Formation and growth of multicellular spheroids of human origin

Carlsson, Jörgen; Nilsson, Kenneth; Westermark, Bengt; Pontén, Jan; Sundström, Christer; Larsson, Erik; Bergh, Jonas; Påhlman, Sven; Busch, Christer; Vp, Collins

doi:10.1002/ijc.2910310502

Cited by 141 publications

(103 citation statements)

References 38 publications

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“…Observations of such an effect were initially made decades ago (Warburg, 1956), and experiments with V79 and EMT6 spheroids have shown such an effect (Freyer et al, 1984;Freyer and Sutherland, 1985). Also, necrosis has been observed in human glioma spheroids at relatively high central oxygen levels as determined by microelectrodes (Carlsson et al, 1979(Carlsson et al, , 1983. If down-regulation of oxygen consumption was coordinated at a microregional level, it might provide an explanation for the variable presence of severe hypoxia adjacent to necrosis, as indicated by nitroimidazole binding in the xenografts.…”

Section: Discussionmentioning

confidence: 99%

Anomalous patterns of nitroimidazole binding adjacent to necrosis in human glioma xenografts: possible role of decreased oxygen consumption

Parliament¹,

Franko²,

Allalunis-Turner³

et al. 1997

Br J Cancer

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Summary In contrast to reports of extensive hypoxia in human gliomas in situ measured by P02 histography, non-invasive methods of assessing glioma oxygenation, including nitroimidazole binding, have yielded surprisingly contradictory results. In order to investigate the relationship of necrosis, hypoxia, nitroreductase activity and cellular respiration in human gliomas, subcutaneous models using the human glioma cell lines M059K, M006 and M01 Ob were developed in the murine SCID host. Intracranial growth of the M006 line was achieved in nude rats. The nitroreductive capacity of glioma cell lines was assessed and found to be similar to transplanted tumours previously reported in the literature. This suggests that if substantial numbers of viable hypoxic cells were present in situ in gliomas, then nitroimidazole-binding techniques should be capable of identifying them. Inter-tumour variability in the amount of necrosis was seen. M006 xenografts growing in subcutaneous and intracranial sites revealed extensive necrotic regions histologically, some of which were surrounded by cells labelled heavily for [3H]misonidazole, while other areas were lightly labelled. Similar binding patterns were seen for subcutaneous M059K tumours, while subcutaneous M01 Ob tumours display necroses of which almost all were surrounded by heavily labelled cells. The oxygen consumption rates of tumour cell lines grown in vivo, in which venous P02 concentrations are of the order of 2-5%, were two to sevenfold less than those of the same lines grown as monolayers in vitro under oxygen concentrations of 18%. We postulate that glioma cell lines behave as 'oxygen conformers', in that their rate of oxygen consumption appears to vary with the availability of oxygen. Together with the misonidazole-binding data, the results in this glioma tumour model are consistent with coordinate inhibition or down-regulation of respiration under moderate hypoxia.

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Section: Discussionmentioning

confidence: 99%

Anomalous patterns of nitroimidazole binding adjacent to necrosis in human glioma xenografts: possible role of decreased oxygen consumption

Parliament¹,

Franko²,

Allalunis-Turner³

et al. 1997

Br J Cancer

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“…The 6 different human anaplastic thyroid carcinoma cell lines used in our study have been characterized previously: C643; 21,22 HTh 7; 23 HTh 74; 24 HTh 83; 9 and KAT-4. 25 The KAT-4 cell line was obtained from Dr. K.B.…”

Section: Cell Culturementioning

confidence: 99%

Collagen type I expression in experimental anaplastic thyroid carcinoma: Regulation and relevance for tumorigenicity

