The Antiangiogenesis Effect of Interleukin 12 During Early Growth of Human Pancreatic Cancer in SCID Mice

Abstract

Interleukin 12 (IL-12) is a heterodimeric cytokine that exerts a potent antitumor effect through its pleiotropic actions. It was recently reported that IL-12 has also a potent antiangiogenic effect through the induction of IFN-gamma, which triggers the production of chemokines such as IP-10 that has been shown to have antiangiogenesis properties. In this study we transfected the IL-12 gene into a human pancreatic adenocarcinoma cell line (PK-1). PK-1 cells transfected with the green fluorescence protein (gfp) gene were used as positive controls. The in vitro growth curve and in vivo tumor growth of transfectants (IL-12/PK-1 and gfp/PK-1) were compared with those of parental cells. The SCID mice used in this study were administered antiasialo GM-1 Ab (100 microg, i.p., twice weekly) to deplete the remaining immunoeffector cells, NK cells. Using a skinfold chamber model, we observed and recorded tumor angiogenesis by intravital microscopy. In vitro growth of IL-12/PK-1 and gfp/PK-1 cells was not different from that of wild-type PK-1 cells (wt/PK-1). However, IL-12 transfected PK-1 cells did not develop into tumors as did the wt/PK-1 cells after subcutaneous inoculation in antiasialo GM-1 Ab administered SCID mice. The growth of IL-12/PK-1 tumors was restored in mice treated with anti-IL-12 antibody. We found that IL-12/PK-1, in contrast to gfp/PK-1 and wt/PK-1, failed to initiate an angiogenic response, as observed in the skinfold chamber model. These results indicate that the antiangiogenesis effect of IL-12 alone, without immune system involvement, is sufficient to block the growth of human pancreatic cancer.

Ethanol Regulates Angiogenic Cytokines During Neural Development: Evidence From an in Vitro Model of Mitogen‐Withdrawal–Induced Cerebral Cortical Neuroepithelial Differentiation

“…Increasing evidence suggests that it is the neural tube that signals this perineural vascular network to initiate vasculogenesis (Hogan et al, 2004). Interleukin-12 (i.e., IL-12p70), a heterodimeric protein complex comprised of a 40 kDa subunit (IL-12p40), and a 35 kDa subunit, is a potent antiangiogenic factor Sunamura et al, 2000). Our data indicate that neural cells ordinarily express very little IL-12 (either the p40 subunit, or the p70 heterodimeric complex), at any stage of development, especially when compared with proangiogenic factors VEGF-A, MCP-1, and GM-CSF.…”

Inhibition of a vascular ocular tumor growth by IL-12 gene transfer

“…Recently gene therapy approaches have shown IFN-c inde- pendent angiogenesis repression [3,33,34]. Since IFN-c may be responsible for IL-12 associated hepatotoxicity [35], the concept that it may be dispensable for the antiangiogenic activity could be useful for management of patients on IL-12 therapy.…”

Patients undergoing treatment for pancreatic adenocarcinoma can mount an effective immune response to vaccinations

“…Although some investigators have demonstrated variable immune responses in pancreatic cancer patients [22] , the prevailing view remains that these patients are immunosuppressed [9,10] . This immunosuppression is thought to be mediated by tumor growth factor ␤ [8,23,24] and/or other mediators of immune response [25][26][27][28] . In future work, measurement of serum and tissue levels of these immune modulators would be of scientifi c and clinical interest.…”