Faculty Bibliography

Neil Theise speaks to Georgia Patey, Commissioning Editor: Neil Theise is a diagnostic liver pathologist, adult stem cell researcher and complexity theorist in New York City, where he is a Professor of Pathology at the Mount Sinai Beth Israel Medical Center of Icahn School of Medicine at Mount Sinai. He received his medical degree from Columbia University College of Physicians and Surgeons, where he also received his training in Anatomic Pathology. Subspecialty training was pursued in gastrointestinal (NYU), liver (Royal Free Hospital) and liver transplant (Mount Sinai, NYC) pathology. His earliest research focus was on defining the premalignant dysplastic nodules in human chronic liver disease. He revised understandings of human liver microanatomy, which in turn, led directly to identification of possible liver stem cell niches and the marrow-to-liver regeneration pathway. He is considered a pioneer of multiorgan adult stem cell plasticity. His publications on these topics in model systems and human liver stem cells have been highlighted on a record five covers of Hepatology.

A large number of cancer stem cells (CSCs) have been isolated and identified; however, none has been cultured in an unlimited manner in vitro without losing tumorigenicity and multipotency. In this study, we successfully clonogenically cultured a newly identified CD34+ liver CSC (LCSC) on feeder cells up to 22 passages (to date) without losing CSC property. Cloned CD34+ LCSC formed a round packed morphology and it could also be cryopreserved and recultured. Stem cell markers, CD34, CD117, and SOX2; normal liver stem cell markers, alpha fetoprotein, CK19, CK18, and OV6; putative CSC markers, CD44, CD133, EpCAM, and CD90; as well as CD31 were expressed in cloned CD34+ LCSC. SOX2 was the major factor in maintaining this LCSC before colonization, and interestingly, OCT4, SOX2, NAONG, Klf4, c-Myc, and Lin28 were upregulated in association with symmetric self-renewal for colony growth of CD34+ LCSC on feeder cells. Gene expression patterns of in vitro differentiation were consistent with our in vivo finding; furthermore, the tumorigenicity of cloned CD34+ LCSC was not different from uncloned CD34+ LCSC sorted from parental PLC. These results show that our cloned CD34+ LCSC maintained CSC property, including self-renewal, bipotency, and tumorigenicity after long-term culture, demonstrating that this LCSC can be cultured in an unlimited manner in vitro. Thus, establishing pure population of CSCs isolated from the patients will provide an opportunity to explore the mechanisms of tumorigenesis and cancer development, and to identify unique biomarkers presenting potential indicators of drug efficacy against CSCs for establishment of a novel strategy for cancer therapy.

Recent WHO classification for combined hepatocellular-cholangiocarcinoma and recognized stem cell subtypes has increased attention to such tumors; however, the resulting burst of reporting and research indicates that this classification, while provocative, is incomplete for description of the full array of primary liver carcinomas with biphenotypic (hepatobiliary) differentiation. We review the history of such lesions and consider the wider array of such tumors previously described. Mixed hepatobiliary phenotypes and immunophenotypes are found in individual tumors at the tissue level - with architectural and cytologic features supportive of both differentiation states - and at the cellular level, with individual cells that display cytology of one cell type, but immunophenotypically showing mixed expression. Pathobiologic and clinical questions to be answered by future research are suggested.