Dahlman

Lammerts

Bergström

et al. 2001

Intl Journal of Cancer

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Fibrosis in solid malignancies plays a significant role in tumor pathophysiology. Potential mechanisms for collagen type I deposition in anaplastic thyroid carcinoma (ATC) were investigated using 6 characterized ATC cell lines. Three of these cell lines, which produced collagen type I, had, as a group, a poor tumorigenicity when inoculated in athymic mice. This group of cells generated tumors in 4 of 24 injected animals (17%). Pro-␣1(I) collagen mRNA-expressing carcinoma and stromal cells were interdispersed in the tumors generated by these ATC cells. By contrast, the 3 noncollagen-producing ATC cell lines were all tumorigenic with a tumor take of 60% in the whole group. In the latter tumors, pro-␣1(I) collagen mRNA-expressing cells were confined to the stromal compartment, well delineated from carcinoma cell islets. To study the influence of ATC cells on collagen type I synthesis by fibroblasts, we used AG 1518 diploid human fibroblasts cultured on poly-(2-hydroxyethyl methacrylate) (poly[HEMA])-coated plates. This culture condition allows the study of the effect of collagen mRNA translation in the regulation of collagen type I synthesis. Conditioned media from the 6 ATC cell lines did not influence collagen synthesis. The ATC cell line KAT-4 stimulated fibroblast synthesis of collagen type I when the two cell types were cocultured on poly[HEMA]-coated substrates. Specific inhibitors of PDGF and TGF-␤ reduced the KAT 4 carcinoma cell-induced stimulation of collagen type I synthesis. Our data suggest that collagen type I production by carcinoma cells correlates negatively with tumorigenicity and that the formation of a well-defined stroma is of importance for tumor growth. Furthermore, our data suggest that tumor cells are able to stimulate collagen mRNA translation in stromal fibroblasts in direct cell-cell contact by, at least in part, transferring PDGF or TGF-␤.

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“…However, it is well known that cells growing under different environmental conditions may respond differently to specific therapeutic procedures. Factors such as nutrient supply, oxygen tension, pH and other microenvironmental conditions may affect the cellular sensitivity to paclitaxel (Carlsson et al, 1983;Mueller-Klieser, 1987). The three-dimensional arrangement of multicellular spheroids provides a cellular micromilieu that includes different environmental conditions in different parts of the spheroid, and it has been shown that spheroids from both normal and malignant tissues maintain several biochemical and morphological characteristics similar to those present in the corresponding tissue in vivo (Sutherland et al, 1986;Sutherland, 1988).…”

mentioning

confidence: 99%

Proliferation, migration and invasion of human glioma cells exposed to paclitaxel (Taxol) in vitro

Terzis

Thorsen²,

Heese³

et al. 1997

Br J Cancer

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Summary Paclitaxel (Taxol), an anti-cancer drug derived from Taxus species, was tested for its anti-migrational, anti-invasive and antiproliferative effect on two human glioma cell lines (GaMg and D-54Mg) grown as multicellular tumour spheroids. In addition, the direct effect of paclitaxel on glioma cells was studied using flow cytometry and scanning confocal microscopy. Both cell lines showed a dose-dependent growth and migratory response to paclitaxel. The GaMg cells were found to be 5-10 times more sensitive to paclitaxel than D-54Mg cells. Paclitaxel also proved to be remarkably effective in preventing invasion in a co-culture system in which tumour spheroids were confronted with fetal rat brain cell aggregates. Control experiments with Cremophor EL (the solvent of paclitaxel for clinical use) in this study showed no effect on tumour cell migration, cell proliferation or cell invasion. Scanning confocal microscopy of both cell lines showed an extensive random organization of the microtubules in the cytoplasm. After paclitaxel exposure, the GaMg and the D-54Mg cells exhibited a fragmentation of the nuclear material, indicating a possible induction of apoptosis. In line with this, flow cytometric DNA histograms showed an accumulation of cells in the G/M phase of the cell cycle after 24 h of paclitaxel exposure. After 48 h, a deterioration of the DNA histograms was observed indicating nuclear fragmentation.

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Formation and growth of multicellular spheroids of human origin

Cited by 141 publications

References 38 publications

Anomalous patterns of nitroimidazole binding adjacent to necrosis in human glioma xenografts: possible role of decreased oxygen consumption

Anomalous patterns of nitroimidazole binding adjacent to necrosis in human glioma xenografts: possible role of decreased oxygen consumption

Collagen type I expression in experimental anaplastic thyroid carcinoma: Regulation and relevance for tumorigenicity

Proliferation, migration and invasion of human glioma cells exposed to paclitaxel (Taxol) in vitro

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