The Anti-Colon Cancer Effects of Essential Oil of Curcuma phaeocaulis Through Tumour Vessel Normalisation

BackgroundNormalising tumour vessels had become a significant research focus in tumour treatment research in recent years. Curcumae rhizoma (CR) is an essential plant in traditional Chinese medicine as it promotes blood circulation and removes blood stasis. Similarly, CR improves local blood circulation.PurposeWe explored the anti-colon cancer effects of essential oil from CR (OCR) by investigating its role in normalising tumour vessels. We also provided a basis for research and development into new anti-cancer drugs.MethodsWe used colon cancer as a research focus to investigate OCR. We established an in vitro co-culture model of colon cancer cells and human umbilical vein endothelial cells (HUVEC). We also established an in vivo subcutaneous implant colon cancer model in nude mice. These studies allowed us to evaluate the comprehensive effects of OCR in in vivo and in vitro colon cancer and its role in normalising tumour blood vessels.ResultsIn vitro, we found that OCR inhibited Human colon cancer cells (HCT116) and HUVEC cell proliferation and inhibited vascular endothelial growth factor-a (VEGFa) mRNA and protein expression in HUVECs in a co-culture system. Our in vivo studies showed that OCR inhibited colon cancer tumour growth, reduced angiogenesis in tumours and increased vascular endothelial (VE)-cadherin and pericyte coverage in tumour vessels.ConclusionsOCR inhibited colon cancer growth both in in vivo and in vitro models, reduced angiogenesis in tumours, improved tumour vessel structures and normalised tumour vessels.

Phosphorylation of pericyte FAK-Y861 affects tumour cell apoptosis and tumour blood vessel regression

Focal adhesion kinase (FAK) is a non-receptor tyrosine kinase that is overexpressed in many cancer types and in vivo studies have shown that vascular endothelial cell FAK expression and FAK-phosphorylation at tyrosine (Y) 397, and subsequently FAK-Y861, are important in tumour angiogenesis. Pericytes also play a vital role in regulating tumour blood vessel stabilisation, but the specific involvement of pericyte FAK-Y397 and FAK-Y861 phosphorylation in tumour blood vessels is unknown. Using PdgfrβCre + ;FAKWT/WT, PdgfrβCre + ;FAKY397F/Y397F and PdgfrβCre + ;FAKY861F/Y861F mice, our data demonstrate that tumour growth, tumour blood vessel density, blood vessel perfusion and pericyte coverage were affected only in late stage tumours in PdgfrβCre + ;FAKY861F/Y861F but not PdgfrβCre + ;FAKY397F/Y397F mice. Further examination indicates a dual role for pericyte FAK-Y861 phosphorylation in the regulation of tumour vessel regression and also in the control of pericyte derived signals that influence apoptosis in cancer cells. Overall this study identifies the role of pericyte FAK-Y861 in the regulation of tumour vessel regression and tumour growth control and that non-phosphorylatable FAK-Y861F in pericytes reduces tumour growth and blood vessel density.

Phosphorylation of pericyte FAK-Y861 affects tumour cell apoptosis and tumour blood vessel regression

Focal adhesion kinase (FAK) is a non-receptor tyrosine kinase that is overexpressed in many cancer types and in vivo studies have shown that vascular endothelial cell FAK expression and FAK-phosphorylation at tyrosine (Y) 397, and subsequently FAK-Y861, are important in tumour angiogenesis. Pericytes also play a vital role in regulating tumour blood vessel stabilisation, but the involvement of pericyte FAK-Y397 and FAK-Y861 phosphorylation in tumour blood vessels is unknown. Using PdgfrβCre+;FAKWT/WT, PdgfrβCre+;FAKY397F/Y397F and PdgfrβCre+;FAKY861F/Y861F mice, our data demonstrate that tumour growth, tumour blood vessel density, blood vessel perfusion and pericyte coverage were affected only in late stage tumours in PdgfrβCre+;FAKY861F/Y861F but not PdgfrβCre+;FAKY397F/Y397F mice. Further examination indicates a dual role for pericyte FAK-Y861 phosphorylation in the regulation of tumour vessel regression and also in the control of a pericyte derived ‘pericrine’ signals that influence apoptosis in cancer cells. Overall this study identifies the role of pericyte FAK-Y861 in the regulation of tumour vessel regression and tumour growth control and that non-phosphorylatable FAK-Y861F in pericytes reduces tumour growth and blood vessel density.

Tumour vessel remodelling: new opportunities in cancer treatment

Tumour growth critically depends on a supportive microenvironment, including the tumour vasculature. Tumour blood vessels are structurally abnormal and functionally anergic which limits drug access and immune responses in solid cancers. Thus, tumour vasculature has been considered an attractive therapeutic target for decades. However, with time, anti-angiogenic therapy has evolved from destruction to structural and functional rehabilitation as understanding of tumour vascular biology became more refined. Vessel remodelling or normalisation strategies which alleviate hypoxia are now coming of age having been shown to have profound effects on the tumour microenvironment. This includes improved tumour perfusion, release from immune suppression and lower metastasis rates. Nevertheless, clinical translation has been slow due to challenges such as the transient nature of current normalisation strategies, limited in vivo monitoring and the heterogeneity of primary and/or metastatic tumour environments, calling for more tailored approaches to vascular remodelling. Despite these setbacks, harnessing vascular plasticity provides unique opportunities for anti-cancer combination therapies in particular anti-angiogenic immunotherapy which are yet to reach their full potential.

Tumour-vessel-on-a-chip models for drug delivery

In this review, we present the use of tumour-vessels-on-a-chip to investigate and screen nanoparticles for cancer targeted drug delivery.