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Carcinoids of different organs appear morphologically indistinguishable. We studied the usefulness of differential expression of CDX2 and thyroid transcription factor-1 (TTF-1) in 78 gastrointestinal and pulmonary carcinoids and their metastases (n = 10). CDX2 staining of gastric biopsy specimens with neuroendocrine hyperplasia (n = 11) and various gastritides (n = 10) was also performed. All ileal (6/6 [100%]), 6 (86%) of 7 appendiceal, 3 (75%) of 4 duodenal, 1 (50%) of 2 ampullary, 12 (33%) of 18 rectal, 6 (30%) of 20 pancreatic, and 1 (17%) of 6 gastric carcinoids expressed CDX2 with variable intensity; none of the pulmonary carcinoids stained. Of 15 pulmonary carcinoids, 8 (53%) stained with TTF-1, but none of the gastrointestinal carcinoids did. CDX2 and TTF-1 staining profiles of primary and metastatic carcinoids were similar. CDX2+ gastric endocrine cells had a distribution similar to that of gastrin and enterochromaffin cells but not enterochromaffin-like cells. Our results suggest that CDX2 and TTF-1 have high specificity for gastrointestinal and pulmonary carcinoids, respectively.

Pluripotent cells can be derived from various types of somatic cells by nuclear reprogramming using defined transcription factors. It is, however, unclear whether human cancer cells can be similarly reprogrammed and subsequently terminally differentiated with abrogation of tumorigenicity. Here, using sarcomas we show that human-derived complex karyotype solid tumors: (1) can be reprogrammed into a pluripotent-like state as defined by all in vitro criteria used to define pluripotent stem cells generated from somatic cells; (2) can be terminally differentiated into mature connective tissue and red blood cells; and (3) terminal differentiation is accompanied with loss of both proliferation and tumorigenicity. We go on to perform the first global DNA promoter methylation and gene expression analyses comparing human cancers to their reprogrammed counterparts and report that reprogramming/differentiation results in significant epigenetic remodeling of oncogenes and tumor suppressors, while not significantly altering the differentiation status of the reprogrammed cancer cells, in essence dedifferentiating them to a state slightly before the mesenchymal stem cell differentiation stage. Our data demonstrate that direct nuclear reprogramming can restore terminal differentiation potential to human-derived cancer cells, with simultaneous loss of tumorigenicity, without the need to revert to an embryonic state. We anticipate that our models would serve as a starting point to more fully assess how nuclear reprogramming overcomes the multitude of genetic and epigenetic aberrancies inherent in human cancers to restore normal terminal differentiation pathways. Finally, these findings suggest that nuclear reprogramming may be a broadly applicable therapeutic strategy for the treatment of cancer. [ABSTRACT FROM AUTHOR]