A possible factor in genetic instability of cancer cells: stress-induced secreted proteins lead to decrease in replication fidelity

Abstract

Ultraviolet irradiation triggers a response in mammalian cells known as the UV response. Part of the UV response forms the enhanced synthesis of various extracellular proteins able to transmit the response to non-irradiated cells. Because several cancer-prone syndromes with enhanced genetic instability also have an enhanced synthesis of the same set of proteins without prior stimulation it is possible that induction of these stress responsive proteins may be involved in the process of carcinogenesis and genetic instability. To test this hypothesis mouse T lymphoma cells, GRSL13, were treated with the conditioned medium of UV-induced cells under various experimental conditions. Overall the mutation rate is enhanced 1.8-fold (P < 0.01). However, the degree of enhancement is strongly influenced by culture conditions. UV-induced factors only lead to an enhanced mutation rate when cells, both for the production and response to those factors, originate from a similar cell density. In addition, it was found that fresh medium interferes with this response. To eliminate the hindrance of these factors on the effect of the conditioned medium on the mutation rate, serum-starved cells at high density were treated with serum-free medium derived from high-density UV-irradiated cultures. Using these conditions a 2.8-fold (P < 0.002) enhancement of the mutation rate was found. Fluctuation analysis indicated that the enhancement is 10-fold during the first five generations after treatment. UV-induced factors have also been found to induce cell growth, and the degree of induction was linearly correlated with the enhancement in mutation rate. These experiments are in agreement with the hypothesis that induction of stress responses leads to genetic instability.

Ultraviolet radiation and skin cancer: molecular mechanisms

“…Subsequently, these proteins promote activation of the genes encoding extracellular proteins, 109 cytokines, 110 and several yet unidentified proteins. These proteins are also involved in inducing replication infidelity and favor genetic instability 107,111,112 …”

Genomic instability in radial growth phase melanoma cell lines after ultraviolet irradiation

“…These three protein classes are also involved in inducing replication infidelity, and may favour genetic instability and oncogenic transformation. 4 48 In support of this concept, the secretion of these proteins was found to induce genetic instability in mouse T lymphoma cell lines after UVR, 4 and oxidative stress induced DNA damage, replication infidelity, or a combination of these factors some of these proteins are constitutively expressed in several cancer prone syndromes 49 and tumour cell lines. 50 The absence of LOH after UV irradiation in WM cells is in agreement with previous studies, 51 and suggests that the initial genetic events after UVR do not include LOH at an early stage.…”

“…The incorrect repair of these products generates mutations and increases genetic instability. 2 3 Exposure to UVB also leads to transcriptional activation of several oncogenes, 4 and the generation of photoxidative stress, which inhibits the anti-oxidative defence mechanisms. 5 In contrast, UVA genotoxicity is induced by the generation of reactive oxygen radicals, 6 which can cause DNA damage that is potentially tumorigenic.…”

Radiation‐induced genomic instability: A role for secreted soluble factors in communicating the radiation response to non‐irradiated cells

“…There is evidence in the literature that stress induced secreted proteins can lead to decreased replication fidelity and subsequent genomic instability in cells irradiated with non-ionizing ultra violet radiation [Boesen et al, 1992] and that induced extracellular factors can communicate the ultra violet light response to nonirradiated cells [Schorpp et al, 1984]. This emphasizes the point that soluble factors may have a generic role in the long-term consequences of cellular exposure to DNA damaging agents.…”