Abstract
Overexpresssion of HER-2 in the MDA-MB-435/LCC6 (LCC6HER-2) tumour model is associated with significantly increased hypoxia and reduced necrosis compared to isogenic control tumours (LCC6Vector); this difference was not related to tumour size or changes in vascular architecture. To further evaluate factors responsible for HER-2-associated changes in the tumour microenvironment, small animal magnetic resonance imaging (MRI) and positron emission tomography (PET) were used to measure tumour tissue perfusion and metabolism, respectively. The imaging data was further corroborated by analysis of molecular markers pertaining to energy homeostasis, and measurements of hypoxia and glucose consumption. The results showed a strong trend towards higher perfusion rates (~58% greater, p = 0.14), and significantly higher glucose uptake in LCC6HER-2 (~2-fold greater; p = 0.025), relative to control tumours. The expression of proteins related to energy stress (P-AMPK, P-ACC) and glucose transporters (GLUT1) were lower in LCC6HER-2 tumours (~2- and ~4-fold, respectively). The in vitro analysis showed that LCC6HER-2 cells become more hypoxic in 1% oxygen and utilise significantly more glucose in normoxia compared to LCC6Vectorcells (p < 0.005). Amalgamation of all the data points suggests a novel metabolic adaptation driven by HER-2 overexpression where higher oxygen and glucose metabolic rates produce rich energy supply but also a more hypoxic tumour mass.
Highlights
The identity of the LCC6 parental cell line, MDA-MB-435, was determined to be of melanoma origin rather than breast following a period of controversy and confusion[13,14]
We showed that HER-2 overexpression in the LCC6 (LCC6HER-2) tumour model increases tissue hypoxia and overall tumour viability without changing vascular parameters; i.e., vessel density, numbers of functional Hoechst 33342 perfused vessels and the median distance of tissue to blood vessels (MDV)[10]
The classical model of tumour hypoxia is based on an oxygen gradient that emanates outwards from the blood vessel to tissue[24]; an increase in hypoxia without changes in the vascular parameters would imply that factors other than oxygen delivery are at play
Summary
Overexpresssion of HER-2 in the MDA-MB-435/LCC6 (LCC6HER-2) tumour model is associated with significantly increased hypoxia and reduced necrosis compared to isogenic control tumours (LCC6Vector); this difference was not related to tumour size or changes in vascular architecture. The results showed a strong trend towards higher perfusion rates (~58% greater, p = 0.14), and significantly higher glucose uptake in LCC6HER-2 (~2-fold greater; p = 0.025), relative to control tumours. Amalgamation of all the data points suggests a novel metabolic adaptation driven by HER-2 overexpression where higher oxygen and glucose metabolic rates produce rich energy supply and a more hypoxic tumour mass. Our group showed that overexpressing HER-2 in the aggressive MDA-MB-435/LCC6 tumour model[9] (LCC6HER-2) increased the tumour’s viability and levels of hypoxia compared to isogenic control tumours transfected with vector alone (LCC6Vector)[10]. The data indicate that HER-2 expression is associated with improved cell bioenergetics which may provide a survival advantage for HER-2 overexpressing tumours
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