We can detect MYCN amplification of tumor tissue noninvasively and quantitatively by measuring the MYCN copy number in blood plasma. Determination of MYCN copy number in plasma may be useful when evaluating surgery and neoadjuvant chemotherapy.

Our previous report demonstrated a good correlation between high telomerase activity of cancer tissues and a poor prognosis of patients with colorectal cancers, except for several cases. To elucidate the additional factors that contribute to patient prognosis, the correlation among the expression levels of telomere binding proteins (TBP), the lengths of telomeres, the lengths of telomere 3¢-overhang (3¢-OH) and telomerase activity in 106 paired colorectal cancer and corresponding noncancerous mucosa (NCM) specimens were examined. The expression levels of eight TBP genes (TRF1, TRF2, TIN2, TANK1, TANK2, POT1, RAP1 and TPP1) were analyzed. Among the 106 cases, 35 cases had shortened telomeres (<7 kb), 15 had shortened 3¢-OH (3¢-OH length ratio of cancer/NCM <0.5) and 88 were classified as telomerase-activated cancers (activity ratio of cancer/NCM >2). Comparison between NCM and cancer in each case showed that all TBP except for POT1 were downregulated in cancers. A survival analysis using a Cox proportional hazard model showed that the survival rate of the telomerase-activated cases with shortened 3¢-OH and that of telomerase-inactivated cases were significantly better than that of telomerase-activated cases without 3¢-OH shortening, that is, restored or maintained 3¢-OH (P = 0.018). In the telomeraseactivated cancers, the length of 3¢-OH was significantly correlated with the expression levels of POT1. Elongation of telomeric overhang by telomerase, which might be regulated by POT1, may contribute to the increase of malignant potential in colorectal cancers. (Cancer Sci 2011; 102: 330-335) T he ends of chromosomes, named telomeres, are characterized by guanine-rich tandem hexamers (5¢-TTAGGG-3¢) with an average length of 5-15 kb and they serve as protective caps.(1,2) During DNA replication in cell division, telomeres gradually shorten at a rate of 50-200 bp as a result of the incomplete replication of linear chromosomes, the so-called 'end-replication problem'.(3) The telomeres terminate in a 3¢-single-stranded overhang of 12-300 bp, that is, ''telomere 3¢-overhang (3¢-OH)'' of the G-rich strand, which can be extended by telomerase in the S phase, followed by fill-in of the C strand in the late S phase.(4) Telomerase is a ribonucleoprotein that catalyzes de novo synthesis and elongation of telomeric repeats at chromosomal ends using an intrinsic RNA template in eukaryotic cells with an extended lifespan. The telomere overhang folds back into the D-loop of the duplex telomeric DNA to form a protective ''T-loop'' that prevents degradation by exonucleases or processing as damaged DNA.(5) This loop hides the 3¢ end also from telomerase. Furthermore, the telomeric repeats are bound to a large protein complex called ''shelterin'',which involves several telomere binding proteins (TBP). This complex is proposed to regulate telomere length, telomere protection and other cell functions such as proliferative activity.(5) When the telomere length shortens to a limited length, cells fall into senescence due to cleavage of ...

Abstract. The low percentage of human mesenchymal stem cells (hMSCs) in bone marrow necessitates their in vitro expansion prior to clinical use in regenerative medicine. We evaluated the effect of long-term culture of hMSCs on telomere length and transformation capacity by TERT transfection. hMSCs were isolated from the bone marrow aspirates of 24 donors and cultured with fibroblast growth factor-2 (FGF-2). Six cell lines with >500 population doubling levels were considered immortalized. TERT was transfected into two of the six lines for a comparison of telomere length, telomerase activity, differential capacity, colony formation capacity in soft agar and tumorigenicity in immunodeficient (NOD-SCID) mice. hMSC lines exhibited elongated telomeres without the activation of telomerase and retained multi-lineage differentiation potential upon chondrogenic or adipogenic differentiation, while non-immortalized hMSCs showed a marked reduction in telomere length in the differentiation process. Immortalized hMSCs showed anchorage-independence and formed tumors in NOD-SCID mice. Histologically, these tumors consisted of differentiated cells such as fat tissue and cartilage. Two TERTtransfected hMSC lines showed high rates of tumor formation in NOD-SCID mice. These tumors were histologically similar to teratocarcinoma without differentiated cells. These cells may provide a model for the origin of cancer stem cells from adult stem cells, and indicate the possibility that telomerase activation has a major role in the malignant transformation of human stem cells. These data suggest that adult hMSCs have a potential for neoplastic transformation and have implications for the use of hMSCs in tissue engineering and regenerative medicine.

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A significant difference in the methylation status within the CpG island of CASP8 was shown between favorable and unfavorable subtypes, and CASP8 methylation detected by oligoarray may be useful in the clinical evaluation of neuroblastomas.

Thus, we propose three loci, 1p36.1-2, 1p32-34, and 1p36.3, as the candidate loci of neuroblastoma suppressor genes on chromosome 1p responsible for groups I, LT, and ST, respectively. Among them, the 1p32-34 locus may be associated with aggressiveness of tumor progression, possibly due to MYCN amplification and/or telomerase reactivation, while the remaining two loci may not.

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Regulation mechanism of lung fibroblast proliferation remains unknown. To elucidate the key molecules in it, the authors here established mortal and immortal nontransformed lung fibroblast cell line/strains with elongated life span by telomerase reverse transcriptase gene transfection. Comparing the expression profiles of them, 51 genes were explored to be the candidates responsible for regulation of cellular proliferation of lung fibroblasts. This set of fibrobrast strains of same origin with different proliferative capacities may become useful model cells for research on lung fibroblast growth regulation and the candidate genes explored in this study may provide biomarkers or therapeutic targets of pulmonary fibrosis.