Feedback inhibitors in normal and tumor tissues

Negative feedback represents the principal mechanism for regulating growth in biological systems. Over the past 20 years, our understanding of the role played by inhibitory factors governing this process has advanced considerably. This is particularly well illustrated in the field of experimental hematology with the recognition of hemopoietic progenitor cell proliferation inhibitors, an expanding group of unrelated peptides that act to limit proliferation in hemopoietic precursor cells. The characterization and subsequent production of these molecules by chemical synthesis or recombinant DNA technology has enabled investigators to explore their role in normal hemopoiesis and define a potential role in clinical medicine. A number of inhibitory factors, including macrophage inflammatory protein-1 alpha (MIP-1 alpha) and the tetrapeptide AcSDKP appear to share a relative specificity to hemopoietic progenitor cell subsets. Others, such as interferon and tumor necrosis factor, have a more complex action and their hemopoietic effects are likely to be indirect and nonspecific. In addition to the role of inhibitors in normal steady state, it has become increasingly evident that loss of sensitivity to the normal feedback inhibitory signals may be of central importance in carcinogenesis and tumor promotion. This presumably represents a developmental strategy that allows the neoplastic cell to maintain a growth advantage over its normal cell counterpart. The underlying mechanisms that terminate in inhibitor-resistance are yet to be elucidated, but in some instances they may be associated with aberrant tumor suppressor gene function.