Searching for the link; mechanisms underlying liver regeneration and recurrence of colorectal liver metastasis post partial hepatectomy

Abstract

Despite excellent treatment of primary colorectal cancer, the majority of deaths occur as a result of metastasis to the liver. Recent population studies have estimated that one quarter of patients with colorectal cancer will incur synchronous or metachronous colorectal liver metastasis. However, only one quarter of these patients will be eligible for potentially curative resection. Tumor recurrence occurs in reportedly 60% of patients undergoing hepatic resection, and the majority of intrahepatic recurrence occurs within the first 6 months of surgery. The livers innate ability to restore its homeostatic size, and volume facilitates major hepatic resection that currently offers the only chance of cure to patients with extensive hepatic metastases. Experimental and clinical evidence supports the notion that following partial hepatectomy, liver regeneration (LR) paradoxically drives tumor progression and increases the risk of recurrence. It is becoming increasingly clear that the processes that drive liver organogenesis, regeneration, and tumor progression are inextricably linked. This presents a major hurdle in the management of colorectal liver metastasis and other hepatic malignancies because therapies that reduce the risk of recurrence without hampering LR are sought. The processes and pathways underlying these phenomena are multiple, complex, and cross‐communicate. In this review, we will summarize the common mechanisms contributing to both LR and tumor recurrence.

Captopril, a Renin-Angiotensin System Inhibitor, Attenuates Features of Tumor Invasion and Down-Regulates C-Myc Expression in a Mouse Model of Colorectal Cancer Liver Metastasis

“…Down-regulation of c-myc is likely to be one mechanism through which captopril and other RASi are capable of attenuating tumor growth and progression. RASi are commonly used to treat hypertension and cardiac failure; however, they also have a wide range of effects which are not limited to the cardiovascular system [ 29 , 48 ]. RASi have established roles in multiple processes influencing cancer progression, including angiogenesis, extracellular matrix remodeling, cellular proliferation, EMT and immunomodulation [ 27 , 29 , 30 , 48 ].…”

“…RASi are commonly used to treat hypertension and cardiac failure; however, they also have a wide range of effects which are not limited to the cardiovascular system [ 29 , 48 ]. RASi have established roles in multiple processes influencing cancer progression, including angiogenesis, extracellular matrix remodeling, cellular proliferation, EMT and immunomodulation [ 27 , 29 , 30 , 48 ]. Recently, it has been demonstrated that RAS genes are also down-stream targets of Wnt signaling, and that blocking Wnt signaling down-regulates the expression of RAS genes, reversing the clinical effects of renal fibrosis [ 24 ].…”

Clinical Outcomes and Prognosis Factors of Nivolumab Plus Chemotherapy or Multitarget Tyrosine Kinase Inhibitor in Multi-Line Therapy for Recurrent Hepatitis B Virus-Related Hepatocellular Carcinoma: A Retrospective Analysis

“…Nivolumab led to shorter OS in patients with previously treated advanced squamous non-small-cell lung cancer with ECOG PS 2 vs. 0-1 (25). Multiple overlapping signaling pathways are involved in liver regeneration and hepatocarcinogenesis, including Wnt/β-catenin and Notch (26). These signaling pathways play an important role in regulating the crosstalk between the different compartments of the tumor microenvironment (27,28), which has been observed to correlate with the response to checkpoint blocking antibodies (29,30).…”

Regeneration linked miRNA modify tumor phenotype and can enforce multi-lineage growth arrest in vivo

“…Furthermore, they may explain the high incidence of cancers that arise in the liver, representing a global health burden, which may result from preserved regenerative competence 24 . Clinical data indicate potentially deleterious effects of liver regeneration, induced by therapeutic interventions such as live-donor liver transplantation and liver resection, on tumor biology and outcomes in the context of primary liver cancer 25 and metastatic tumors 26 . Our findings may provide a mechanistic basis of these clinical observations.…”