Autocrine

( autocrine growth factor ; sometimes abbreviated: AGF ) A term referring to a mechanism of growth control, called also autostimulatory growth control , in which a cell secretes a soluble factor (see also: Conditioned medium ) that binds to its receptor, which is expressed also by the factor-producing cell. This effectively creates an autogenous loop in which a product (for example, Cytokines ) acts back on the cells that produce it.

Simple and complex autocrine growth control loops.

Upper panel: The stimulation of cells (1) induces the expression and secretion of a mediator (2) and its membrane-bound receptor. By interacting with its receptor (3) the mediator can elicit further responses in the cell by which it is produced.

Lower panel: Concentration-dependent complex control of an autocrine loop.

A) At low concentrations binding of TGF to its membrane receptor (1) induces the production of PDGF-AA (2). PDGF-AA then binds to its own receptor which is also expressed by the cell and thus can stimulate cell proliferation.

B ) High concentrations of TGF (1) down-regulate expression of receptors for PDGF-AA (2). Biological responses elicited by PDGF-AA are thus diminished due to a paucity of PDGF-AA receptors. The effect is reduced cell proliferation. Concentration-dependent differential actions involving an interplay of several factors and down-regulation of receptors have been observed also for a number of other cytokines.

Autocrine loops effected through the interaction of growth factors with their corresponding receptors can take simple forms involving only a single growth factor or rather complex forms involving two or more growth factors .

Example of complex multiple autocrine growth control loops in gastric carcinoma cells.

Gastric carcinoma cells secrete large amounts of IL1-alpha and express significant amounts of the IL1 receptor. IL1-alpha can enhance expression of itself and is provided also by nearby stromal cells such as macrophages, fibroblasts, and vascular endothelial cells. In addition, production of IL1-alpha by gastric carcinoma cells is induced also by EGF and TGF-alpha . Autocrine growth of gastric carcinoma cells mediated by an interplay between IL1 and its receptor is demonstrated by the fact that antibodies against IL1-alpha and also IL1 receptor antagonist (IL1ra ) significantly suppress cell growth.

Gastric carcinoma cell lines also produce EGF and TGF-alpha and their receptors. IL1-alpha can induce expression of EGF and TGF-alpha receptors. EGF and TGF-alpha can induce expression of IL1-alpha .

EGF and TGF-alpha can induce the synthesis of their own receptors and also of stromelysin and collagenase . This sets in motion a cascade of events leading to extracellular matrix degradation, which is convenient for tumor progression and invasion.

HGF (hepatocyte growth factor ) can be produced by stromal fibroblasts and its synthesis by these cells can be enhanced by TGF-alpha , TGF-beta , and IL1-alpha . HGF can also stimulate growth of gastric carcinoma cells which express the HGF receptor met . In addition, gastric carcinoma cells can also secrete IL2 and IL6.

A study designed by Laufenberger et al to measure autocrine signaling through the EGF receptor by TGF-alpha has revealed that autocrine signaling can be blocked more effectively with anti-receptor antibodies than with anti-ligand antibodies. This result seems to suggest that local restriction of autocrine-based signals may provide cells with information on their local microenvironment.

The uncontrolled synthesis of such autocrine growth factors by cells that also express the corresponding receptors is a mechanisms allowing, for example, tumor cells to regulate their own growth and to become independent of exogenous growth control mechanisms (see also: Factor-dependent cell lines ). In some cases an activated Oncogene is responsible for the constitutive synthesis of aberrant proteins that take over the role of authentic growth factors . The regulated expression of growth factor receptors observed frequently appears to be a safeguard against a catastrophic spread of cell proliferation by a growth factor stimulus. Again, the uncontrolled expression of receptor genes subverts this mechanism of orderly growth.

The existence of such autocrine loop in tumor cells has been demonstrated by in vitro experiments showing that factor-specific neutralizing antibodies are capable of inhibiting further proliferation of the factor-producing cells. The immunization of mice with an autocrine growth factor effectively blocks the in vivo growth of the tumor cells expressing and secreting this growth factor (see: hst ).

Examples for the endogenous production of tumor-associated growth factors are, among many others, IL3 , EGF , bFGF , IGF and PDGF . In some instances autocrine loops have been shown to be very complicated mechanisms involving more than a single factor and its receptor gene.

The establishment of autocrine growth control loops is not restricted to regulatory peptide factors. It has been observed, for example, that Epstein-Barr virus-transformed B-lymphocytes secrete protein factors but that the main mediator allowing autocrine growth is lactate. The neurotransmitter serotonin appears to be an autocrine growth factor for small cell lung carcinomas (see also: Bombesin ).

The autocrine growth control model is the basis for a number of therapeutical concepts that, at least in principle, should allow direct interference with the growth control mechanisms of tumor cells.

A reduction in the tissue and plasma concentrations of growth factors can be achieved by the administration of antibodies directed against the growth factor. At least experimentally this has been shown to inhibit the growth of Factor-dependent cell lines derived from tumor cells and also of human tumor cells transplanted into nude mice (see also: Immunodeficient mice ).

The reverse, i. e. the provision of additional growth factors for the purpose of inhibiting tumor cell growth, is based on the observation that many growth factors induce the down-modulation of receptor expression (see also: Receptor transmodulation ). It may be envisaged that increased doses of growth factors may induce resting tumor cells to enter the Cell cycle and hence to become vulnerable to chemotherapy. A similar concept is used, for example, in the therapy of mammary carcinomas which may involve low-dose treatment with estrogens before chemotherapy.

Another way of blocking tumor cell growth might be a blockade of the growth factor receptors by specific monoclonal antibodies. Antibodies directed against, and blocking, the EGF receptor have been shown to lead to tumor regression of transplanted epithelial carcinomas in the nude mouse model (see also: Immunodeficient mice ).

Yet another possibility of exploiting the autocrine growth control concept might be Antisense RNA that can be used to interfere with the expression of growth factors and growth factor receptor genes at the level of transcription (see also: Gene expression ).

For other mechanisms of growth control see also: intracrine , juxtacrine , paracrine , retrocrine .

For other entries pertaining to cell lines and cell culture see also: Cells MiniCOPE Dictionary .

Status: date of last revision: 07/01/1999

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