Cell killing, radiosensitization and cell cycle redistribution induced by chronic hypoxia

Spiro, Ira J.; Rice, Glenn C.; Durand, Ralph E.; Stickler, Rebecca; Ling, C. Clifton

doi:10.1016/0360-3016(84)90332-8

Cited by 49 publications

(33 citation statements)

References 5 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The detachment of viable cells is an interesting finding as it is commonly perceived that detachment of cells by stress-inducing agents is indicative of cell death by apoptosis. Hypoxia is known to be toxic to cells in culture (Shrieve et al, 1983;Spiro et al, 1984) and is also reported to induce DNA damage-independent apoptosis in cells, including those of the HT29 line (Yao et al, 1995). This might help to explain our finding that HT29 only partly recovered after detachment by hypoxia.…”

Section: Discussionmentioning

confidence: 54%

Hypoxia facilitates tumour cell detachment by reducing expression of surface adhesion molecules and adhesion to extracellular matrices without loss of cell viability

Hasan

Adams²,

Joiner³

et al. 1998

Br J Cancer

View full text Add to dashboard Cite

Summary The effects of acute hypoxia on integrin expression and adhesion to extracellular matrix proteins were investigated in two human melanoma cell lines, HMB-2 and DX3, and a human adenocarcinoma cell line, HT29. Exposure to hypoxia caused a significant downregulation of cell surface integrins and an associated decrease in cell adhesion. Loss of cell adhesion and integrin expression were transient and levels returned to normal within 24 h of reoxygenation. Other cell adhesion molecules, such as CD44 and N-CAM, were also downregulated after exposure of cells to hypoxia. Acute exposure to hypoxia of cells at confluence caused rapid cell detachment. Cell detachment preceded loss of viability. Detached HMB-2 and DX3 cells completely recovered upon reoxygenation, and floating cells re-attached and continued to grow irrespective of whether they were left in the original glass dishes or transferred to new culture vessels, while detached HT29 cells partly recovered upon reoxygenation. Cell detachment after decreased adhesion appears to be a stress response, which may be a factor enabling malignant cells to escape hypoxia in vivo, with the potential to form new foci of tumour growth.

show abstract

Section: Discussionmentioning

confidence: 54%

Hypoxia facilitates tumour cell detachment by reducing expression of surface adhesion molecules and adhesion to extracellular matrices without loss of cell viability

Hasan

Adams²,

Joiner³

et al. 1998

Br J Cancer

View full text Add to dashboard Cite

show abstract

“…Prolonged hypoxia treatment also resulted in inactivation of a significant fraction of the D-12 cells. Since cell inactivation by hypoxia can be cell cycle-dependent (Spiro et al, 1984), the cell cycle distribution of the noninactivated D-12 cells might have differed from that of the aerobic control cells. The lung colonization ability of cells can depend on their position in the cell cycle (Suzuki et al, 1977).…”

Section: Discussionmentioning

confidence: 99%

Hypoxia-induced metastasis of human melanoma cells: involvement of vascular endothelial growth factor-mediated angiogenesis

1999

View full text Add to dashboard Cite

Tumour cells exposed to hypoxia have been shown to up-regulate the expression of vascular endothelial growth factor (VEGF). The purpose of the present work was to investigate whether hypoxia-induced VEGF up-regulation can result in increased metastatic efficiency of human melanoma cells. Two melanoma lines, one showing high (A-07) and the other showing low (D-12) VEGF secretion under aerobic conditions, were included in the study. Cell cultures were exposed to hypoxia (oxygen concentrations < 10 ppm) in vitro and metastatic efficiency, i.e. lung colonization efficiency, as well as transplantability and angiogenic potential were assessed in BALB/c- nu/nu mice. Both cell lines showed significantly increased VEGF secretion under hypoxic conditions as measured by enzyme-linked immunosorbent assay. The D-12 cells showed increased metastatic efficiency, transplantability and angiogenic potential following exposure to hypoxia. The metastatic efficiency increased with the duration of the hypoxia treatment and decreased with the time after reoxygenation. The A-07 cells on the other hand showed unchanged metastatic efficiency, transplantability and angiogenic potential following exposure to hypoxia. Both cell lines showed significantly decreased metastatic efficiency and angiogenic potential in mice treated with neutralizing antibody against VEGF. These results suggest that (a) VEGF is a limiting factor for the rate of angiogenesis in low but not in high VEGF-expressing melanomas under normoxic conditions and (b) transient hypoxia might promote the development of metastases in low VEGF-expressing melanomas by upregulating the expression of VEGF and hence enhancing the angiogenic potential of the tumour cells. © 1999 Cancer Research Campaign

