Metabolic carcinogenesis--induction of murine lymphoma by CO2-treatment in vivo and in vitro.

Metabolic carcinogenesis may be viewed as a process in which a chronic disturbance of metabolic homeostasis leads to malignancy. Fluctuation in the CO2 tension in tissues is accompanied by changes in the intracellular pH. This prompted investigations into the long-term clinical effects of high CO2 tensions on various normal tissues in mice by two different methods. The first consisted of exposing different tissues in vitro to a high CO2% in air before transplantation into syngeneic or autologous hosts. The second method consisted of exposing intraperitoneal tissues in vivo to CO2-infusion, thus avoiding graft-host interactions. This is a report of the most significant findings in the series of investigations analyzed, 1. High incidences of malignant lymphoma in strains of mice with a low or zero spontaneous incidence followed: (a) syngeneic transplantation, (b) autologous transplantation, (c) in vivo exposure to CO2-infusion. 2. Syngeneic graft recipients developed similar high lymphoma incidences, irrespective of the tissue grafted or the pretransplantation treatment of the graft. 3. In the autologous system, however, the clinical results reflect the differences in the pretransplantation treatment, in contrast to those in the syngeneic system. 4. Whereas intraperitoneal CO2-infusion induced lymphoma, air-infusion did not. 5. Non-lymphoid grafts exposed in vitro to elevated CO2 induced only lymphoid malignancies. But non-lymphoid tissues exposed in vivo to elevated CO2 developed tumors of other tissues, such as lung tumor, in addition to lymphoid malignancies. 6. The same morphological lymphoid abnormalities occurred in all lymphoma-developing animals in these three experimental models. Hyperplasia in the splenic T-cell areas appeared most frequently. 7. The presence of immune-associated lesions in experimental animals (amyloidosis, interstitial nephritis and myocarditis) points to the activation of immune mechanisms in this lymphoma development. The evidence as a whole suggests the possibility that chronic immunological stimulation of host lymphoid tissue may be involved in the development of lymphoid malignancies in these animal models.