Micro regional heterogeneity of 64Cu-ATSM and 18F-FDG uptake in canine soft tissue sarcomas: relation to cell proliferation, hypoxia and glycolysis

Kamilla Westarp Zornhagen; Anders E Hansen; Jytte Oxbøl; Andreas Ettrup Clemmensen; Henrik H. El Ali; Annemarie Thuri Kristensen; Andreas Kjær

doi:10.1371/journal.pone.0141379

Micro regional heterogeneity of ⁶⁴Cu-ATSM and ¹⁸F-FDG uptake in canine soft tissue sarcomas: relation to cell proliferation, hypoxia and glycolysis

Kamilla Westarp Zornhagen, Anders E Hansen, Jytte Oxbøl, Andreas Ettrup Clemmensen, Henrik H. El Ali, Annemarie Thuri Kristensen, Andreas Kjær

2 Citationer (Scopus)

120 Downloads (Pure)

Abstract

Objectives Tumour microenvironment heterogeneity is believed to play a key role in cancer progression and therapy resistance. However, little is known about micro regional distribution of hypoxia, glycolysis and proliferation in spontaneous solid tumours. The overall aim was simultaneous investigation of micro regional heterogeneity of ⁶⁴Cu-ATSM (hypoxia) and ¹⁸F-FDG (glycolysis) uptake and correlation to endogenous markers of hypoxia, glycolysis, proliferation and angiogenesis to better therapeutically target aggressive tumour regions and prognosticate outcome. Methods Exploiting the different half-lives of ⁶⁴Cu-ATSM (13h) and ¹⁸F-FDG (2h) enabled simultaneous investigation of micro regional distribution of hypoxia and glycolysis in 145 tumour pieces from four spontaneous canine soft tissue sarcomas. Pairwise measurements of radioactivity and gene expression of endogenous markers of hypoxia (HIF-1a, CAIX), glycolysis (HK2, GLUT1 and GLUT3), proliferation (Ki-67) and angiogenesis (VEGFA and TF) were performed. Dual tracer autoradiography was compared with Ki-67 immunohistochemistry. Results Micro regional heterogeneity in hypoxia and glycolysis within and between tumour sections of each tumour piece was observed. The spatial distribution of ⁶⁴Cu-ATSM and ¹⁸F-FDG was rather similar within each tumour section as reflected in moderate positive significant correlations between the two tracers (? = 0.3920-0.7807; p = 0.0180 -<0.0001) based on pixel-to-pixel comparisons of autoradiographies and gamma counting of tumour pieces. ⁶⁴Cu-ATSM and ¹⁸F-FDG correlated positively with gene expression of GLUT1 and GLUT3, but negatively with HIF-1a and CAIX. Significant positive correlations were seen between Ki-67 gene expression and ⁶⁴Cu-ATSM (? = 0.5578, p = 0.0004) and ¹⁸F-FDG (? = 0.4629- 0.7001, p = 0.0001-0.0151). Ki-67 gene expression more consistently correlated with ¹⁸FFDG than with ⁶⁴Cu-ATSM. Conclusions Micro regional heterogeneity of hypoxia and glycolysis was documented in spontaneous canine soft tissue sarcomas. ⁶⁴Cu-ATSM and ¹⁸F-FDG uptakes and distributions showed significant moderate correlations at the micro regional level indicating overlapping, yet different information from the tracers.¹⁸F-FDG better reflected cell proliferation as measured by Ki-67 gene expression than ⁶⁴Cu-ATSM.

Originalsprog	Engelsk
Artikelnummer	e0141379
Tidsskrift	PloS one
Vol/bind	10
Udgave nummer	10
Antal sider	25
ISSN	1932-6203
DOI	https://doi.org/10.1371/journal.pone.0141379
Status	Udgivet - 26 okt. 2015

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Micro regional heterogeneity of 64Cu-ATSM and 18F-FDG uptake in canine soft tissue sarcomasForlagets udgivne version, 7,69 MB

