Stuart A. Aaronson

SUMMARY-A series of 200 human tumors were cultivated in vitro in an attempt to es-tablish cell lines. Lines were established with explant and trypsinization techniques, fr~m 13 tumors including ~arcinomas, sarcomas, mel-anomas, and brain tumors. All these lines in culture for over 1 year, exhibited marked refractility, multilayering, and criss-crossing and were morphologically distinct from nor-mal contact-inhibited human fibroblast or epithelial lines. They also formed colonies on IT!0nolay.e~s of n.ormal cells and grew with a high efficiency In soft agar. Preliminary re-sults!ndica~ed abnormal chromosomal pat-terns In all lines tested, and 8 of 9 cell lines

Hepatocyte growth factor (HGF) is a plasminogen-like protein thought to be a humoral mediator of liver regeneration. A 145-kilodalton tyrosyl phosphoprotein observed in rapid response to HGF treatment of intact target cells was identified by immunoblot analysis as the beta subunit of the c-met proto-oncogene product, a membrane-spanning tyrosine kinase. Covalent cross-linking of 125I-labeled ligand to cellular proteins of appropriate size that were recognized by antibodies to c-met directly established the c-met product as the cell-surface receptor for HGF.

Signaling pathways that mediate the normal functions of growth factors are commonly subverted in cancer. Oncogenes identified by a variety of approaches have been shown to function at critical steps in mitogenic signaling. Progression through the cell cycle requires the coordinated actions of members of two complementary classes of growth factors, and oncogenes appear to replace the actions of one set of these growth factors. Growth factors can also influence normal cell differentiation, and constitutive activation of growth-promoting pathways in cancer cells can modulate the cell phenotype as well. Paracrine actions of growth factors and cytokines may also influence the stepwise series of genetic events that lead to malignancy. New approaches for cancer therapy are being developed that intervene at various steps in growth factor signaling pathways.

The transforming protein of a primate sarcoma virus and a platelet-derived growth factor are derived from the same or closely related cellular genes. This conclusion is based on the demonstration of extensive sequence similarity between the transforming protein derived from the simian sarcoma virus onc gene, v-sis, and a human platelet-derived growth factor. The mechanism by which v-sis transforms cells could involve the constitutive expression of a protein with functions similar or identical to those of a factor active transiently during normal cell growth.