▁as ▁well ▁as ▁their ▁size ▁and ▁whether ▁they ▁are ▁apo pt otic . ▁In ▁general , ▁C TC s ▁are ▁ano ik is - res istant , ▁which ▁means ▁that ▁they ▁can ▁surv ive ▁in ▁the ▁blood stream ▁without ▁att aching ▁to ▁a ▁substr ate . ▁ ▁Trad itional ▁C TC s ▁are ▁character ised ▁by ▁an ▁int act , ▁vi able ▁nucle us ; ▁the ▁expression ▁of ▁Ep C AM ▁and ▁cy to ker at ins , ▁which ▁demonstrate ▁ep ith el ial ▁origin ; ▁the ▁absence ▁of ▁CD 4 5 , ▁indicating ▁the ▁cell ▁is ▁not ▁of ▁h emat opo iet ic ▁origin ; ▁and ▁their ▁larger ▁size , ▁irregular ▁shape ▁or ▁sub cell ular ▁morph ology . ▁ ▁Cy to ker atin - negative ▁C TC s ▁are ▁character ised ▁by ▁the ▁lack ▁of ▁Ep C AM ▁or ▁cy to ker at ins , ▁which ▁may ▁indicate ▁an ▁und iffer enti ated ▁phen ot ype ▁( cir cul ating ▁cancer ▁stem ▁cells ) ▁or ▁the ▁ac quisition ▁of ▁a ▁mes en ch ym al ▁phen ot ype ▁( known ▁as ▁ep ith el ial - mes en ch ym al ▁transition ▁or ▁E MT ). ▁These ▁populations ▁of ▁C TC s ▁may ▁be ▁the ▁most ▁resist ant ▁and ▁most ▁pr one ▁to ▁met ast asis . ▁They ▁are ▁also ▁more ▁difficult ▁to ▁isol ate ▁because ▁they ▁express ▁neither ▁cy to ker at ins ▁nor ▁CD 4 5 . ▁Otherwise , ▁their ▁morph ology , ▁gene ▁expression ▁and ▁genom ics ▁are