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@article{e5ecd0d825d0415ba1a2150c9a2c20c3,

title = "Micro regional heterogeneity of 64Cu-ATSM and 18F-FDG uptake in canine soft tissue sarcomas: relation to cell proliferation, hypoxia and glycolysis",

abstract = "Objectives Tumour microenvironment heterogeneity is believed to play a key role in cancer progression and therapy resistance. However, little is known about micro regional distribution of hypoxia, glycolysis and proliferation in spontaneous solid tumours. The overall aim was simultaneous investigation of micro regional heterogeneity of 64Cu-ATSM (hypoxia) and 18F-FDG (glycolysis) uptake and correlation to endogenous markers of hypoxia, glycolysis, proliferation and angiogenesis to better therapeutically target aggressive tumour regions and prognosticate outcome. Methods Exploiting the different half-lives of 64Cu-ATSM (13h) and 18F-FDG (2h) enabled simultaneous investigation of micro regional distribution of hypoxia and glycolysis in 145 tumour pieces from four spontaneous canine soft tissue sarcomas. Pairwise measurements of radioactivity and gene expression of endogenous markers of hypoxia (HIF-1a, CAIX), glycolysis (HK2, GLUT1 and GLUT3), proliferation (Ki-67) and angiogenesis (VEGFA and TF) were performed. Dual tracer autoradiography was compared with Ki-67 immunohistochemistry. Results Micro regional heterogeneity in hypoxia and glycolysis within and between tumour sections of each tumour piece was observed. The spatial distribution of 64Cu-ATSM and 18F-FDG was rather similar within each tumour section as reflected in moderate positive significant correlations between the two tracers (? = 0.3920-0.7807; p = 0.0180 -<0.0001) based on pixel-to-pixel comparisons of autoradiographies and gamma counting of tumour pieces. 64Cu-ATSM and 18F-FDG correlated positively with gene expression of GLUT1 and GLUT3, but negatively with HIF-1a and CAIX. Significant positive correlations were seen between Ki-67 gene expression and 64Cu-ATSM (? = 0.5578, p = 0.0004) and 18F-FDG (? = 0.4629- 0.7001, p = 0.0001-0.0151). Ki-67 gene expression more consistently correlated with 18FFDG than with 64Cu-ATSM. Conclusions Micro regional heterogeneity of hypoxia and glycolysis was documented in spontaneous canine soft tissue sarcomas. 64Cu-ATSM and 18F-FDG uptakes and distributions showed significant moderate correlations at the micro regional level indicating overlapping, yet different information from the tracers.18F-FDG better reflected cell proliferation as measured by Ki-67 gene expression than 64Cu-ATSM.",

author = "Zornhagen, {Kamilla Westarp} and Hansen, {Anders E} and Jytte Oxb{\o}l and Clemmensen, {Andreas Ettrup} and {El Ali}, {Henrik H.} and Kristensen, {Annemarie Thuri} and Andreas Kj{\ae}r",

year = "2015",

month = oct,

day = "26",

doi = "10.1371/journal.pone.0141379",

language = "English",

volume = "10",

journal = "PLoS Computational Biology",

issn = "1932-6203",

publisher = "Public Library of Science",

number = "10",

}

TY - JOUR

T1 - Micro regional heterogeneity of 64Cu-ATSM and 18F-FDG uptake in canine soft tissue sarcomas

T2 - relation to cell proliferation, hypoxia and glycolysis

AU - Zornhagen, Kamilla Westarp

AU - Hansen, Anders E

AU - Oxbøl, Jytte

AU - Clemmensen, Andreas Ettrup

AU - El Ali, Henrik H.

