Abstract
ObjectivesTumour 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.MethodsExploiting 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-1α, 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.ResultsMicro 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 (ρ = 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-1α and CAIX. Significant positive correlations were seen between Ki-67 gene expression and 64Cu-ATSM (ρ = 0.5578, p = 0.0004) and 18F-FDG (ρ = 0.4629–0.7001, p = 0.0001–0.0151). Ki-67 gene expression more consistently correlated with 18F-FDG than with 64Cu-ATSM.ConclusionsMicro 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.
Highlights
Phenotypic and cellular heterogeneity within malignant tumours has been recognized since the early days of cancer biology [1,2,3]
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
The spatial distribution of 64Cu-ATSM and 18F-FDG was rather similar within each tumour tissue section, which was reflected in the positive correlations found in all AR images between the spatial distribution of 64Cu-ATSM and 18F-FDG based on pixel-to-pixel analysis (Fig 2)
Summary
Phenotypic and cellular heterogeneity within malignant tumours has been recognized since the early days of cancer biology [1,2,3]. Complex mechanisms involving both the cancer cells, with their acquired hallmarks [7, 8], and the tumour microenvironment appear important during carcinogenesis, progression and metastasis [8,9,10] and simultaneously contribute to the cellular and phenotypic heterogeneity of malignant tumours [3, 11]. Key factors in the microenvironment of malignant tumours include hypoxia, glycolysis and proliferation. The complex interplay and the changes occurring in the tumour microenvironment result in a vicious circle driving the cancer cells towards a more aggressive and malignant phenotype showing treatment resistance [17, 19,20,21,22,23,24]. As hypoxia, increased glycolytic activity and proliferation have been associated with a poor prognosis in different human cancers [25,26,27,28,29,30,31], it is of special interest to evaluate cancers and potentially target therapy with respect to these microenvironmental phenotypes and their heterogeneity
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