show abstract

“…The slow dephosphorylation of pRB, however, can explain why cells that are in G2 at the onset of hypoxia complete the cell cycle and enter GI of the next cell cycle during hypoxia (Figure 2). Hypoxic stress, which becomes increasingly toxic with time, particularly to cells in Sphase (Merz and Schneider, 1983;Spiro et al, 1984;Amellem and Pettersen, 1991a), may activate pRB to prevent harmful effects that could follow from continued DNA replication during hypoxia. Several lines of evidence have linked the under-phosphorylated form of pRB to its role as an inhibitor of cell cycle progression through G, (reviewed by Weinberg, 1995).…”

Section: Discussion Cell Cycle Regulation During Moderate Hypoxia In mentioning

confidence: 99%

“…Cells in the G, phase have developed such protective properties (Merz and Schneider, 1983;Spiro et al, 1984;Amellem and Pettersen, 1991a). Recent studies have indicated that the tumour suppressor proteins, p53 and pRB, play important roles in the maintenance of cellular homeostasis under and after hypoxic stress (Graeber et al, 1996;Amellem et al, 1996Amellem et al, , 1997.…”

mentioning

confidence: 99%

The retinoblastoma protein-associated cell cycle arrest in S-phase under moderate hypoxia is disrupted in cells expressing HPV18 E7 oncoprotein

Åmellem

Sandvik²,

Stokke³

et al. 1998

Br J Cancer

View full text Add to dashboard Cite

Summary We have studied the role of the oxygen-dependent pyrimidine metabolism in the regulation of cell cycle progression under moderate hypoxia in human cell lines containing functional (T-47D) or non-functional (NHIK 3025, SAOS-2) retinoblastoma gene product (pRB). Under aerobic conditions, pRB exerts its growth-regulatory effects during early G, phase of the cell cycle, when all pRB present has been assumed to be in the underphosphorylated form and bound in the nucleus. We demonstrate that pRB is dephosphorylated and re-bound in the nucleus in approximately 90% of T-47D cells located in S and G2 phases under moderately hypoxic conditions. Under these conditions, no T-47D cells entered S-phase, and no progression through S-phase was observed. Progression of cells through G2 and mitosis seems independent of their functional pRB status. The p21 WAF1/CIP1 protein level was significantly reduced by moderate hypoxia in p53-deficient T-47D cells, whereas p1 6INK4a was not expressed in these cells, suggesting that the hypoxia-induced cell cycle arrest is independent of these cyclindependent kinase inhibitors. The addition of pyrimidine deoxynucleosides did not release T-47D cells, containing mainly underphosphorylated pRB, from the cell cycle arrest induced by moderate hypoxia. However, NHIK 3025 cells, in which pRB is abrogated by expression of the HPV18 E7 oncoprotein, and SAOS-2 cells, which lack pRB expression, continued cell cycle progression under moderate hypoxia provided that excess pyrimidine deoxynucleosides were present. NHIK 3025 cells express high levels of p16INK4a under both aerobic and moderately hypoxic conditions, suggesting that the inhibitory function of p1 6INK4a would not be manifested in such pRB-deficient cells. Thus, pRB, a key member of the cell cycle checkpoint network, seems to play a major role by inducing growth arrest under moderate hypoxia, and it gradually overrides hypoxia-induced suppression of pyrimidine metabolism in the regulation of progression through S-phase under such conditions.

show abstract

Cell killing, radiosensitization and cell cycle redistribution induced by chronic hypoxia

Cited by 49 publications

References 5 publications

Hypoxia facilitates tumour cell detachment by reducing expression of surface adhesion molecules and adhesion to extracellular matrices without loss of cell viability

Hypoxia facilitates tumour cell detachment by reducing expression of surface adhesion molecules and adhesion to extracellular matrices without loss of cell viability

Hypoxia-induced metastasis of human melanoma cells: involvement of vascular endothelial growth factor-mediated angiogenesis

The retinoblastoma protein-associated cell cycle arrest in S-phase under moderate hypoxia is disrupted in cells expressing HPV18 E7 oncoprotein

Contact Info

Product

Resources

About