Disruption of Trp53 in livers of mice induces formation of carcinomas with bilineal differentiation.

BACKGROUND & AIMS: p53 limits the self-renewal of stem cells from various tissues. Loss of p53, in combination with other oncogenic events, results in aberrant self-renewal and transformation of progenitor cells. It is not known whether loss of p53 is sufficient to induce tumor formation in liver. METHODS: We used AlfpCre mice to create mice with liver-specific disruption of Trp53 (AlfpCre(+)Trp53(Δ2-10/Δ2-10) mice). We analyzed colony formation and genomic features and gene expression patterns in liver cells during hepatocarcinogenesis in mice with homozygous, heterozygous, and no disruption of Trp53. RESULTS: Liver-specific disruption of Trp53 consistently induced formation of liver carcinomas that had bilineal differentiation. In nontransformed liver cells and cultured primary liver cells, loss of p53 (but not p21) resulted in chromosomal imbalances and increased clonogenic capacity of liver progenitor cells (LPCs) and hepatocytes. Primary cultures of hepatocytes and LPCs from AlfpCre(+)Trp53(Δ2-10/Δ2-10) mice, but not Cdkn1a(-/-) mice, formed tumors with bilineal differentiation when transplanted into immunocompromised mice. Spontaneous liver tumors that developed in AlfpCre(+)Trp53(Δ2-10/Δ2-10) mice had significant but complex alterations in expression of Rb checkpoint genes compared with chemically induced liver tumors that developed mice with wild-type Trp53. CONCLUSIONS: Deletion of p53 from livers of mice is sufficient to induce tumor formation. The tumors have bilineal differentiation and dysregulation of Rb checkpoint genes.

Parathyroid identification during thyroid and parathyroid operations: A pilot study evaluating a novel low cost autofluorescence based device.

BACKGROUND: The aim of this study was to develop a low-cost prototype near-infrared fluorescence device that enables contrast-free, real time, high-resolution intraoperative visualization of normal and pathological parathyroid glands (PGs) by imaging their autofluorescence (AF). METHODS: A novel near-infrared parathyroid AF (NIR-PAF) imaging device with visible laser PG targeting was developed. The device was evaluated during parathyroid and thyroid operations in a pilot clinical study. RESULTS: Overall, of the 6 parathyroidectomies carried out in the study population a parathyroid adenoma was found to exhibit AF ex vivo in 6/6 (100%) of cases, and in vivo in 3/3 (100%) of these cases. Two of 4 thyroidectomies were evaluated in vivo and all PGs (6 PGs total) were identified by the NIR-PAF device. The NIRPAF device cost less than $1200 Canadian to build. CONCLUSION: The inexpensive NIR-PAF device that we developed can successfully intraoperatively identify both normal and pathological PGs.

Transient telomere dysfunction induces chromosomal instability and promotes carcinogenesis.

Telomere shortening limits the proliferative capacity of a cell, but perhaps surprisingly, shortening is also known to be associated with increased rates of tumor initiation. A current hypothesis suggests that telomere dysfunction increases tumor initiation by induction of chromosomal instability, but that initiated tumors need to reactivate telomerase for genome stabilization and tumor progression. This concept has not been tested in vivo, since appropriate mouse models were lacking. Here, we analyzed hepatocarcinogenesis in a mouse model of inducible telomere dysfunction on a telomerase-proficient background, in telomerase knockout mice with chronic telomere dysfunction (G3 mTerc-/-), and in WT mice with functional telomeres and telomerase. Transient or chronic telomere dysfunction enhanced the rates of chromosomal aberrations during hepatocarcinogenesis, but only telomerase-proficient mice exhibited significantly increased rates of macroscopic tumor formation in response to telomere dysfunction. In contrast, telomere dysfunction resulted in pronounced accumulation of DNA damage, cell-cycle arrest, and apoptosis in telomerase-deficient liver tumors. Together, these data provide in vivo evidence that transient telomere dysfunction during early or late stages of tumorigenesis promotes chromosomal instability and carcinogenesis in telomerase-proficient mice.