Expression of Transforming Growth Factor-Beta (TGF-B) in Prostate Cancer Progression

Abstract

Abstract : We have demonstrated that a non-immunogenic Dunning's rat prostate cancer cell line, MATLyLu, had become immunogenic by reducing the endogenous production of TGF-beta1. MATLyLu cells are immunogenic, when the endogenous production of TGF-beta1 is down regulated. The objective of the project was to evaluate the role of TGF-beta in prostate cancer progression. There are three specific aims. Specific aim 1 was to study the effect of TGF-beta expression on the in vivo and in vitro growth of the rat prostate cancer MATLyLu cells. Specific aim 2 was to study the effect of TGF-beta expression on the host's immune reaction against MATLyLu cells. Specific aim 3 was to assess the effect of TGF-beta expression in MATLyLu cells on non-immune hosts. An expression construct containing TGF-beta l antisense was stably transfected into MATLyLu cells. Following transfection, cellular content of TGF-beta1 reduced from 70 pg to 10 pg per 2x10(4) cells and the rate of in vitro (3)H-thymidine incorporation increased 3-5 fold. After subcutaneous injection of tumor cells into syngeneic male hosts (Copenhagen rats), the tumor incidence was 100% (15/15) for the wild type MATLyLu cells and cells transfected with the control construct, but only 43% (9/21, p < 0.05) for cells transfected with TGF-p beta1 antisense. However, when cells were injected into athymic nude rats, the incidence of tumor development was 100% (10/10) for both the wild type MATLyLu cells and cells transfected with the control construct and 90% (9/10) for cells transfected with TGF-beta1 antisense. The proposed study is highly relevant to prostate cancer research. In this study, we have demonstrated that TGF-beta overexpression by cancer cells can render these cells resistant to host's immune surveillance program. This information is critical for us to propose the Phase II research in TGF-beta-based gene therapy in prostate cancer.