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Temporal heterogeneity in oxygen tension in human melanoma xenografts.

ABSTRACT: The spatial heterogeneity of the oxygen tension (pO(2)) in human and experimental tumours has been studied extensively, whereas studies of the temporal heterogeneity in pO(2) are sparse. In the work reported here, pO(2) was measured continuously over periods of at least 60 min in A-07 human melanoma xenografts by using the OxyLite fibre-optic oxygen-sensing device. The main purpose of the work was to establish the usefulness of the OxyLite system in measuring the temporal heterogeneity in pO(2) in tissues and to characterise the fluctuations in tissue pO(2) in A-07 tumours. The OxyLite device was found to be suitable for studies of the temporal heterogeneity in pO(2) in tumours. However, potential pitfalls were identified, and reliable pO(2) measurements require that precautions are taken to avoid these pitfalls, that is, erroneous pO(2) readings caused by tissue trauma induced by the probe, probe movements induced by reflex actions of the host mouse and occasional probe drift. Significant fluctuations in pO(2) were detected in the majority of the 70 tumour regions subjected to measurement. The fluctuations in different regions of the same tumour were in general temporally independent, implying that they were caused primarily by redistribution of the tumour perfusion rather than fluctuations in global perfusion. Fourier analysis of the pO(2) traces showed that the pO(2) usually fluctuated at frequencies lower than 1.5-2.0 mHz, corresponding to less than 0.1 cycle min(-1). Haemodynamic effects may cause pO(2) fluctuations in this frequency range, and hence, the redistribution of the perfusion could have been caused by morphological abnormalities of the tumour microvasculature. Moreover, acute hypoxia, that is, pO(2) fluctuations around 10 or 5 mmHg, was detected in 20 of 70 regions, that is, 29% (10 mmHg), or 27 of 70 regions, that is, 39% (5 mmHg). The median fraction of the time these regions were acutely hypoxic was 73% (10 mmHg) or 53% (5 mmHg). Consequently, if A-07 tumours are adequate models of tumours in man, acute hypoxia may be a commonly occurring phenomenon in neoplastic tissues, and hence, acute hypoxia is likely to cause resistance to radiation therapy and promote tumour aggressiveness.

SUBMITTER: Brurberg KG

PROVIDER: S-EPMC2394245 | biostudies-other | 2003 Jul

REPOSITORIES: biostudies-other

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Project description:Unlabelled: Mesenchymal stem cells (MSCs) have captured the attention and research endeavors of the scientific world because of their differentiation potential. However, there is accumulating evidence suggesting that the beneficial effects of MSCs are predominantly due to the multitude of bioactive mediators secreted by these cells. Because the paracrine potential of MSCs is closely related to their microenvironment, the present study investigated and characterized select aspects of the human MSC (hMSC) secretome and assessed its in vitro and in vivo bioactivity as a function of oxygen tension, specifically near anoxia (0.1% O2) and hypoxia (5% O2), conditions that reflect the environment to which MSCs are exposed during MSC-based therapies in vivo. In contrast to supernatant conditioned media (CM) obtained from hMSCs cultured at either 5% or 21% of O2, CM from hMSCs cultured under near anoxia exhibited significantly (p < .05) enhanced chemotactic and proangiogenic properties and a significant (p < .05) decrease in the inflammatory mediator content. An analysis of the hMSC secretome revealed a specific profile under near anoxia: hMSCs increase their paracrine expression of the angiogenic mediators vascular endothelial growth factor (VEGF)-A, VEGF-C, interleukin-8, RANTES, and monocyte chemoattractant protein 1 but significantly decrease expression of several inflammatory/immunomodulatory mediators. These findings provide new evidence that elucidates aspects of great importance for the use of MSCs in regenerative medicine and could contribute to improving the efficacy of such therapies.SignificanceThe present study investigated and characterized select aspects of the human mesenchymal stem cell (hMSC) secretome and assessed its in vitro and in vivo biological bioactivity as a function of oxygen tension, specifically near anoxia (0.1% O2) and hypoxia (5% O2), conditions that reflect the environment to which MSCs are exposed during MSC-based therapies in vivo. The present study provided the first evidence of a shift of the hMSC cytokine signature induced by oxygen tension, particularly near anoxia (0.1% O2). Conditioned media obtained from hMSCs cultured under near anoxia exhibited significantly enhanced chemotactic and proangiogenic properties and a significant decrease in the inflammatory mediator content. These findings provide new evidence that elucidates aspects of great importance for the use of MSCs in regenerative medicine, could contribute to improving the efficacy of such therapies, and most importantly highlighted the interest in using conditioned media in therapeutic modalities.

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Temporal heterogeneity in oxygen tension in human melanoma xenografts.

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