another for detection of reactivities with standard autoantibody control serum by 2D Western blotting (Figures 1-2, middle row), and a third for discovery of reactivities with the cancer patient’s own serum (Figures 1-2, bottom row)
We decided to narrow our focus to proteins that are immunogenic in cancer tissue, i.e., proteins in cancer tissue that are capable of inducing the production of specific serum antibodies in the patient
Summary
Colon cancer is amongst the most common cancers and poses a major health burden worldwide [1]. When diagnosed early, localized colon cancer can be surgically removed, and the 5-year survival rate of patients can be as high as over 90%. Patients with later stages of colon cancer and metastases have an average survival rate of less than 10% [3]. Development of effective markers for early diagnosis, prognosis, and therapeutic decision-making is essential for advancing of colon cancer management [4]. Cancer development is a complex multistep process that is influenced not just by genetic changes but, more www.impactjournals.com/oncotarget importantly, by alterations of downstream molecular expression and function [5]. Cancer develops through steps of initiation, promotion, progression, and metastasis. The initial step is commonly attributed to genetic changes that may be spontaneous or triggered by carcinogens. Cancer cells invade nearby tissues or migrate to distant tissue via circulatory systems, leading to metastasis
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