Growth stimulation of microenvironment-dependent mouse leukemias by tumor-promoting phorbol esters

The effects of 12-O-tetradecanoylphorbol 13-acetate (TPA) and related tumor-promoting phorbol esters on 23 symbiotic cell lines from AKR thymic leukemias were studied. The phorbol derivatives with in vivo cocarcinogenic activity increased the viable yield of leukemia cells of most symbiotic cell lines in the absence of growth-supporting adherent cells. Particularly, in 10 cell lines remarkable growth stimulation was observed with 1 to 10 ng TPA/ml. The effect of TPA was reversible, since the leukemia cells exposed to TPA for 48 hours failed to grow without TPA or adherent cells. The leukemia cells from a symbiotic cell line could be maintained in TPA-containing medium for as long as 8 weeks without losing dependence. The leukemia cells were refractory to growth stimulation by TPA after they acquired the capability to grow independently. Furthermore, by affecting the leukemia cells, TPA and active tumor promoters inhibited pseudoemperipolesis (i.e., localization of leukemia cells under or between adherent cells), which is the basic cell interaction in symbiotic complexes. These effects of tumor-promoting phorbol esters are discussed with a special reference to the multistage hypothesis of leukemogenesis.