Suppression of angiogenesis, tumorigenicity, and metastasis by human prostate cancer cells engineered to produce interferon-beta

We determined whether the IFN-beta gene can he used to suppress angiogenesi s, tumor growth, and metastasis of human prostate cancer cells growing in t he prostate of nude mice. Highly metastatic PC-3M human prostate cancer cel ls were engineered to constitutively produce murine IFN-beta subsequent to infection with a retroviral vector containing murine IFN-beta cDNA, Parenta l (PC-3M-P), control vector-transduced (PC-3M-Neo), and IFN-beta-transduced (PC-3M-IFN-beta) cells were injected into the prostate (orthotopic) or sub cutis (ectopic) of nude mice, PC-3M-P and PC-3M-Neo cells produced rapidly growing tumors and regional lymph node metastases, whereas PC-3M-IFN-beta c ells did not. PC-3M-IFN-beta cells also suppressed the tumorigenicity of by stander nontransduced prostate cancer cells. PC-3M-IFN-beta cells produced small tumors (3-5 mm in diameter) in nude mice treated with anti-asialo G(M 1) antibodies and in severe combined immunodeficient/Beige mice. Immunohist ochemical staining revealed that PC-3M-IFN-beta tumors were homogeneously i nfiltrated by macrophages, whereas control tumors contained fewer macrophag es at their periphery. Most tumor cells in the control tumors were stained positive by an antibody to proliferative cell nuclear antigen; very few wer e positively stained by terminal deoxynucleotidyl transferase-mediated dUTP -biotin nick-end labeling. In sharp contrast, PC-3M-IFN-beta tumors contain ed fewer proliferative cell nuclear antigen-positive cells and many termina l deoxynucleotidyl transferase-mediated dUTP-biotin nick-end labeling-posit ive cells, Staining with antibody against CD31 showed that control tumors c ontained more blood vessels than PC-3M-IFN-beta tumors. PC-3M-IFN-beta cell s were more sensitive to lysis mediated by natural killer cells in vitro or to cytostasis mediated by macrophages than control transduced cells. Condi tioned medium from PC-3M-IFN-beta cells augmented splenic cell-mediated cyt olysis to control tumor cells, which could be neutralized by antibody again st IFN-P, Collectively, the data suggest that the suppression of tumorigeni city and metastasis of PC-3M-IFN-beta cells is due to inhibition of angioge nesis and activation of host effector cells.