In vivo and in vitro effects of TGF-beta 1 on normal and neoplastic haemopoiesis.
TGF-beta 1 and TGF-beta 2 are equipotent selective inhibitors of murine and human haemopoiesis in vitro. Primitive haemopoietic cells such as the high proliferative potential progenitor cell and the colony-forming unit (CFU)-GEMM are directly inhibited by TGF-beta whereas the more differentiated CFU-G, CFU-M and CFU-E are not. Recombinant TGF-beta 1 administered intraperitoneally or intravenously to mice selectively inhibits haemopoietic colony formation in a time- and dose-dependent manner to the same extent as seen in vitro. The progenitors are reversibly prevented from entering the cell cycle. This inhibitory action of TGF-beta functions on at least two levels: (1) down-modulation of the cell surface expression of receptors for growth stimulatory molecules and (2) interference with the intracellular signalling pathways of these molecules. In addition, expression of TGF-beta receptors is regulated during cytokine stimulation of haemopoiesis. Neoplastic B lymphocytes can proliferate by escaping from a TGF-beta-mediated autocrine inhibitory loop. Activation signals (e.g. phorbol esters) inhibit tumour cell growth by stimulating active TGF-beta production and inducing cell surface expression of TGF-beta receptors. These results indicate that TGF-beta may be useful as a bone marrow protective and/or an antitumour agent.
Ruscetti
F W
FW
Biological Response Modifiers Program, National Cancer Institute-Frederick Cancer Research and Development Center, MD 21701-1201.
Dubois
C
C
Falk
L A
LA
Jacobsen
S E
SE
Sing
G
G
Longo
D L
DL
Wiltrout
R H
RH
Keller
J R
JR
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D001402:B-Lymphocytes / Q000187:drug effects; D002453:Cell Cycle / Q000187:drug effects; D002478:Cells, Cultured; D016207:Cytokines / Q000494:pharmacology; D015536:Down-Regulation; D004357:Drug Synergism; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000494:pharmacology; D006410:Hematopoiesis / Q000187:drug effects*; D006412:Hematopoietic Stem Cells / Q000187:drug effects*; D006801:Humans; D007155:Immunologic Factors / Q000494:pharmacology; D015473:Leukemia, Promyelocytic, Acute / Q000473:pathology; D016393:Lymphoma, B-Cell / Q000473:pathology; D051379:Mice; D014411:Neoplastic Stem Cells / Q000187:drug effects*; D011956:Receptors, Cell Surface / Q000096:biosynthesis; D018125:Receptors, Transforming Growth Factor beta; D011994:Recombinant Proteins / Q000494:pharmacology; D016212:Transforming Growth Factor beta / Q000494:pharmacology*; D014407:Tumor Cells, Cultured / Q000187:drug effects
D000970:Antineoplastic Agents; D016207:Cytokines; D007155:Immunologic Factors; D011956:Receptors, Cell Surface; D018125:Receptors, Transforming Growth Factor beta; D011994:Recombinant Proteins; D016212:Transforming Growth Factor beta; D016178:Granulocyte-Macrophage Colony-Stimulating Factor