Ribozyme to TGF-beta1 mRNA abrogates immunosuppressive effects of human colorectal adenocarcinoma HRT-18 cells in vitro and in vivo.
Transforming growth factor-beta1 (TGF-beta1) is overexpressed in a variety of malignant epithelial tumors and was suggested to be a marker of colorectal cancer. Moreover, there is growing evidence that TGF-beta1 contributes to tumor progression by regulating tumor cell proliferation and differentiation, inducing a favorable tumor microenvironment, promoting migration and invasion, and suppressing macrophage cytotoxicity. Therefore, we stably transfected an anti-TGF-beta1 hammerhead ribozyme into the human colorectal adenocarcinoma cell line HRT-18. Expression of this ribozyme resulted in significant inhibition of TGF-beta1 expression on mRNA and protein level. This was associated with an enhanced tumor cell differentiation and a reduced tumor growth in vivo. The capability of tumor cells to suppress ROI production of co-cultivated human macrophages was abrogated in transfectants. Taken together, inhibition of TGF-beta1 in colorectal carcinoma cells might be an interesting therapeutic tool leading to reduced tumor cell growth and increased macrophage cytotoxicity. Thus, a gene-therapeutic approach using anti-TGF-beta1 ribozyme in combination with established anti-tumor agents is of great promise.
Schmitt
Wolfgang Daniel
WD
Institute of Pathology, Martin-Luther-University, 06097 Halle, Germany.
Siegert
Antje
A
Lach
Sandra Stephanie
SS
Fuhrmann
Stephan
S
Kondla
Anke
A
Holm
Per Sonne
PS
Hauptmann
Steffen
S
D000230:Adenocarcinoma / Q000235:genetics / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D000818:Animals; D002448:Cell Adhesion; D002454:Cell Differentiation / Q000235:genetics; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D018920:Coculture Techniques; D015179:Colorectal Neoplasms / Q000235:genetics / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D015536:Down-Regulation; D005260:Female; D015316:Genetic Therapy; D006801:Humans; D007108:Immune Tolerance; D008264:Macrophages / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D016513:Mice, SCID; D016337:RNA, Catalytic / Q000096:biosynthesis* / Q000235:genetics; D017382:Reactive Oxygen Species / Q000378:metabolism; D013997:Time Factors; D014162:Transfection; D053773:Transforming Growth Factor beta1 / Q000235:genetics / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays
D016337:RNA, Catalytic; D017382:Reactive Oxygen Species; D053773:Transforming Growth Factor beta1; C427204:hammerhead ribozyme