Representation of the mitosis of a cell nucleus in red on a black background.

Embryonic stem cells and cancer risks

The trans­plan­ta­ti­on of undif­fe­ren­tia­ted embryo­nic stem cells into immu­n­o­com­pa­ti­ble organs, in con­trast to the trans­plan­ta­ti­on of fetal or adult stem cells, pro­du­ces ter­ato­mas or teratocarcinomas.

The risk of tumor for­ma­ti­on decrea­ses with advan­cing matu­ra­ti­on and, accor­ding to gene­ral opi­ni­on, can be relia­bly avo­ided by pre-dif­fe­ren­tia­ting the stem cells. This hypo­the­sis is sup­port­ed by num­e­rous stu­dies in which no for­ma­ti­on of tumors was obser­ved after trans­plan­ta­ti­on of pre­dif­fe­ren­tia­ted embryo­nic stem cells.

Howe­ver, the­se expe­ri­ments main­ly invol­ved xeno­log­ous trans­plants, i.e. ani­mal expe­ri­ments in which pre-dif­fe­ren­tia­ted embryo­nic stem cells from one spe­ci­es (e.g. mou­se or human) were trans­fer­red to ano­ther spe­ci­es. In a more recent stu­dy, howe­ver, it tur­ned out that in the xeno­lo­gi­cal sys­tem not only the trans­plan­ta­ti­on of pre­dif­fe­ren­tia­ted but also the trans­plan­ta­ti­on of undif­fe­ren­tia­ted embryo­nic stem cells did not show any tumor for­ma­ti­on (1).

In this stu­dy, published in the Pro­cee­dings of the Natio­nal Aca­de­my of Sci­ence, undif­fe­ren­tia­ted muri­ne embryo­nic stem cells were trans­plan­ted into the brain of immu­no­sup­pres­sed rats. A stro­ke was expe­ri­men­tal­ly indu­ced in the­se ani­mals by occlu­si­on of the midd­le cere­bral artery.
The stem cells migra­ted from the trans­plan­ta­ti­on site via the cor­pus cal­lo­sum into the oppo­si­te hemi­sphe­re affec­ted by the stro­ke and, after spon­ta­neous dif­fe­ren­tia­ti­on into neu­rons and gli­al cells, sett­led in the peri­phe­ral zone of the infarc­tion. The­se fin­dings rai­sed the hope that in the brain — in con­trast to
other body organs — even the trans­plan­ta­ti­on of undif­fe­ren­tia­ted embryo­nic stem cells does not lead to tumor for­ma­ti­on, but to a dise­a­se-ori­en­ted, self-con­trol­led repla­ce­ment of the lost brain cells.

Howe­ver, the repe­ti­ti­on of this expe­ri­ment in the homo­log­ous sys­tem — ie the trans­plan­ta­ti­on of muri­ne stem cells into the brain of mice — reve­a­led that this is not the case (2). Ins­tead, not only after trans­plan­ta­ti­on of undif­fe­ren­tia­ted, but also after trans­plan­ta­ti­on of pre­dif­fe­ren­tia­ted stem cells, high-gra­de mali­gnant tera­to­c­ar­ci­no­mas were indu­ced in almost 100 per­cent, accor­ding to the work published in the Jour­nal of Cere­bral Blood Flow and Meta­bo­lism. The high tumor inci­dence was inde­pen­dent of gen­der, age, mou­se strain or con­co­mi­tant immunosuppression. 

The small num­ber of undif­fe­ren­tia­ted stem cells, which was suf­fi­ci­ent for tumor induc­tion, was also asto­nis­hing: as few as 500 undif­fe­ren­tia­ted cells deve­lo­ped into macro­sco­pi­cal­ly visi­ble tumors within two weeks. This also explains the tumor induc­tion of the pre-dif­fe­ren­tia­ted cells: alt­hough the degree of puri­ty of the nes­tin-posi­ti­ve/Oc­t4-nega­ti­ve cells used was more than 99 per­cent, the­re were obvious­ly still enough undif­fe­ren­tia­ted cells to trig­ger tumor growth.

The reason for the striking dif­fe­rence in the tumor risk of homo­log­ous and xeno­log­ous stem cell trans­plants is curr­ent­ly unknown. If, as is to be feared, this is a fun­da­men­tal pro­blem of homo­log­ous trans­plan­ta­ti­on, this would have serious con­se­quen­ces for the safe­ty assess­ment of human embryo­nic stem cells. Sin­ce human stem cells can only be tes­ted pre­cli­ni­cal­ly for their tumo­ri­ge­ni­ci­ty in the xeno­lo­gic sys­tem, their beha­vi­or under homo­log­ous cli­ni­cal con­di­ti­ons can­not be pre­dic­ted. With the test methods curr­ent­ly available, it will the­r­e­fo­re not be pos­si­ble to check the safe­ty of embryo­nic human stem cells befo­re they are used cli­ni­cal­ly. hsm

1. Hoehn M, Küs­ter­mann E, Blunk J, Wie­der­mann D, Trapp T, Wecker S, Föcking M, Arnold H, Hesche­ler J, Fleisch­mann BK, Schwindt W, Bühl C: Moni­to­ring of implan­ted stem cell migra­ti­on in vivo: A high­ly resol­ved in vivo magne­tic reso­nan­ce ima­ging inves­ti­ga­ti­on of expe­ri­men­tal stro­ke in rat. Proc Nat Acad Sci (USA) 2002; 99: 16267–16272.
2. Erdö F, Bühr­le C, Blunk J, Hoehn M, Xia Y, Fleisch­mann B, Föcking M, Küs­ter­mann E, Kolos­s­ov E, Hesche­ler J, Hoss­mann K‑A, Trapp T: Host-depen­dent tumo­rig­e­ne­sis of embryo­nic stem cell trans­plan­ta­ti­on in expe­ri­men­tal stro­ke. J Cereb Blood Flow Metab 2003; 23: 780–785.

Prof. Dr. Konstantin‑A. Hoss­mann, Max-Planck-Insti­tut für neu­ro­lo­gi­sche For­schung, Gleue­ler Stra­ße 50, 50931 Köln, E‑Mail:


Leave a Reply