Intravascular HbO2 saturations, perfusion and hypoxia in spontaneous and transplanted tumor models

Fenton, Bruce M.; Lord, Edith M.; Paoni, Scott F.

doi:10.1002/ijc.1401

Cited by 19 publications

(13 citation statements)

References 24 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…S4), suggesting that endothelial cell apoptosis does not contribute to the radiation response of primary sarcomas. Because previous studies have demonstrated differences between the vasculature of transplanted and primary cancers (15, 31, 32), our discordant results on the contribution of endothelial cell death might reflect differences in the vasculatures of tumors derived from transplanted cell lines versus the autochthonous tumors studied herein. Taken together, these findings illustrate the importance of studying the tumor microenvironment using multiple complementary models, including GEMMs.…”

Section: Resultsmentioning

confidence: 58%

Tumor cells, but not endothelial cells, mediate eradication of primary sarcomas by stereotactic body radiation therapy

et al. 2015

View full text Add to dashboard Cite

Cancer clinics currently use high-dose stereotactic body radiation therapy as a curative treatment for several kinds of cancers. However, the contribution of vascular endothelial cells to tumor response to radiation remains controversial. Using dual-recombinase technology, we generated primary sarcomas in mice with targeted genetic mutations specifically in tumor cells or endothelial cells. We selectively mutated the proapoptotic gene Bax or the DNA damage–response gene Atm to genetically manipulate the radiosensitivity of endothelial cells in primary soft tissue sarcomas. Bax deletion from endothelial cells did not affect radiation-induced cell death in tumor endothelial cells or sarcoma response to radiation therapy. Although Atm deletion increased endothelial cell death after radiation therapy, deletion of Atm from endothelial cells failed to enhance sarcoma eradication. In contrast, deletion of Atm from tumor cells increased sarcoma eradication by radiation therapy. These results demonstrate that tumor cells, rather than endothelial cells, are critical targets that regulate sarcoma eradication by radiation therapy. Treatment with BEZ235, a small-molecule protein kinase inhibitor, radiosensitized primary sarcomas more than hearts. These results suggest that inhibiting ATM kinase during radiation therapy is a viable strategy for radiosensitization of some tumors.

show abstract

Section: Resultsmentioning

confidence: 58%

Tumor cells, but not endothelial cells, mediate eradication of primary sarcomas by stereotactic body radiation therapy

et al. 2015

View full text Add to dashboard Cite

show abstract

“…In contrast, immunohistochemical staining of hypoxia markers permits microregional variations in hypoxia to be spatially mapped in two dimensions across an entire tumour section. By comparing the hypoxia marker images with corresponding images of vessel staining, proliferation markers, or angiogenic/anti-angiogenic cytokines, relationships among a variety of pathophysiological factors can also be correlated (Fenton et al, 2001b;Wijffels et al, 2001;Rijken et al, 2000;Zeman et al, 1993).…”

Section: Discussionmentioning

confidence: 99%

“…Although this analysis is relatively straight-forward and corresponds to the notion of tumour hypoxic fraction, a substantial amount of information is not taken into account. Another approach has been to measure mean hypoxia marker intensities (Evans et al, 2001;Fenton, 2001;Fenton et al, 2001b), which again provides only an overall appraisal of changes in tumour hypoxia. Here, results can be especially misleading in the presence of large regions of necrosis, which do not metabolize EF5.…”

Section: Discussionmentioning

confidence: 99%

Zonal image analysis of tumour vascular perfusion, hypoxia, and necrosis

et al. 2002

View full text Add to dashboard Cite

A number of laboratories are utilising both hypoxia and perfusion markers to spatially quantify tumour oxygenation and vascular distributions, and scientists are increasingly turning to automated image analysis methods to quantify such interrelationships. In these studies, the presence of regions of necrosis in the immunohistochemical sections remains a potentially significant source of error. In the present work, frozen MCa-4 mammary tumour sections were used to obtain a series of corresponding image montages. Total vessels were identified using CD31 staining, perfused vessels by DiOC 7 staining, hypoxia by EF5/Cy3 uptake, and necrosis by haematoxylin and eosin staining. Our goal was to utilise image analysis techniques to spatially quantitate hypoxic marker binding as a function of distance from the nearest blood vessel. Several refinements to previous imaging methods are described: (1) hypoxia marker images are quantified in terms of their intensity levels, thus providing an analysis of the gradients in hypoxia with increasing distances from blood vessels, (2) zonal imaging masks are derived, which permit spatial sampling of images at precisely defined distances from blood vessels, as well as the omission of necrotic artifacts, (3) thresholding techniques are applied to omit holes in the tissue sections, and (4) The relationship between tumour hypoxia and therapeutic response has been well documented in the literature for quite some time, and direct measures of tumour oxygenation have been shown to correlate with both long-term survival (Hockel et al, 1996) and the occurrence of distant metastases (Brizel et al, 1996). Two of the more prominent techniques for measuring tumour hypoxia are: (1) the Eppendorf electrode for determination of tumour pO 2 levels, and (2) nitroimidazole hypoxia markers, e.g., EF5, NITP, and pimonidazole, which covalently bind to hypoxic tumour cells and allow immunohistochemical or flow cytometric determination of hypoxia distributions (Koch et al, 1995;Hodgkiss and Wardman, 1992;Raleigh et al, 1987). The presence of tumour necrosis can have substantial effects on each of these types of measurements. With the Eppendorf technique, necrotic regions result in a reduction in measured pO 2 levels that is not reflective of a corresponding reduction in clonogenic survival of the tumour cells (Fenton et al, 1995). This leads to overestimates of the fraction of radiobiologically resistant tumour cells. In the case of hypoxia markers, regions of necrosis can also lead to inaccurate predictions in overall tumour hypoxia. Since these drugs are not metabolized in necrotic areas, such regions appear well oxygenated and lead instead to an underestimate of overall tumour hypoxia. Several recent studies have described methods for quantifying hypoxia marker distribution as a function of distance from either perfused or anatomical blood vessels. The first (Rijken et al, 2000) is an elegant, multiparameter analysis of vascularity, perfusion, and hypoxia that characterises uptake of two hypoxia markers,...

show abstract

“…These discordant results may reflect differences between melanomas and sarcomas or differences in the tumor vasculature between tumors derived from cell lines and autochthonous tumors. Previous studies have demonstrated that the structure, oxygenation, perfusion, and response to therapy of tumor vasculature changes with transplantation (19,48,49). Genetically engineered mouse models (GEMMs), such as the soft tissue sarcoma model used in the present study, develop within the native tumor microenvironment in immunocompetent mice (50) and may more faithfully recapitulate the tumor stroma and microenvironment of human cancer compared with xenograft models (51).…”

Section: Loss Of Atm Sensitizes Proliferating But Not Quiescent Endmentioning

confidence: 93%

Atm deletion with dual recombinase technology preferentially radiosensitizes tumor endothelium

Moding¹,

Lee²,

Castle³

et al. 2014

J. Clin. Invest.

View full text Add to dashboard Cite

Intravascular HbO2 saturations, perfusion and hypoxia in spontaneous and transplanted tumor models

Cited by 19 publications

References 24 publications

Tumor cells, but not endothelial cells, mediate eradication of primary sarcomas by stereotactic body radiation therapy

Tumor cells, but not endothelial cells, mediate eradication of primary sarcomas by stereotactic body radiation therapy

Zonal image analysis of tumour vascular perfusion, hypoxia, and necrosis

Atm deletion with dual recombinase technology preferentially radiosensitizes tumor endothelium

Contact Info

Product

Resources

About