Growth factor balance and tumor progression

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The role of balance of negative and positive autocrine growth factors in malignant progression is reviewed with an emphasis on transforming growth factor α (TGF-α) as a stimulating factor and transforming growth factor β (TGF-β) as an inhibiting factor. Evidence suggests that in normal cells TGF-α is down regulated in non-dividing or quiescent states in vitro. Tumor cells which have early stage characteristics as represented by poor clonal growth and poor tumorigenicity in athymic mice also show repression of TGF-α in non-dividing states. Progression of this phenotype is induced by uncontrolled low level expression of TGF-α by transfection with a constitutive expression vector for the polypeptide. Transfection of the unprogressed phenotype with a constitutive anti-sense vector for TGF-β, also leads to tumor progression by repressing the autocrine negative TGF-β activity normally expressed by these cells. Both the upregulation of TGF-α and the repression of TGF-β generated in vivo progression without changing growth rates in vitro. Instead, clonality and ability to reenter the cell cycle from quiescence were increased. Thus, it is concluded that an autocrine balance of positive and negative factors is important for maintaining controlled re-entry into dividing states from non-dividing states and that disruption of this balance leads to malignant progression characterized by greater independence of the malignant cells from the control of exogenous growth factors.

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