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More than 20 years ago, it was initially predicted that hormones and growth factors might promote cell growth by binding and thereby inactivating tumor suppressors, as exemplified by the proposed complex formation between insulin and retinoblastoma protein (RB). This mainly intracellular/nuclear growth-regulatory circuit was termed "the nucleocrine pathway" and the physical interaction between insulin and RB was subsequently proven through several methods, primarily by immunofluorescence and co-immunoprecipitation. Meanwhile, additional nucleocrine pairs have emerged through further experimental studies, specifically the FGF1-p53 and angiogenin-p53 heterodimers. Moreover, first experimental clues have been obtained as to the intranuclear presence of the previously surmised heterodimer between the EGF precursor and the p130 tumor suppressor. In addition, RB-binding motifs have recently been discovered in interleukin-6 (IL-6) and cellular apoptosis susceptibility (CAS) protein. These findings point to a more general significance of the nucleocrine pathway in cell growth regulation and as a particularly useful target in cancer therapy.

Tumor suppressors constitute the body's primary defense line against malignant transformation. Since Theodor Boveri's initial insight one century ago, a huge amount of knowledge on these molecules has been generated. However, the final step of application of this profound understanding in the clinical setting, i.e., the treatment of cancer patients with tumor suppressors and their derivatives, is still ahead. Nevertheless, the important success achieved with similar biomimetic approaches in the therapy of other diseases suggests that tumor suppressor-based antineoplastic interventions should be accomplished soon as they may be equally rewarding.

In this brief survey, I look back upon a quarter of a century of my personal experience with synthetic peptides. Thereby, I focus on major steps in the design and experimental exploration of peptides that I have derived from the retinoblastoma tumor suppressor protein (RB). Along this way, both Merrifield's solid phase peptide synthesis method and collaborations with established investigators in the peptide and cancer research fields have played an important role.

In this survey, the initial insights on the sub- and transcellular process of oncoprotein metastasis (OPM) are linked to recent observations and advances in related fields. The six proteins described here, i.e. insulin, osteopontin, interleukin-6, anterior gradient-2 protein, cellular apoptosis susceptibility protein and hepatoma-derived growth factor, as well as distinct peptide fragments thereof might henceforth serve as pivotal biomarkers for OPM in clinical chemistry, molecular morphology, pathology and oncology and, as a result, guide as potential targets future structure-based interventions in cancer treatment.