Orofacial and gastrointestinal hyperplasia and neoplasia in smad4(+/-) and elf(+/-)/smad4(+/-) mutant mice

BACKGROUND: Smad4 is vital to the roles of Smads 2 and 3 in transforming growth factor-beta (TGF)-beta signal transduction, and inactivated Smad4 is common to human gastrointestinal cancers. The embryonic liver fodrin (ELF) is a beta-spectrin that facilitates the nuclear translocation of activated Smad4. METHODS: Smad4(+/-) mice, known to develop gastrointestinal cancer, were crossbred with elf(+/-) mice. The smad4(+/-) and smad4(+/-)/elf(+/-) offspring were autopsied as abnormalities developed. RESULTS: In addition to polyps and adenocarcinomas of the stomach and duodenum, the smad4(+/-) mice developed squamous cell carcinomas of the skin, oral mucosa and forestomach, benign neoplasms of connective tissue and lacrimal gland, and a lymphoma. The smad4(+/-)/elf(+/-) mice developed extensive hyperplasia and neoplasia of the gastric mucosa. CONCLUSION: These findings indicate that investigating interactions among smad4, elf, and other genes involved in TGF-beta signaling should be useful in further delineating the processes of neoplasia in a wide variety of tissues.