High levels of serum cholesterol positively correlate with the risk of the development of vessel co-opting tumours in colorectal cancer liver metastases

Abstract

Colorectal cancer liver metastatic (CRCLM) tumours present as two main histopathological growth patterns (HGPs) including desmoplastic HGP (DHGP) and replacement HGP (RHGP). The DHGP tumours obtain their blood supply by sprouting angiogenesis, whereas the RHGP tumours utilize an alternative vascularisation known as vessel co-option. In vessel co-option, the cancer cells hijack the mature sinusoidal vessels to obtain blood supply. Vessel co-option has been reported as an acquired mechanism of resistance to anti-angiogenic treatment in CRCLM. Here, we show the connection between the concentration of serum cholesterol and the development of vessel co-option in CRCLM. Our clinical data suggested that the elevation of serum cholesterol levels correlates with the risk of developing vessel co-opting tumours. Moreover, inhibition of the key modulators of cholesterol metabolism including HMGCR or PCSK9 attenuated the development of CRCLM tumours, as well as vessel co-option in vivo. Altogether, our data uncovered the importance of cholesterol in the development of vessel co-option tumours and demonstrated PCSK9 and HMGCR inhibitors as promising strategies to mitigate the development of vessel co-option tumours in CRCLM.

Vitamin D supplementation improves the prognosis of patients with colorectal cancer liver metastases

“…The RHGP tumours are characterized by vessel co-option vascularization and the patients with RHGP tumours have the worse prognosis compared to their counterparts as demonstrated in this manuscript and previous publications 27,39 . Since RHGP tumours do not utilize angiogenesis, the tumours are resistant to anti-angiogenic agents, such as Bevacizumab 15,27 .…”

A Retrospective Study on the Role of Metformin in Colorectal Cancer Liver Metastases

“…It has been reported that metformin reduces the serum levels of low-density lipoprotein cholesterol (LDL-C) by suppressing the transcription of proprotein convertase subtilisin/kexin type 9 (PCSK9) [ 61 ]. Importantly, we previously showed upregulation of PCSK9 in the liver parenchyma of vessel co-opting CRCLM specimens [ 62 ]. Moreover, our preclinical data suggested that using hypocholesterolemic drugs, including anti-PCSK9 (Evolocumab), significantly attenuates the development of vessel co-opting CRCLM tumours [ 62 ].…”

“…Importantly, we previously showed upregulation of PCSK9 in the liver parenchyma of vessel co-opting CRCLM specimens [ 62 ]. Moreover, our preclinical data suggested that using hypocholesterolemic drugs, including anti-PCSK9 (Evolocumab), significantly attenuates the development of vessel co-opting CRCLM tumours [ 62 ]. Therefore, we postulate that metformin may also affect the generation of vessel co-option tumours in CRCLM via regulation of PCSK9 and LDL-C levels.…”

Inhibition of proprotein convertase subtilisin-like kexin type 9 (PCSK9) potentiates anti-angiogenic therapy in colorectal cancer liver metastases

“…We performed immunohistochemical staining for formalin-fixed paraffin-embedded (FFPE) specimens as described in previous publications (24,25). We performed staining using RUNX1 antibody 1:200 (LS Bio, #LS-C353932).…”

“…We previously reported that treating tumours with evolocumab attenuates the generation of vessel co-opting tumours in CRCLM (25). However, the role of evolocumab in increasing the efficacy of anti-angiogenic (anti-VEGF) therapy in CRCLM is unclear.…”