Key processes in development, including responses to trophic stimuli, cell-cell interactions, migration, differential cell multiplication, and programmed cell death, are recapitulated in a pathologic manner during oncogenesis and metastasis, suggesting an aberrant regulation or 're-activation' of such processes.
The aim of this project is to isolate developmental control genes that regulate pattern formation; in particular, the patterning of the primary embryonic axis and the appendicular axis. Many of the same regulatory and signalling cascades appear to operate during both of these processes. Several new transcription factors have been isolated (homeobox and brachyury-related genes) that are specifically and selectively expressed during gastrulation and limb development. The homeobox gene Hoxd-12 plays a role in determining the anteroposterior pattern of bones in the limb. Hoxd-12 appears to upregulate c-fos expression in vitro. If this also occurs in developing cartilage/bone, c-fos may be a direct target of Hoxd-12 action. Gnot1 and Gnot2 homeobox genes are expressed in tissues with 'organizer' activity and notochord during gastrulation and may play a role in the formation of the embryonic axis. Gnot1 is also expressed in the limb bud and may regulate proximodistal limb pattern. Several new members of the brachyury (T) gene family, a new type of transcription factor known to be critical in the formation of the embryonic axis and for motility of primary mesoderm in mouse, have been isolated in the chick (Ch-T, -TbxT, -Tbx6L). These brachyury- or T-related genes are expressed in partly overlapping domains of 'organizer' tissues during gastrulation. Interestingly, one of these genes is also expressed in the developing limb bud. Gnot1 appears to be upstream of brachyury in its action and may initiate notochord formation. Studies are underway to further elucidate the function of these new homeobox and brachyury members, using molecular-genetic and biochemical approaches in both chick and mouse embryos. Finally, the potential for misexpression of these genes and its consequences with respect to oncogenesis and tumor progression can be investigated by analyzing human tumors. Hoxd-12, which regulates c-fos (a known skeletal oncogene), is being evaluated in chondro and osteogenic sarcomas. We have found that T is expressed in chordomas and its potential role in regulating motility in several tumors is being investigated.
