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Actions of insulin-like growth factors.

Three different lines of research and three entirely different observations have led to the discovery of the insulin-like growth factors (IGFs). In 1957, Salmon & Daughaday carried out an important experiment (44). They observed that serum stimulated the incorporation of 35S into incubated cartilage. Serum of hypophysectomized rats was devoid of this sulfation activity. It could not be reconstituted by addition of growth hormone to the incubation medium but reappeared after administration of growth hormone to hypophysectomized rats (44). These observations led Daughaday to postulate that growth hormone itself does not stimulate growth processes in vitro and in vivo, but rather induces the formation of factors that mediate the message of growth hormone. These factors-first called sulfation factors, later soma­ tomedins-Iead to sulfation of cartilage in vitro, which reflects growth in vivo. As we shall see, this hypothesis has been proven to be valid. Most cultured cells need serum to grow. Several growth factors in serum are responsible for growth-promoting effects, an aspect that will be discussed below in more detail. In 1972, Pierson & Temin extracted factors from serum, which they called multiplication-stimulating activity (MSA) (37). These fac­ tors had molecular weights below 10,000. When added to culture medium, they stimulated cells to replicate. Later it was found that cultured liver cells secrete MSA into the culture medium (10). This was the first demonstration that MSA is produced in the liver and that MSA may lead to autocrine stimulation of the same cells by which it is secreted. The third road towards the discovery of insulin-like growth factors departed from an entirely different observation: Serum exerts insulin-like effects on