AuthorsLord, Brian I
AffiliationPaterson Institute for Cancer Research, Christie Hospital, Manchester, UK.
MetadataShow full item record
AbstractRegulation of cell behaviour and population size is presumed to be not unlike classical regulation in non-biological systems, i.e. it is controlled by the cybernetic principle of negative feedback whereby the performance of progenitor cells depends inversely on a signal from their product, the size of which is proportional to the mass of the product. This signal may be inhibitory, acting directly on the progenitor cells. Alternatively, it may operate via an indirect and integrated inhibitor/stimulator feedback loop in which the one influences the production of the other. Illustrations taken from the various phases of haemopoietic development show the operation of these loops. Haemopoietic stem cells are under the direct influence of both inhibitor and stimulator but it is a feedback signal from the stem cell population that dictates the production of the one rather than the other. A second inhibitor acting at the stem cell level is a low molecular weight tetrapeptide which blocks the entry of cells into DNA synthesis, thus protecting them during a regimen of treatment with an S-phase cytotoxic drug. Proliferation of the maturing cells is also inhibited by feedback products of their fully mature descendants. Here, the effect is one of cell cycle modulation, whereas in the stem cell population the inhibitor and stimulator effect an on/off switch. Attempts to characterize the molecules involved have been limited. A series of tri- to pentapeptides has been described for haemopoietic or epithelial cell inhibitors. A common feature of several is a pGlu-Glu end though whether this has any significance is not known. In tumours it has been shown that some ascites are self-limiting and treatment of small tumours with cell-free fluid from a mature growth blocks their further growth. It appears that many tumour cells produce the feedback signals characteristic of their normal counterparts but are themselves less sensitive to it. The same is true of transforming growth factor-beta which is produced and detected by virtually all cell types. In this case, the factor, inhibiting in most cases, is produced in inactive form and achieves its target specificity by a localized capacity to activate it. Some tumours, while responding to exogenous active TGF-beta are incapable of activating the latent molecule. It is concluded that the differential sensitivity of normal and neoplastic tissues to physiological feedback regulators is a potentially exploitable property in cancer therapy.
CitationFeedback regulators in normal and tumour tissues. 1988, 10:231-42 J Cell Sci Suppl
JournalJournal of Cell Science Supplement
- Feedback inhibitors in normal and tumor tissues.
- Authors: Marshall E, Lord BI
- Issue date: 1996
- Identification and characterization of an inhibitor of haemopoietic stem cell proliferation.
- Authors: Graham GJ, Wright EG, Hewick R, Wolpe SD, Wilkie NM, Donaldson D, Lorimore S, Pragnell IB
- Issue date: 1990 Mar 29
- Controls on the cell cycle.
- Authors: Lord BI
- Issue date: 1986 Feb
- Granulocyte-macrophage colony-stimulating factor modulation of the inhibitory effect of transforming growth factor-beta on normal and leukemic human hematopoietic progenitor cells.
- Authors: Cashman JD, Eaves AC, Eaves CJ
- Issue date: 1992 Sep
- In vivo and in vitro effects of TGF-beta 1 on normal and neoplastic haemopoiesis.
- Authors: Ruscetti FW, Dubois C, Falk LA, Jacobsen SE, Sing G, Longo DL, Wiltrout RH, Keller JR
- Issue date: 1991