Augmented expression of cytokines in mouse epidermal tumor cells and its possible involvement in the induction of hematopoietic alterations.
Mice with skin tumors induced either by 7,12-dimethylbenz[a]anthracene complete carcinogenesis or subcutaneous injection of a carcinogenic keratinocyte cell line showed moderate to severe splenomegaly as a result of an increase in splenic granulocyte-macrophage and erythroid (erythroid burst-forming unit) progenitors. To test whether the observed alterations involve the release of soluble factors by the epidermal component of skin tumors, we used an in vitro approach. A series of mouse keratinocyte cell lines resembling progressive stages of skin carcinogenesis and carrying either normal or activated Ha-ras genes were assayed for their ability to produce the factors required for colony growth of hematopoietic-committed progenitors. Only the conditioned media of keratinocytes harboring activated Ha-ras genes were able to support the growth of granulocyte-macrophage colony-forming units. In addition, preincubation of normal bone-marrow cells with conditioned media from the transformed epidermal cell lines stimulated in vitro amplification of the hematopoietic granulocyte-macrophage progenitor compartment. To identify the possible factors responsible for the activities detected in the keratinocyte-conditioned media, we performed northern blot analysis using the cytokine probes granulocyte colony-stimulating factor, macrophage colony-stimulating factor, granulocyte-macrophage colony-stimulating factor, stem cell factor, interleukin-1 alpha, interleukin-3, and tumor necrosis factor-alpha. The cell lines expressed different cytokine mRNA combinations that positively correlated with the colony-stimulating activity detected in the corresponding conditioned medium. These results suggest that transformed epidermal tumor cells in vivo may alter normal hematopoiesis as a consequence of the production of cytokines that act in autocrine or paracrine loops probably related to tumor growth.
Bauluz
C
C
Department of Cell and Molecular Biology, Centro de Investigaciones Energéticas, Medioambientales, y Tecnológicas, Madrid, Spain.
Larcher
F
F
Ballestin
C
C
Grande
T
T
Jorcano
J L
JL
D015127:9,10-Dimethyl-1,2-benzanthracene; D000818:Animals; D001854:Bone Marrow Cells; D002460:Cell Line; D016207:Cytokines / Q000096:biosynthesis* / Q000235:genetics; D005260:Female; D015870:Gene Expression; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000502:physiology*; D015603:Keratinocytes / Q000378:metabolism / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012878:Skin Neoplasms / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism*; D013154:Spleen / Q000166:cytology; D014407:Tumor Cells, Cultured
D016207:Cytokines; D012333:RNA, Messenger; D015127:9,10-Dimethyl-1,2-benzanthracene