Activated stress response pathways within multicellular aggregates utilize an autocrine component.
Multicellular aggregates (spheroids) of primary human foreskin fibroblasts (HFF-2) and a glioblastoma cell line (T98G) entered and exited from long term (2 weeks) metabolic arrest utilizing an autocrine response. Cytokine production (specifically IFN-gamma) activated a Gadd45alpha/p38 pathway that led to increased AP-1 (c-jun and ATF3) transcription factor levels, augmenting cytokine production in an autocrine fashion. Whereas HFF-2 aggregates were capable of surviving long term arrest and recovery during NF-kappaB inhibition independent of JNK activation, T98G aggregates were not. Such endogenous processes are not easily observed with adherent monolayer cell culturing systems, strongly suggesting that more emphasis needs to be placed on determining the operational signal transduction cascades within multicellular aggregates. Extracellular inputs such as spheroid formation, arrest, and regrowth as monolayers invoke intracellular signaling responses converging at the AP-1 transcription factor level. Variations in responses are both cell type and transformation state dependent and require an autocrine cytokine component. The data are discussed in relation to the wounding response and avascular tumor growth mechanisms.
Jack
Graham D
GD
Department of Biochemistry, Virginia Tech, Blacksburg, VA 24061, USA.
Cabrera
M Carla
MC
Manning
Michael L
ML
Slaughter
Stephen M
SM
Potts
Malcolm
M
Helm
Richard F
RF
D019898:Autocrine Communication; D002453:Cell Cycle; D002460:Cell Line; D002470:Cell Survival; D016207:Cytokines / Q000378:metabolism; D005347:Fibroblasts; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D005909:Glioblastoma / Q000235:genetics / Q000473:pathology*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D016328:NF-kappa B / Q000037:antagonists & inhibitors; D015398:Signal Transduction; D018874:Spheroids, Cellular / Q000166:cytology* / Q000378:metabolism*; D013997:Time Factors; D014157:Transcription Factors / Q000378:metabolism; D014407:Tumor Cells, Cultured; D000097642:GADD45 Proteins
D016207:Cytokines; D047908:Intracellular Signaling Peptides and Proteins; D016328:NF-kappa B; D014157:Transcription Factors; D000097642:GADD45 Proteins