AU - Kristensen, Annemarie Thuri

AU - Kjær, Andreas

PY - 2015/10/26

Y1 - 2015/10/26

N2 - Objectives Tumour microenvironment heterogeneity is believed to play a key role in cancer progression and therapy resistance. However, little is known about micro regional distribution of hypoxia, glycolysis and proliferation in spontaneous solid tumours. The overall aim was simultaneous investigation of micro regional heterogeneity of 64Cu-ATSM (hypoxia) and 18F-FDG (glycolysis) uptake and correlation to endogenous markers of hypoxia, glycolysis, proliferation and angiogenesis to better therapeutically target aggressive tumour regions and prognosticate outcome. Methods Exploiting the different half-lives of 64Cu-ATSM (13h) and 18F-FDG (2h) enabled simultaneous investigation of micro regional distribution of hypoxia and glycolysis in 145 tumour pieces from four spontaneous canine soft tissue sarcomas. Pairwise measurements of radioactivity and gene expression of endogenous markers of hypoxia (HIF-1a, CAIX), glycolysis (HK2, GLUT1 and GLUT3), proliferation (Ki-67) and angiogenesis (VEGFA and TF) were performed. Dual tracer autoradiography was compared with Ki-67 immunohistochemistry. Results Micro regional heterogeneity in hypoxia and glycolysis within and between tumour sections of each tumour piece was observed. The spatial distribution of 64Cu-ATSM and 18F-FDG was rather similar within each tumour section as reflected in moderate positive significant correlations between the two tracers (? = 0.3920-0.7807; p = 0.0180 -<0.0001) based on pixel-to-pixel comparisons of autoradiographies and gamma counting of tumour pieces. 64Cu-ATSM and 18F-FDG correlated positively with gene expression of GLUT1 and GLUT3, but negatively with HIF-1a and CAIX. Significant positive correlations were seen between Ki-67 gene expression and 64Cu-ATSM (? = 0.5578, p = 0.0004) and 18F-FDG (? = 0.4629- 0.7001, p = 0.0001-0.0151). Ki-67 gene expression more consistently correlated with 18FFDG than with 64Cu-ATSM. Conclusions Micro regional heterogeneity of hypoxia and glycolysis was documented in spontaneous canine soft tissue sarcomas. 64Cu-ATSM and 18F-FDG uptakes and distributions showed significant moderate correlations at the micro regional level indicating overlapping, yet different information from the tracers.18F-FDG better reflected cell proliferation as measured by Ki-67 gene expression than 64Cu-ATSM.

AB - Objectives Tumour microenvironment heterogeneity is believed to play a key role in cancer progression and therapy resistance. However, little is known about micro regional distribution of hypoxia, glycolysis and proliferation in spontaneous solid tumours. The overall aim was simultaneous investigation of micro regional heterogeneity of 64Cu-ATSM (hypoxia) and 18F-FDG (glycolysis) uptake and correlation to endogenous markers of hypoxia, glycolysis, proliferation and angiogenesis to better therapeutically target aggressive tumour regions and prognosticate outcome. Methods Exploiting the different half-lives of 64Cu-ATSM (13h) and 18F-FDG (2h) enabled simultaneous investigation of micro regional distribution of hypoxia and glycolysis in 145 tumour pieces from four spontaneous canine soft tissue sarcomas. Pairwise measurements of radioactivity and gene expression of endogenous markers of hypoxia (HIF-1a, CAIX), glycolysis (HK2, GLUT1 and GLUT3), proliferation (Ki-67) and angiogenesis (VEGFA and TF) were performed. Dual tracer autoradiography was compared with Ki-67 immunohistochemistry. Results Micro regional heterogeneity in hypoxia and glycolysis within and between tumour sections of each tumour piece was observed. The spatial distribution of 64Cu-ATSM and 18F-FDG was rather similar within each tumour section as reflected in moderate positive significant correlations between the two tracers (? = 0.3920-0.7807; p = 0.0180 -<0.0001) based on pixel-to-pixel comparisons of autoradiographies and gamma counting of tumour pieces. 64Cu-ATSM and 18F-FDG correlated positively with gene expression of GLUT1 and GLUT3, but negatively with HIF-1a and CAIX. Significant positive correlations were seen between Ki-67 gene expression and 64Cu-ATSM (? = 0.5578, p = 0.0004) and 18F-FDG (? = 0.4629- 0.7001, p = 0.0001-0.0151). Ki-67 gene expression more consistently correlated with 18FFDG than with 64Cu-ATSM. Conclusions Micro regional heterogeneity of hypoxia and glycolysis was documented in spontaneous canine soft tissue sarcomas. 64Cu-ATSM and 18F-FDG uptakes and distributions showed significant moderate correlations at the micro regional level indicating overlapping, yet different information from the tracers.18F-FDG better reflected cell proliferation as measured by Ki-67 gene expression than 64Cu-ATSM.

U2 - 10.1371/journal.pone.0141379

DO - 10.1371/journal.pone.0141379

M3 - Journal article

C2 - 26501874

SN - 1932-6203

VL - 10

JO - PLoS Computational Biology

JF - PLoS Computational Biology

IS - 10

M1 - e0141379

ER -