Adult human mesenchymal stem cell as a target for neoplastic transformation

Abstract

The neoplastic process may involve a cancer stem cell. This concept has emerged largely from the careful analysis of tumour biopsy systems from haematological, breast and brain tumours. However, the experimental systems necessary to provide the cellular and molecular evidence to support this important concept have been lacking. We have used adult mesenchymal stem cells (hMSC) transduced with the telomerase hTERT gene to investigate the neoplastic potential of adult stem cells. The hTERT-transduced line, hMSC-TERT20 at population doubling level (PDL) 256 showed loss of contact inhibition, anchorage independence and formed tumours in 10/10 mice. hMSC-TERT4 showed loss of contact inhibition at PDL 95, but did not exhibit anchorage independence and did not form tumours in mice. Both lines had a normal karyotype but showed deletion of the Ink4a/ ARF locus. At later passage, hMSC-TERT4 also acquired an activating mutation in KRAS. In hMSC-TERT20, expression of the cell cycle-associated gene, DBCCR1 was lost due to promoter hypermethylation. This epigenetic event correlated with acquisition of tumorigenicity. These data suggest that the adult hMSCs can be targets for neoplastic transformation and have implications for the development of novel anticancer therapeutics and for the use of hMSC in tissue engineering and transplantation protocols.

Controversial issue: Is it safe to employ mesenchymal stem cells in cell-based therapies?

“…The cells employed in these cultures were however not obtained from healthy individuals but isolated from subcutaneous fat during operation of complicated appendicitis and it is thus likely that they are not comparable to normal MSC Kassem et al, 2005). The second study broaches the issue of spontaneous transformation in the unphysiological case of immortalizing human MSC with hTERT, thereby gaining high levels of telomerase activity Serakinci et al, 2004). Such MSC showed various genetic and epigenetic changes in spite of maintaining a normal karyotype Serakinci et al, 2004).…”

DBC1 re-expression alters the expression of multiple components of the plasminogen pathway

“…In Rattus norvegicus, the gene was identified as a bone morphogenetic protein/retinoic acid-inducible transcript in the brain and is involved in perinatal development of sympathetic neurons (Kawano Toshiyuki and Ichiro, 2004). DBC1 expression is lost by promoter hypermethylation in bladder tumours, hepatocellular carcinomas and during transformation in hMSC transduced with the hTERT gene, indicating an important tumour suppressor role in addition to its role in the developing nervous system (Habuchi et al, 1998;Yu et al, 2003;Serakinci et al, 2004). Thus, DBC1 could have multiple functions in eukaryotic cells.…”

“…It has been suggested that hypermethylation of DBC1 is one of the earliest events in the development of transitional cell carcinoma (TCC) (Habuchi et al, 2001). Recently, loss of DBC1 expression by promoter hypermethylation was reported during transformation of adult mesenchymal stem cells (hMSC) transduced with the hTERT gene (Serakinci et al, 2004), where methylation correlated with the acquisition of the tumorigenic phenotype. Thus, DBC1 alteration might be one of the essential changes during neoplastic development in hMSC.…”

Cellules souches mésenchymateuses

“…En utilisant des CSM immortalisées après transduction de hTERT (human telomerase reverse transcriptase), on a pu montrer que la transformation des CSM est un processus long et multi-étapes qui fait intervenir la délétion de p16 ink4a [22]. Depuis 2005, différents articles avaient rapporté que les CSM en culture (issues de moelle osseuse ou de tissu adipeux) présentaient des anomalies caryotypiques (anomalies de structure) et finissaient par se transformer et exprimer un potentiel oncogénique [23,24].…”

“…La sénescence et la transformation sont des processus liés ; ainsi les cellules devenant sénescentes peuvent se transformer après une crise transitoire et l'abrogation des mécanismes de sénescence avec une réaug-mentation de la longueur des télomères ou la répression de l'activité de p16 ink4a et de p53 [22]. Par ailleurs, les cellules devenant sénescentes ont un phénotype sécrétoire spécifique avec production de différentes molécules comme l'IL6 (interleukine 6), des MMP (métalloprotéases), l'hepatocyte growth factor, le FGF2 et GROa (la chimiokine CXCL1).…”