Abstract
BackgroundAngiogenesis is not essential for tumours to develop and expand, as cancer can also grow in a non-angiogenic fashion, but why this type of growth occurs is unknown. Surprisingly, our data from mRNA transcription profiling did not show any differences in the classical angiogenic pathways, but differences were observed in mitochondrial metabolic pathways, suggesting a key role for metabolic reprogramming. We then validated these results with mRNA profiling by investigating differential protein expression via immunohistochemistry in angiogenic and non-angiogenic non-small cell lung cancers (NSCLCs).MethodsImmunohistochemical staining for 35 angiogenesis- and hypoxia-related biomarkers were performed on a collection of 194 angiogenic and 73 non-angiogenic NSCLCs arranged on tissue microarrays. Sequencing of P53 was performed with frozen tissue samples of NSCLC.ResultsThe non-angiogenic tumours were distinguished from the angiogenic ones by having higher levels of proteins associated with ephrin pathways, mitochondria, cell biogenesis, and hypoxia-inducible factor 1 (HIF1) regulation by oxygen and transcription of HIF-controlled genes but lower levels of proteins involved in the stroma, cell–cell signaling and adhesion, integrins, and Delta-Notch and epidermal growth factor (EGF)-related signaling. However, proteins classically associated with angiogenesis were present in both types of tumours at very comparable levels. Cytoplasmic expression of P53 was strongly associated with non-angiogenic tumours. A pilot investigation showed that P53 mutations were observed in 32.0% of angiogenic cases but in 71.4% of non-angiogenic tumours.ConclusionsOur observations thus far indicate that both angiogenic and non-angiogenic tumours experience hypoxia/HIF and vascular endothelial growth factor (VEGF) pathway protein expression in a comparable fashion. However, angiogenesis does not ensue in the non-angiogenic tumours. Surprisingly, metabolic reprogramming seems to distinguish these two types of neoplastic growth. On the basis of these results, we raise the hypothesis that in some, but not in all cases, initial tissue remodeling and/or inflammation could be one of the secondary steps necessary to trigger angiogenesis. In the non-angiogenic tumours, in which neovascularisation fails to occur, HIF pathway activation could be the driving force toward metabolic reprogramming.Electronic supplementary materialThe online version of this article (doi:10.1186/s40880-016-0082-6) contains supplementary material, which is available to authorized users.
Highlights
Angiogenesis is not essential for tumours to develop and expand, as cancer can grow in a nonangiogenic fashion, but why this type of growth occurs is unknown
The non-angiogenic tumours are distinguished from the angiogenic tumours by having higher levels of proteins related to ephrin pathways, response to hypoxia, hypoxia-inducible factor 1 (HIF1) regulation by oxygen, and transcription
Because neovascularisation is found in some tumours but not in others, we suggest that activation of the classical angiogenic pathways is necessary, but not sufficient, to induce the sprouting of new vessels in cancer
Summary
Angiogenesis is not essential for tumours to develop and expand, as cancer can grow in a nonangiogenic fashion, but why this type of growth occurs is unknown. In 1927, Otto Warburg described what would be called the “Warburg effect,” in which tumour cells exhibited characteristic changes in metabolism, the use of glycolysis rather than oxidative phosphorylation, despite the presence of adequate amounts of oxygen [1, 2]. Warburg believed that this process was the actual cause of neoplastic transformation [3]. The shift in energy production to aerobic glycolysis, while allowing for more rapid production of adenosine triphosphate (ATP), yields far less energy than oxidative phosphorylation: there are two net molecules of ATP per glucose molecule in glycolysis versus 36 molecules of ATP via oxidative phosphorylation [5]
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
