Inhibition of tumor growth and enhancement of metastasis after transfection of the gamma-interferon gene.
Cells from the spontaneous metastatic TS/A mammary adenocarcinoma of a BALB/c mouse were transfected with the murine gamma-interferon (IFN-gamma) gene. Six clones (IFN-gamma clones) releasing between 2 and 6,000 international units (IU) of IFN-gamma/ml culture medium, were compared to TS/A parental cells (TS/A-pc) and to cells transfected with neomycin resistance gene only (NEO cells). Autocrine IFN-gamma up-regulated membrane expression of H-2 class-I and Ly-6 glycoproteins, but did not alter cellular proliferation in vitro. All IFN-gamma clones gave rise to progressive tumors with a growth rate significantly slower than that of tumors induced by TS/A-pc and NEO cells, and inversely correlated with the amount of IFN-gamma secreted. TS/A-pc and NEO tumors displayed a marginal reactive infiltrate, whereas those formed by IFN-gamma clones were massively infiltrated mostly by macrophages. In T- and NK-deficient mice the growth of tumors formed by IFN-gamma clones was not enhanced. In vitro tests showed that IFN-gamma clone cells were markedly more lysed by macrophages than TS/A-pc and NEO cells, while they remained poorly sensitive to NK and LAK cells. These data as a whole suggest that the development of solid tumors by IFN-gamma clones is primarily hampered by macrophages and not by T-lymphocytes or NK cells. When spontaneous metastatic ability was compared, 2 IFN-gamma clones releasing 2-4 IFN-gamma IU/ml were significantly more metastatic, while most IFN-gamma clones appeared to be as metastatic as NEO cells. By contrast, following intravenous challenge, all IFN-gamma clones produced 5-10 times more experimental metastases than NEO cells. The higher metastatic ability of IFN-gamma clones was attributed to increased resistance to NK cells since, in NK-depleted BALB/c mice, metastatic spread of IFN-gamma clones was not enhanced, whereas a 50-fold increase in the number of metastases was found upon injection of NEO cells.
Lollini
P L
PL
Istituto di Cancerologia, Università di Bologna, Italy.
Bosco
M C
MC
Cavallo
F
F
De Giovanni
C
C
Giovarelli
M
M
Landuzzi
L
L
Musiani
P
P
Modesti
A
A
Nicoletti
G
G
Palmieri
G
G
D000230:Adenocarcinoma / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D000818:Animals; D000951:Antigens, Neoplasm / Q000032:analysis; D000954:Antigens, Surface / Q000032:analysis; D001943:Breast Neoplasms / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D002455:Cell Division / Q000187:drug effects / Q000276:immunology; D003001:Cloning, Molecular; D003601:Cytotoxicity Tests, Immunologic; D003602:Cytotoxicity, Immunologic; D005260:Female; D007371:Interferon-gamma / Q000235:genetics / Q000494:pharmacology / Q000502:physiology; D008175:Lung Neoplasms / Q000276:immunology* / Q000473:pathology / Q000556:secondary*; D008562:Membrane Glycoproteins / Q000032:analysis; D051379:Mice; D008807:Mice, Inbred BALB C; D009362:Neoplasm Metastasis / Q000276:immunology; D014162:Transfection
D000951:Antigens, Neoplasm; D000954:Antigens, Surface; D008562:Membrane Glycoproteins; D007371:Interferon-gamma