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

Abstract

Colorectal cancer liver metastases (CRCLMs) have two main histopathological growth patterns (HPGs): desmoplastic (DHGP) and replacement (RHGP). The vascularization in DHGP tumours is angiogenic, while the RHGP tumours exert vessel co-option vasculature. The presence of vessel co-option tumours is associated with poor response to anti-angiogenic agents and chemotherapy, as well as a worse prognosis. Metformin has been shown to influence the progression and vasculature of tumours in different cancers. However, its role in CRCLM is poorly understood. Herein, we conducted a retrospective cohort study to examine the role of metformin in CRCLM. A dataset of 108 patients was screened, of which 20 patients used metformin. The metformin user patients did not use metformin as an anticancer agent. We noticed a significantly lower percentage of CRCLM patients with vessel co-opting RHGP tumours in the population that used metformin compared to CRCLM patients who did not use metformin. Similar results were obtained when we compared the ratio of recurrence and extrahepatic metastases incidence. Moreover, the metformin user patients had significantly higher survival outcome compared to nonusers. Collectively, our data suggest that metformin administration is likely associated with better prognosis of CRCLM.

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

“…Therefore, the tumours that utilize vessel co-option vascularization are resistant to anti-angiogenic therapy (7). Vessel co-option is a predominant vascularization in CRCLM (7,9). We previously reported that CRCLM patients with predominantly angiogenic metastasis receiving neoadjuvant antiangiogenic plus chemotherapy have significantly higher 5-year overall survival compared to the patients with co-opting tumours who have received the same treatment (7).…”

“…The fundamental histopathological feature of DHGP lesions is the presence of a desmoplastic rim at the tumour periphery that separates cancer cells from liver parenchyma (7). However, the desmoplastic rim is absent in RHGP lesions, and the cancer cells infiltrate through adjacent liver plates (9,10). Moreover, angiogenesis is the predominant vascularization in DHGP tumours (7).…”

Vessel co-option: a unique vascular-immune niche in liver cancer

“…In addition, some scholars have begun to study the effect of metformin on VC of liver cancer in recent years. A study showed that CRCLM patients treated with metformin have fewer co-option vessels than unused patients (99). At the same time, Li et al have shown that metformin can improve the chemotherapy resistance of non-angiogenic colorectal cancer by increasing microvessel density and restoring vascular function and maturity (100).…”

Role of Metformin in the Management of Colorectal Cancer: A Systematic Review

“…Also, the Rada et al study in 108 liver mCRC patients has shown a decrease in mortality rates and better prognosis in the metformin group than in non-diabetic and other anti-diabetic medication users. They related such metformin benefits to the ability of metformin to decrease co-option vasculature in liver metastasis, a strong indicative of poor prognosis[34]. On the contrary, the observational study by Cossor et al analyzed 2066 post-menopausal diabetic CRC women for a median follow-up period of 4.1 years and showed no significant difference in CRC-specific survival in the metformin group in comparison to non-diabetics and other oral anti-diabetic medication groups[35].…”